Category: Hem/Onc Updates

This is an example

RR

Written by: Dr. Eric Lander
Sponsored by Boehringer Ingelheim

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare and phenotypically aggressive malignancies arising from neuroendocrine cells. While EP-NECs are currently managed with conventional chemotherapy in most cases, numerous therapies are in development which may show promise to improve disease management and prognosis for patients.

EP-NECs originate from neuroendocrine cells located in many different organs, most commonly arising from the GI tract or pancreas, followed by genitourinary tract and gynecologic organs [1]. NECs are often confused with neuroendocrine tumors (NETs). Though both NETs and NECs arise from epithelial neuroendocrine cells expressing pan-cytokeratin, synaptophysin, and Chromogranin A, by definition NETs are well-differentiated while NECs are poorly differentiated. Though NETs can be defined as grades 1-3, they are more commonly grade 1-2 (Ki-67 <20%); NECs must be grade 3 (Ki-67 ≥20% and/or mitotic count >20 per mm2), and the Ki-67 usually exceeds 50%. The remainder of this article will focus on EP-NECs and will not include discussion about grade 3 NETs. Please reference the NCCN Guidelines or the Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society (NANETS) to learn about management strategies for G3 NETs [2].

EP-NECs most commonly result from TP53 and RB1 inactivation, similar to small cell lung neuroendocrine carcinoma (SCLC), though EP-NECs often contribute their own unique genetic mutational background (e.g. BRAF, KRAS, PIK3CA, APC, etc.) based on their site of origin, unlike most SCLC cases. If the primary site of EP-NEC origin is unknown, as occurs in up to one third of cases, encouraging pathology to perform transcription factor IHC can facilitate a site of origin assignment. Certain transcription factors (in parentheses) are unique to each organ: midgut (CDX2); pancreas (PAX6, PAX8, islet 1, or PR); rectum (SATB2); lung (OTP, TTF-1). Delineating site of origin is of particular importance as EP-NEC may be treated according to its primary site of origin at time of relapse following platinum-based chemotherapy.

Since EP-NECs are aggressive, high-grade carcinomas, patients most commonly have metastatic disease at the time of presentation. Many patients initially present for the first time to the hospital because some symptom of their disease, such as severe pain or fracture in the case of bone metastases, necessitated their presentation to the emergency room. Initial workup following tissue diagnosis should consist of imaging of the chest/abdomen/pelvis with CT or FDG-PET/CT imaging. Notably, high grade NECs have lower somatostatin receptor (SSTR) expression than NETs; therefore, FDG is preferred over SSTR-PET radiotracers [3, 4]. For EP-NECs, the incidence of brain metastases is less than 2%; thus, brain MRI should only be considered at time of diagnosis in cases of high disease burden or in symptomatic patients [5].

For molecular workup, since many EP-NECs can harbor mutations in BRAF (particularly in colorectal EP-NECs) and tumor agnostic indications for other therapies exist, NGS testing may be considered. Mismatch repair (MMR) testing or MSI testing is also recommended since 10% of NECs are deficient MMR, opening the door to immunotherapies as therapeutic options. Delta-like ligand 3 (DLL3) is an emerging target in EP-NEC; reserving tissue for DLL3 IHC is recommended in cases where patients may enroll in a clinical trial investigating a drug targeting DLL3 – which will be discussed later.

For the management of localized EP-NEC, discussion at tumor board is recommended to provide a multidisciplinary treatment approach. Data surrounding the long-term curative potential of surgery is mixed based on the tumor site of origin when surgery is often invasive, and patients remain at high risk of metastatic disease recurrence. For this reason, neoadjuvant or adjuvant platinum-based chemotherapy may be paired with surgery. Many experts will favor neoadjuvant platinum/etoposide chemotherapy to test the biology of the disease and decrease theoretical risk of micro-metastasis prior to surgery. However, many patients will present to medical oncology following tumor resection, in which case adjuvant chemotherapy may be discussed with eligible patients. Otherwise, definitive chemoradiation for organ preservation may be considered with platinum plus etoposide as the recommended radiosensitizing agents. The accruing French NEONEC trial will prospectively test neoadjuvant chemotherapy followed by surgery or chemoradiation in patients to hopefully offer clarity regarding the optimal multidisciplinary approach [6].

In the case of metastatic EP-NECs, the treatment paradigm initially parallels that of SCLC. Enrollment in clinical trial when available or platinum plus etoposide for four to six cycles remains the current first-line standard-of-care. Unlike SCLC, atezolizumab is not written into the NCCN guidelines for EP-NEC. EP-NEC patients were not included in the IMpower133 trial, and a subsequent retrospective study of a small EP-NEC patient cohort did not demonstrate a PFS or OS benefit of adding atezolizumab to platinum-based chemotherapy [7]. Larger patient numbers in a prospective trial are likely required to detect a benefit of atezolizumab—an ongoing phase II/III SWOG trial is investigating platinum/etoposide with or without atezolizumab to address this evidence gap [8].

Most patients will achieve significant initial tumor shrinkage or disease control in response to carboplatin or cisplatin plus etoposide, especially if Ki-67 ≥ 55%, but the tumor response is not durable in most cases, and tumors are less responsive to chemotherapy upon disease progression. There is currently no standard second- or third-line treatment option for EP-NEC. When assessing patients’ treatment goals and performance status, best supportive care with hospice is a very reasonable approach in light of EP-NEC’s generally poor prognosis upon time of disease relapse.

When second-line and beyond therapy lines are being considered, enrollment in clinical trial is the preferred option for eligible patients. If patients experienced a durable response lasting at least 6 months following first-line platinum/etoposide, rechallenge may be considered. Among patients with gastrointestinal and pancreatic EP-NECs, second-line treatment with FOLFIRI has the most prospective data and lends a 6-month overall survival rate of 60% [9], while gynecologic EP-NEC has data for topotecan, taxanes, single agent irinotecan, or the combination of topotecan, paclitaxel, and bevacizumab that provided an 8-month median PFS in a small retrospective cohort [10]. For patients with dMMR/MSI-H or TMB-High disease, ipilimumab/nivolumab or pembrolizumab may be considered where dual checkpoint inhibition potentially yields a higher response rate [11]. For patients with BRAF V600E mutations, a STAR trial through SCRI is available to open at most US Oncology practices employing BRAF/MEK inhibition with dabrafenib/trametinib and includes patients with EP-NEC [12].

The most promising emerging therapies for EP-NEC remain those in clinical trials targeting DLL3—this assertion is based on extrapolation of promising data from the DeLLphi trials using tarlatamab in SCLC, and initial results investigating obrixtamig in SCLC and EP-NEC. Both tarlatamab and obrixtamig are DLL3/CD3 bispecific T-cell engagers. While DLL3 is expressed in approximately 90% of SCLC, rates of DLL3 expression in EP-NEC are lower [13]. Despite this, most patients with negative DLL3 expression in the DeLLphi-301 trial employing tarlatamab in refractory SCLC still experienced disease control with tarlatamab monotherapy [14]. Emerging therapeutics targeting DLL3 are mostly either DLL3/CD3 bispecific T-cell engagers or DLL3-targeting antibody-drug conjugates.

There are several clinical trials investigating DLL3/CD3 bispecific T-cell engagers and DLL3 antibody-drug conjugates in EP-NEC patients. At the time of writing, three different phase I studies are open and actively recruiting through US Oncology Network practices that include patients with EP-NEC, all of which require tissue for DLL3 IHC testing [15, 16, 17]. Among investigational DLL3/CD3 bispecific agents, Boehringer Ingelheim’s obrixtamig has shown promising results.  Data presented in 2025 from the phase I dose-escalation trial of obrixtamig showed that heavily-pretreated EP-NEC patients with high DLL3 expression had an overall response rate of 40% and duration of response of 7.9 months [18]. While not open in the US Oncology Network, the phase II DAREON-5 trial with obrixtamig is testing two different doses and includes patients with relapsed EP-NEC [19]. The results of ongoing obrixtamig trials will be important to follow and could potentially alter our future therapeutic approach to EP-NEC.

Standard-of-care options in EP-NEC do not yield survival much past one year in most patients. However, for the first time in decades, numerous emerging therapeutic options afford hope to significantly improve the treatment tolerability and prognosis for patients with this aggressive disease.

References:

  1. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018;124(4):807-815. doi:10.1002/cncr.31124.
  2. Eads JR, Halfdanarson TR, Asmis T, et al. Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocr Relat Cancer. 2023;30(8):e220206. Published 2023 Jul 11. doi:10.1530/ERC-22-0206.
  3. Tomimaru Y, Eguchi H, Tatsumi M, et al. Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors. Surgery. 2015;157(2):269-276. doi:10.1016/j.surg.2014.09.011.
  4. Majala S, Seppänen H, Kemppainen J, et al. Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT. EJNMMI Res. 2019;9(1):116. Published 2019 Dec 23. doi:10.1186/s13550-019-0585-7.
  5. Alese OB, Jiang R, Shaib W, et al. High-Grade Gastrointestinal Neuroendocrine Carcinoma Management and Outcomes: A National Cancer Database Study. Oncologist. 2019;24(7):911-920. doi:10.1634/theoncologist.2018-0382.
  6. Efficacy of neoadjuvant chemotherapy in terms of DFS in patients with locally advanced, poorly differentiated digestive neuroendocrine carcinomas (NEONEC). ClinicalTrials.gov identifier NCT04268121. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT04268121
  7. Ho IW, Chiang NJ, Lai JI, et al. Efficacy of atezolizumab combined with platinum and etoposide in the treatment of extrapulmonary neuroendocrine carcinoma. Oncologist. 2025;30(3):oyae372. doi:10.1093/oncolo/oyae372.
  8. Evaluating the addition of the immunotherapy drug atezolizumab to standard chemotherapy treatment for advanced or metastatic neuroendocrine carcinomas that originate outside the lung (SWOG S2012). ClinicalTrials.gov identifier NCT05058651. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05058651
  9. Walter T, Lievre A, Coriat R, et al. Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023;24(3):297-306. doi:10.1016/S1470-2045(23)00001-3.
  10. Frumovitz M, Munsell MF, Burzawa JK, et al. Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2017;144(1):46-50. doi:10.1016/j.ygyno.2016.10.040.
  11. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort. Cancer. 2021;127(17):3194-3201. doi:10.1002/cncr.33591.
  12. ClinicalTrials.gov. Clinical study to further evaluate the efficacy of dabrafenib plus trametinib in patients with rare BRAF V600E mutation-positive unresectable or metastatic solid tumors. Identifier NCT05868629. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05868629
  13. Serrano AG, Rocha P, Freitas Lima C, et al. Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ Precis Oncol. 2024;8(1):268. Published 2024 Nov 19. doi:10.1038/s41698-024-00739-y.
  14. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980.
  15. ClinicalTrials.gov. A study of Peluntamig (PT217) in patients with neuroendocrine carcinomas expressing DLL3 (the SKYBRIDGE study). Identifier NCT05652686. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05652686
  16. ClinicalTrials.gov. A study of IDE849 in patients with DLL3 expressing tumors including small cell lung cancer. Identifier NCT07174583. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT07174583
  17. ClinicalTrials.gov. A Phase Ib/II, open-label, multi-center study of ZL-1310 in participants with selected solid tumors. Identifier NCT06885281. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT06885281
  18. Capdevila J, Gambardella V, Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial. J Clin Oncol. 2025;43(16_suppl):3004. doi: 10.1200/JCO.2025.43.16_suppl.3004.
  19. ClinicalTrials.gov. DAREON-5: A study to test whether different doses of BI 764532 help people with small cell lung cancer or other neuroendocrine cancers. Identifier NCT05882058. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05882058

Extrapulmonary Neuroendocrine Carcinoma: Clinical Overview and Advances in DLL3 Targeted Therapy

RR

Written by: Dr. Eric Lander
Sponsored by Boehringer Ingelheim

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare and phenotypically aggressive malignancies arising from neuroendocrine cells. While EP-NECs are currently managed with conventional chemotherapy in most cases, numerous therapies are in development which may show promise to improve disease management and prognosis for patients.

EP-NECs originate from neuroendocrine cells located in many different organs, most commonly arising from the GI tract or pancreas, followed by genitourinary tract and gynecologic organs [1]. NECs are often confused with neuroendocrine tumors (NETs). Though both NETs and NECs arise from epithelial neuroendocrine cells expressing pan-cytokeratin, synaptophysin, and Chromogranin A, by definition NETs are well-differentiated while NECs are poorly differentiated. Though NETs can be defined as grades 1-3, they are more commonly grade 1-2 (Ki-67 <20%); NECs must be grade 3 (Ki-67 ≥20% and/or mitotic count >20 per mm2), and the Ki-67 usually exceeds 50%. The remainder of this article will focus on EP-NECs and will not include discussion about grade 3 NETs. Please reference the NCCN Guidelines or the Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society (NANETS) to learn about management strategies for G3 NETs [2].

EP-NECs most commonly result from TP53 and RB1 inactivation, similar to small cell lung neuroendocrine carcinoma (SCLC), though EP-NECs often contribute their own unique genetic mutational background (e.g. BRAF, KRAS, PIK3CA, APC, etc.) based on their site of origin, unlike most SCLC cases. If the primary site of EP-NEC origin is unknown, as occurs in up to one third of cases, encouraging pathology to perform transcription factor IHC can facilitate a site of origin assignment. Certain transcription factors (in parentheses) are unique to each organ: midgut (CDX2); pancreas (PAX6, PAX8, islet 1, or PR); rectum (SATB2); lung (OTP, TTF-1). Delineating site of origin is of particular importance as EP-NEC may be treated according to its primary site of origin at time of relapse following platinum-based chemotherapy.

Since EP-NECs are aggressive, high-grade carcinomas, patients most commonly have metastatic disease at the time of presentation. Many patients initially present for the first time to the hospital because some symptom of their disease, such as severe pain or fracture in the case of bone metastases, necessitated their presentation to the emergency room. Initial workup following tissue diagnosis should consist of imaging of the chest/abdomen/pelvis with CT or FDG-PET/CT imaging. Notably, high grade NECs have lower somatostatin receptor (SSTR) expression than NETs; therefore, FDG is preferred over SSTR-PET radiotracers [3, 4]. For EP-NECs, the incidence of brain metastases is less than 2%; thus, brain MRI should only be considered at time of diagnosis in cases of high disease burden or in symptomatic patients [5].

For molecular workup, since many EP-NECs can harbor mutations in BRAF (particularly in colorectal EP-NECs) and tumor agnostic indications for other therapies exist, NGS testing may be considered. Mismatch repair (MMR) testing or MSI testing is also recommended since 10% of NECs are deficient MMR, opening the door to immunotherapies as therapeutic options. Delta-like ligand 3 (DLL3) is an emerging target in EP-NEC; reserving tissue for DLL3 IHC is recommended in cases where patients may enroll in a clinical trial investigating a drug targeting DLL3 – which will be discussed later.

For the management of localized EP-NEC, discussion at tumor board is recommended to provide a multidisciplinary treatment approach. Data surrounding the long-term curative potential of surgery is mixed based on the tumor site of origin when surgery is often invasive, and patients remain at high risk of metastatic disease recurrence. For this reason, neoadjuvant or adjuvant platinum-based chemotherapy may be paired with surgery. Many experts will favor neoadjuvant platinum/etoposide chemotherapy to test the biology of the disease and decrease theoretical risk of micro-metastasis prior to surgery. However, many patients will present to medical oncology following tumor resection, in which case adjuvant chemotherapy may be discussed with eligible patients. Otherwise, definitive chemoradiation for organ preservation may be considered with platinum plus etoposide as the recommended radiosensitizing agents. The accruing French NEONEC trial will prospectively test neoadjuvant chemotherapy followed by surgery or chemoradiation in patients to hopefully offer clarity regarding the optimal multidisciplinary approach [6].

In the case of metastatic EP-NECs, the treatment paradigm initially parallels that of SCLC. Enrollment in clinical trial when available or platinum plus etoposide for four to six cycles remains the current first-line standard-of-care. Unlike SCLC, atezolizumab is not written into the NCCN guidelines for EP-NEC. EP-NEC patients were not included in the IMpower133 trial, and a subsequent retrospective study of a small EP-NEC patient cohort did not demonstrate a PFS or OS benefit of adding atezolizumab to platinum-based chemotherapy [7]. Larger patient numbers in a prospective trial are likely required to detect a benefit of atezolizumab—an ongoing phase II/III SWOG trial is investigating platinum/etoposide with or without atezolizumab to address this evidence gap [8].

Most patients will achieve significant initial tumor shrinkage or disease control in response to carboplatin or cisplatin plus etoposide, especially if Ki-67 ≥ 55%, but the tumor response is not durable in most cases, and tumors are less responsive to chemotherapy upon disease progression. There is currently no standard second- or third-line treatment option for EP-NEC. When assessing patients’ treatment goals and performance status, best supportive care with hospice is a very reasonable approach in light of EP-NEC’s generally poor prognosis upon time of disease relapse.

When second-line and beyond therapy lines are being considered, enrollment in clinical trial is the preferred option for eligible patients. If patients experienced a durable response lasting at least 6 months following first-line platinum/etoposide, rechallenge may be considered. Among patients with gastrointestinal and pancreatic EP-NECs, second-line treatment with FOLFIRI has the most prospective data and lends a 6-month overall survival rate of 60% [9], while gynecologic EP-NEC has data for topotecan, taxanes, single agent irinotecan, or the combination of topotecan, paclitaxel, and bevacizumab that provided an 8-month median PFS in a small retrospective cohort [10]. For patients with dMMR/MSI-H or TMB-High disease, ipilimumab/nivolumab or pembrolizumab may be considered where dual checkpoint inhibition potentially yields a higher response rate [11]. For patients with BRAF V600E mutations, a STAR trial through SCRI is available to open at most US Oncology practices employing BRAF/MEK inhibition with dabrafenib/trametinib and includes patients with EP-NEC [12].

The most promising emerging therapies for EP-NEC remain those in clinical trials targeting DLL3—this assertion is based on extrapolation of promising data from the DeLLphi trials using tarlatamab in SCLC, and initial results investigating obrixtamig in SCLC and EP-NEC. Both tarlatamab and obrixtamig are DLL3/CD3 bispecific T-cell engagers. While DLL3 is expressed in approximately 90% of SCLC, rates of DLL3 expression in EP-NEC are lower [13]. Despite this, most patients with negative DLL3 expression in the DeLLphi-301 trial employing tarlatamab in refractory SCLC still experienced disease control with tarlatamab monotherapy [14]. Emerging therapeutics targeting DLL3 are mostly either DLL3/CD3 bispecific T-cell engagers or DLL3-targeting antibody-drug conjugates.

There are several clinical trials investigating DLL3/CD3 bispecific T-cell engagers and DLL3 antibody-drug conjugates in EP-NEC patients. At the time of writing, three different phase I studies are open and actively recruiting through US Oncology Network practices that include patients with EP-NEC, all of which require tissue for DLL3 IHC testing [15, 16, 17]. Among investigational DLL3/CD3 bispecific agents, Boehringer Ingelheim’s obrixtamig has shown promising results.  Data presented in 2025 from the phase I dose-escalation trial of obrixtamig showed that heavily-pretreated EP-NEC patients with high DLL3 expression had an overall response rate of 40% and duration of response of 7.9 months [18]. While not open in the US Oncology Network, the phase II DAREON-5 trial with obrixtamig is testing two different doses and includes patients with relapsed EP-NEC [19]. The results of ongoing obrixtamig trials will be important to follow and could potentially alter our future therapeutic approach to EP-NEC.

Standard-of-care options in EP-NEC do not yield survival much past one year in most patients. However, for the first time in decades, numerous emerging therapeutic options afford hope to significantly improve the treatment tolerability and prognosis for patients with this aggressive disease.

References:

  1. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018;124(4):807-815. doi:10.1002/cncr.31124.
  2. Eads JR, Halfdanarson TR, Asmis T, et al. Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocr Relat Cancer. 2023;30(8):e220206. Published 2023 Jul 11. doi:10.1530/ERC-22-0206.
  3. Tomimaru Y, Eguchi H, Tatsumi M, et al. Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors. Surgery. 2015;157(2):269-276. doi:10.1016/j.surg.2014.09.011.
  4. Majala S, Seppänen H, Kemppainen J, et al. Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT. EJNMMI Res. 2019;9(1):116. Published 2019 Dec 23. doi:10.1186/s13550-019-0585-7.
  5. Alese OB, Jiang R, Shaib W, et al. High-Grade Gastrointestinal Neuroendocrine Carcinoma Management and Outcomes: A National Cancer Database Study. Oncologist. 2019;24(7):911-920. doi:10.1634/theoncologist.2018-0382.
  6. Efficacy of neoadjuvant chemotherapy in terms of DFS in patients with locally advanced, poorly differentiated digestive neuroendocrine carcinomas (NEONEC). ClinicalTrials.gov identifier NCT04268121. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT04268121
  7. Ho IW, Chiang NJ, Lai JI, et al. Efficacy of atezolizumab combined with platinum and etoposide in the treatment of extrapulmonary neuroendocrine carcinoma. Oncologist. 2025;30(3):oyae372. doi:10.1093/oncolo/oyae372.
  8. Evaluating the addition of the immunotherapy drug atezolizumab to standard chemotherapy treatment for advanced or metastatic neuroendocrine carcinomas that originate outside the lung (SWOG S2012). ClinicalTrials.gov identifier NCT05058651. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05058651
  9. Walter T, Lievre A, Coriat R, et al. Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023;24(3):297-306. doi:10.1016/S1470-2045(23)00001-3.
  10. Frumovitz M, Munsell MF, Burzawa JK, et al. Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2017;144(1):46-50. doi:10.1016/j.ygyno.2016.10.040.
  11. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort. Cancer. 2021;127(17):3194-3201. doi:10.1002/cncr.33591.
  12. ClinicalTrials.gov. Clinical study to further evaluate the efficacy of dabrafenib plus trametinib in patients with rare BRAF V600E mutation-positive unresectable or metastatic solid tumors. Identifier NCT05868629. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05868629
  13. Serrano AG, Rocha P, Freitas Lima C, et al. Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ Precis Oncol. 2024;8(1):268. Published 2024 Nov 19. doi:10.1038/s41698-024-00739-y.
  14. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980.
  15. ClinicalTrials.gov. A study of Peluntamig (PT217) in patients with neuroendocrine carcinomas expressing DLL3 (the SKYBRIDGE study). Identifier NCT05652686. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05652686
  16. ClinicalTrials.gov. A study of IDE849 in patients with DLL3 expressing tumors including small cell lung cancer. Identifier NCT07174583. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT07174583
  17. ClinicalTrials.gov. A Phase Ib/II, open-label, multi-center study of ZL-1310 in participants with selected solid tumors. Identifier NCT06885281. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT06885281
  18. Capdevila J, Gambardella V, Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial. J Clin Oncol. 2025;43(16_suppl):3004. doi: 10.1200/JCO.2025.43.16_suppl.3004.
  19. ClinicalTrials.gov. DAREON-5: A study to test whether different doses of BI 764532 help people with small cell lung cancer or other neuroendocrine cancers. Identifier NCT05882058. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05882058

Apixaban vs Rivaroxaban in Acute VTE: Practice-Changing Insights for Oncology Clinicians

RR

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.

Clinically, VTE is classified as provoked, occurring after transient risk factors such as surgery, trauma, or immobility, or unprovoked, when no clear trigger is identified. Standard management involves 3 months of anticoagulation for provoked events and extended therapy for unprovoked events because of their higher recurrence risk (6–10% per year after discontinuation). However, many patients present with provoked VTE in the context of enduring risk factors such as obesity, chronic inflammatory disease, atherosclerotic cardiovascular disease or chronic pulmonary conditions, factors that may sustain a prothrombotic milieu even after the transient trigger has resolved. Current guidelines offer limited direction for this increasingly common patient subset.

Venous thromboembolism (VTE) is a frequent and clinically significant complication in patients with cancer, contributing substantially to morbidity, disruptions in systemic cancer therapy, and mortality. Direct oral anticoagulants (DOACs) have reshaped management strategies, offering efficacy comparable to vitamin K antagonists with improved convenience and safety.

Among DOACs, Apixaban (ELIQUIS®) and Rivaroxaban (XARELTO®) are widely used. However, until recently, the absence of direct comparative randomized data has limited evidence-based selection between agents, particularly in patients with elevated bleeding risk, such as those with malignancy.

Study Design and Methods

The COBRRA (Comparison of Bleeding Risk between Rivaroxaban and Apixaban) trial was an international, prospective, randomized, open-label study and represents the first randomized, head-to-head comparison of Apixaban and Rivaroxaban in patients with acute symptomatic Pulmonary Embolism or proximal Deep-Vein Thrombosis.

A total of 2,760 patients with acute symptomatic Pulmonary Embolism or proximal Deep-Vein Thrombosis were randomized 1:1 to:

  • Apixaban: 10 mg twice daily for 7 days, followed by 5 mg twice daily
  • Rivaroxaban: 15 mg twice daily for 21 days, followed by 20 mg once daily

The Primary endpoint was clinically relevant bleeding (major or clinically relevant nonmajor bleeding) over 3 months. Secondary outcomes included all-cause mortality and recurrent VTE.

Notably, patients with cancer-associated thrombosis were excluded, reflecting historical standards at the time of trial design.

Key Results: Significant Reduction in Bleeding with Apixaban

At 3 months, Apixaban demonstrated a significant reduction in clinically relevant bleeding:

  • 3.3% (Apixaban) vs 7.1% (Rivaroxaban)
  • Relative Risk (RR): 0.46 (95% CI, 0.33–0.65; P<0.001)

This represents a 54% reduction in bleeding risk with Apixaban.

  • Clinically relevant nonmajor bleeding:
    • 2.9% (Apixaban) vs 4.9% (Rivaroxaban)
  • Major bleeding was also lower with Apixaban (notably rare overall)

Common bleeding events included vaginal and gastrointestinal bleeding, with consistently lower rates observed in the Apixaban arm.

Comparable Efficacy

  • Recurrent VTE rates were similar between groups (~1%)
  • The improved safety profile of Apixaban did not compromise antithrombotic efficacy

Safety

  • No deaths due to bleeding were reported
  • Non-bleeding serious adverse events were comparable between groups

Relevance to Oncology Practice

Although cancer patients were not included, the findings have important indirect implications for oncology:

  1. Bleeding Risk Is Paramount in Cancer

Patients with malignancy often have:

  • Tumor-related mucosal bleeding (e.g., GI, GU cancers)
  • Treatment-related thrombocytopenia
  • Drug–drug interactions with systemic therapies

In this context, the lower bleeding risk observed with Apixaban is highly clinically meaningful, particularly for patients at elevated hemorrhagic risk.

  1. Alignment with Emerging Oncology Data

Subsequent cancer-specific trials (e.g., CARAVAGGIO) have already demonstrated that Apixaban is effective and relatively safe in cancer-associated thrombosis, with a favorable bleeding profile compared with other DOACs in certain settings.

The COBRRA findings reinforce a growing body of evidence suggesting that Apixaban may be the preferred DOAC when bleeding risk is a major concern.

  1. Practical Treatment Considerations
  • Dosing strategy matters: The extended 21-day high-dose phase with Rivaroxaban may contribute to early bleeding risk
  • Pharmacokinetics: Higher peak drug levels with once-daily Rivaroxaban may increase mucosal bleeding, relevant in GI or GU malignancies
  • Adherence: Despite slightly lower adherence with Apixaban in the trial, efficacy remained preserved

Limitations and Applicability to Oncology

  • Exclusion of cancer-associated thrombosis limits direct generalizability
  • Short follow-up (3 months) does not address extended anticoagulation
  • Underrepresentation of diverse populations
  • Not powered for efficacy differences

Despite these limitations, the biologic and pharmacologic insights are highly translatable to oncology populations

Clinical Takeaways

  • Apixaban significantly reduces clinically relevant bleeding compared with Rivaroxaban in acute VTE
  • Efficacy remains equivalent, supporting its use as a first-line agent
  • For oncology patients, particularly those with high bleeding risk, Apixaban may represent a more favorable therapeutic option
  • These findings may help inform DOAC selection in cancer-associated thrombosis, alongside existing oncology-specific trial data and guidelines

Conclusion

The COBRRA trial provides the first randomized evidence demonstrating a clear safety advantage of Apixaban over Rivaroxaban in acute VTE. For oncology clinicians, where balancing thrombosis prevention with bleeding risk is critical, these data support prioritizing Apixaban in appropriate patients, while awaiting further dedicated studies in cancer-associated thrombosis populations.

Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism. Castellucci LA, Chen VM,  Kovacs MJ, et al.for the COBRRA Trial Investigators. N Engl J Med 2026;394:1051-1060

Fixed-Duration vs Continuous Targeted Therapy in Frontline CLL: Insights from the Phase III CLL17 Trial

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SUMMARY: The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Evolving Treatment Paradigms in CLL            

The therapeutic landscape of CLL has undergone a profound transformation over the past decade, moving away from chemoimmunotherapy toward mechanism-based targeted agents. Brutons Tyrosine Kinase (BTK) inhibitors and the BCL2 inhibitor Venetoclax (VENCLEXTA®) have become foundational therapies, delivering durable disease control across biologic risk groups. Historically, BTK inhibitors were administered continuously until progression or intolerance, whereas Venetoclax-based combinations introduced the possibility of time-limited treatment.

The rationale for fixed-duration therapy stems from the observation that rational combinations can induce deeper remissions, including undetectable Minimal Residual Disease (MRD), potentially allowing for treatment-free intervals and reduced cumulative toxicity. While Venetoclax–Rituximab in relapsed disease and Venetoclax–Obinutuzumab in the frontline setting validated this concept, the relative efficacy of fixed-duration regimens compared with continuous BTK inhibition remained an unanswered question, until now.

Trial Design and Patient Population

CLL17 is an international, investigator-initiated, Phase III randomized trial designed to directly compare fixed-duration and continuous targeted treatment strategies, in previously untreated CLL patients. A total of 909 treatment-naïve patients were enrolled across 174 centers in 13 countries and randomly assigned in a 1:1:1 ratio to receive:

Fixed-duration Venetoclax plus Obinutuzumab (N=303)

Fixed-duration Venetoclax plus Ibrutinib (N=305)

Continuous Ibrutinib monotherapy (N=301)

Randomization was stratified by fitness status, IGHV mutation status, and the presence of del(17p) and/or TP53 mutation. The study population reflected real-world heterogeneity, with a median age of 66 years, 44% classified as unfit (based on CIRS scores greater than 6, a creatinine clearance of less than 70 ml per minute, or both), more than half harboring unmutated IGHV, 7.6% of the patients with del(17p) or TP53 mutation (or both), and nearly 20% exhibiting complex karyotypes. High- and very high-risk disease by the CLL International Prognostic Index was present in more than 60% of patients, underscoring the clinical relevance of the cohort. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS), with the trial powered to test the noninferiority of each fixed-duration regimen versus continuous Ibrutinib. Key Secondary endpoints included Overall Survival (OS), MRD negativity, Response Rates, and Safety.

Efficacy Outcomes: Noninferiority Achieved

At a median follow-up of 34.2 months, in this prespecified interim analysis, both fixed-duration strategies met the prespecified criteria for noninferiority compared with continuous Ibrutinib. Three-year PFS rates were remarkably similar across treatment arms:

81.1% with Venetoclax–Obinutuzumab

79.4% with Venetoclax–Ibrutinib

81.0% with continuous Ibrutinib

Hazard ratios for progression or death favored neither continuous nor fixed-duration therapy, providing the first prospective evidence that time-limited targeted regimens can match the disease control achieved with indefinite BTK inhibition in the frontline setting.

Overall Survival at three years exceeded 90% in all groups, with no meaningful differences observed at this interim analysis. Longer follow-up will be required to determine whether survival curves diverge with time, particularly in biologically high-risk subgroups.

Depth of Remission and MRD Dynamics

Marked differences emerged in depth of response. Undetectable MRD in peripheral blood at the end of treatment was achieved in:

73.3% of patients treated with Venetoclax–Obinutuzumab

47.2% of those receiving Venetoclax–Ibrutinib

0% of patients on continuous Ibrutinib

These findings reinforce the well-established limitation of single-agent BTK inhibition in achieving deep molecular remissions and highlight a key advantage of Venetoclax-based combinations. While end-of-treatment MRD has been associated with long-term outcomes in fixed-duration regimens, its prognostic value relative to continuous BTK inhibition remains less clear. Ongoing longitudinal MRD assessments in CLL17 may help clarify whether differences in MRD depth ultimately translate into durable clinical benefit.

Safety and Tolerability Considerations

Adverse events were common across all treatment arms, reflecting the immunocompromised nature of the CLL population. Infections affected nearly 80% of patients overall, with serious and fatal infections occurring more frequently in the Venetoclax–Obinutuzumab arm. Importantly, trial enrollment coincided with the COVID-19 pandemic, and approximately 10% of patients experienced severe COVID-19–related infections.

Cytopenias, particularly neutropenia, were more frequent with combination regimens, especially Venetoclax–Obinutuzumab. However, these events were largely confined to the first year of therapy and resolved after treatment completion. In contrast, cardiac toxicities, including atrial fibrillation and hypertension, were more commonly associated with Ibrutinib-containing regimens, consistent with prior experience.

Tumor lysis syndrome was infrequent (<5%) across Venetoclax-containing arms, demonstrating that standard ramp-up strategies and debulking approaches effectively mitigate this risk, even in older and unfit patients.

Subgroup Insights and Clinical Implications

Fixed-duration therapy performed well across most biologic subgroups. Notably, patients with unmutated IGHV did not experience inferior outcomes with time-limited treatment compared with continuous Ibrutinib, supporting broader use of fixed-duration strategies. Patients with mutated IGHV achieved particularly favorable outcomes with Venetoclax–Obinutuzumab, consistent with the more indolent biology of this subgroup.

For patients with del(17p) or TP53 mutations, outcomes were encouraging with BTK inhibitor–containing regimens, although the small sample size and limited follow-up preclude definitive conclusions. Continuous therapy did not clearly outperform fixed-duration Venetoclax–Ibrutinib in this population, highlighting the need for ongoing observation and biomarker-driven analyses.

Positioning CLL17 in the Current Treatment Landscape

The results of CLL17 complement and extend findings from earlier studies such as CLL13, CLL14, CAPTIVATE, and GLOW, while providing the first direct, randomized comparison between fixed-duration and continuous targeted therapy. Importantly, the trial was conducted during the emergence of next-generation BTK inhibitors with improved cardiac safety profiles, suggesting that the central question addressed by CLL17, time-limited versus continuous therapy, will remain clinically relevant regardless of the specific BTK inhibitor chosen.

Conclusions

The first analysis of the Phase III CLL17 trial demonstrates that fixed-duration Venetoclax–Obinutuzumab and Venetoclax–Ibrutinib are noninferior to continuous Ibrutinib in previously untreated CLL, with comparable Progression-Free Survival and excellent Overall Survival. These findings provide high-level evidence supporting fixed-duration therapy as a viable frontline strategy for most patients, offering the advantages of treatment-free intervals and deep remissions without compromising efficacy. As follow-up matures, CLL17 will further inform patient selection, remission durability, and the long-term significance of MRD. For now, the trial marks a pivotal step toward more personalized, time-limited treatment strategies in CLL.

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia. Al-Sawaf O, Stumpf J,  Zhang C, et al. for the CLL17 Trial Investigators. N Engl J Med 2026;394:1084-1096.

Reassessing the Role of Carboplatin in Neoadjuvant Therapy for HER2-Positive Breast Cancer: Insights from the neoCARHP Trial

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Human epidermal growth factor receptor 2–positive (HER2+) breast cancer accounts for approximately 15%–20% of all breast malignancies and historically has been associated with aggressive disease biology. Over the past decade, the integration of dual HER2 blockade with Trastuzumab (HERCEPTIN®) and Pertuzumab (PERJETA®) alongside cytotoxic chemotherapy has substantially improved outcomes. In patients with Stage II–III disease, neoadjuvant therapy has become the standard treatment approach, enabling early assessment of treatment response and guiding postoperative therapy.

The combination of a Taxane, Carboplatin, Trastuzumab, and Pertuzumab (TCbHP) is widely endorsed by treatment guidelines as a preferred neoadjuvant regimen. However, the inclusion of Carboplatin, originally incorporated as an anthracycline-sparing strategy to mitigate cardiotoxicity, remains a subject of ongoing debate. While platinum agents may enhance antitumor activity through DNA-damaging mechanisms and potential synergy with HER2-targeted therapy, Carboplatin is also associated with increased hematologic and gastrointestinal toxicities that frequently necessitate dose reductions or treatment interruptions.

Several earlier studies have questioned the incremental benefit of Carboplatin in HER2-positive disease. Trials in both metastatic and early-stage settings have suggested that the addition of platinum compounds may not significantly improve response outcomes, while contributing to higher rates of treatment-related toxicity. At the same time, multiple investigations evaluating chemotherapy de-escalation strategies have demonstrated promising activity with taxane-based regimens combined with dual HER2 blockade alone.

Against this evolving backdrop, the Phase III neoCARHP study sought to determine whether Carboplatin could be safely omitted from neoadjuvant therapy without compromising efficacy.

Study Design and Treatment Approach

The neoCARHP trial was a multicenter, open-label, randomized Phase III noninferiority study, conducted across 15 institutions. The study enrolled women aged 18 years or older with previously untreated Stage II or III HER2-positive invasive breast cancer. Patients with metastatic disease, inflammatory breast cancer, bilateral tumors, or prior systemic therapy for breast cancer were excluded.

Participants were randomly assigned in a 1:1 ratio to receive six cycles of either the standard TCbHP regimen or a Carboplatin-free regimen consisting of a Taxane plus Trastuzumab and Pertuzumab (THP). Taxane selection, including Docetaxel, Paclitaxel, or nab-Paclitaxel, was left to investigator discretion. Importantly, Docetaxel dosing differed between arms, with a higher dose used in the THP arm to maintain treatment intensity in the absence of Carboplatin.

All patients received Trastuzumab and Pertuzumab every three weeks. Surgery was scheduled within six weeks following completion of neoadjuvant therapy. Postoperative treatment followed standard guidelines: patients achieving a pathologic Complete Response (pCR) typically continued Trastuzumab with or without Pertuzumab to complete one year of HER2-targeted therapy, while those with residual disease were eligible to receive adjuvant Trastuzumab emtansine (KADCYLA®).

Between April 2021 and August 2024, 774 patients were randomized, and 766 who received at least one dose of study therapy were included in the efficacy analysis. Baseline characteristics were well balanced between the treatment arms, with most patients presenting with Stage II disease and approximately one-third being node-negative.

The Primary endpoint of the trial was the rate of pathologic Complete Response in the breast and axilla (ypT0/is ypN0) in the modified intention-to-treat population.

Efficacy Outcomes

Pathologic Complete Response was achieved in 64.1% of patients treated with the Carboplatin-free THP regimen compared with 65.9% in the TCbHP group. The absolute difference of –1.8% fell well within the prespecified noninferiority margin, confirming that THP was statistically noninferior to the standard Carboplatin-containing regimen.

Per-protocol analyses yielded nearly identical results, with both treatment groups demonstrating a pCR rate of 68.5%. Importantly, subgroup analyses showed consistent outcomes across clinically relevant populations, including both Hormone Receptor–positive and Hormone Receptor–negative disease. Among patients with Hormone Receptor–negative tumors, pCR rates approached 78% in both treatment arms.

Safety and Tolerability

A key finding of the neoCARHP study was the improved safety profile associated with the Carboplatin-free regimen. Grade 3 or 4 adverse events occurred in 20.7% of patients receiving THP compared with 34.6% in those treated with TCbHP. Serious adverse events were also less frequent in the THP arm (1.3% vs 4.7%).

Hematologic toxicities were notably reduced with Carboplatin omission. Rates of neutropenia and leukopenia were significantly lower in the THP group, and gastrointestinal toxicities such as diarrhea occurred less frequently. Overall toxicity rates were similar between groups, but the majority of events were low grade. No treatment-related deaths were reported.

These findings suggest that eliminating Carboplatin may substantially reduce treatment-related morbidity while preserving efficacy.

Clinical Context and Emerging Evidence

The results of neoCARHP align with a growing body of evidence supporting chemotherapy de-escalation strategies in HER2-positive breast cancer. Multiple prior trials, including NeoSphere, WSG-ADAPT, COMPASS-HER2-pCR, and DAPHNe, have demonstrated that taxane-based regimens combined with dual HER2 blockade can achieve high pCR rates, particularly in Hormone Receptor–negative tumors.

Collectively, these studies suggest that approximately half of patients with Stage II–III HER2-positive breast cancer may achieve pCR after four cycles of THP, with response rates exceeding 60% after six cycles. For patients with Hormone Receptor–negative disease, pCR rates may approach 80%. Importantly, omitting Carboplatin appears to improve tolerability without compromising early efficacy outcomes, raising the possibility that selected patients with low- or intermediate-risk disease may safely receive less intensive chemotherapy.

Future Directions and Biomarker-Guided Treatment

Despite these encouraging results, several important questions remain. Long-term outcomes, including Event-Free Survival, invasive Disease–Free Survival, and Overall Survival, are still maturing in the neoCARHP trial. Because pCR is not universally validated as a surrogate for survival across all breast cancer subtypes, extended follow-up will be critical to confirm the durability of these findings.

Advances in biomarker-driven treatment selection may also play a key role in refining neoadjuvant strategies. Emerging tools such as PET-guided response assessment, genomic assays like HER2DX, and intrinsic subtype classification may help identify patients most likely to benefit from treatment de-escalation while ensuring that higher-risk individuals continue to receive optimal therapy.

Meanwhile, antibody–drug conjugates are rapidly entering the early-stage setting and could further reshape treatment paradigms. Agents such as Trastuzumab deruxtecan (ENHERTU&reg;) are currently being investigated in neoadjuvant and adjuvant trials and may eventually offer additional Carboplatin-free therapeutic options.

Clinical Takeaway

The Phase III neoCARHP trial demonstrates that a neoadjuvant regimen consisting of a taxane combined with Trastuzumab and Pertuzumab achieves pathologic Complete Response rates comparable to the standard TCbHP regimen while significantly reducing high-grade toxicities.

These findings support the potential omission of Carboplatin in selected patients with Stage II–III HER2-positive breast cancer and represent another step toward individualized, toxicity-conscious treatment strategies in early HER2-positive disease.

Neoadjuvant Taxane Plus Trastuzumab and Pertuzumab With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: The Randomized Noninferiority Phase III neoCARHP Trial. Gao H-F, Ye G-L, Lin Y, et al. J Clin Oncol. DOI: 10.1200/JCO-25-02176

Late Breaking Abstract – ASCO GI: 2026. Identifying a Less Neurotoxic First-Line Backbone in Metastatic Esophagogastric Cancer: Insights from the LyRiCX Trial

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Background

First-line systemic therapy for metastatic or unresectable esophagogastric adenocarcinoma has traditionally relied on platinum-based chemotherapy, most commonly Oxaliplatin-containing regimens combined with fluoropyrimidines. While these regimens have demonstrated meaningful activity, cumulative peripheral neuropathy remains a significant treatment-limiting toxicity. Oxaliplatin-induced neurotoxicity can adversely affect patient quality of life and frequently restricts the duration of therapy or the ability to deliver subsequent lines of treatment.

With the integration of immune checkpoint inhibitors such as Nivolumab into the first-line management of selected patients with advanced gastroesophageal cancers, the choice of chemotherapy backbone has become increasingly relevant. Selecting regimens that maintain antitumor efficacy while minimizing long-term toxicity is particularly important, in a treatment landscape where patients may receive multiple sequential therapies.

The Phase II LyRiCX trial was designed to address this challenge by comparing three first-line chemotherapy backbones in patients with HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, with a focus on balancing efficacy and neurotoxicity.

Study Design and Patient Population

LyRiCX was a multicenter, open-label, randomized Phase II study conducted across medical centers in the Netherlands. Adults with previously untreated, pathologically confirmed HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, with no pre-existing neuropathy more than Grade 1, were eligible for enrollment.

Participants were randomized to one of three chemotherapy regimens:

  • F-Nal-Iri: Nanoliposomal Irinotecan 70 mg/m2, Leucovorin 400 mg/m2, and Fluorouracil 2400 mg/m2 every 2 weeks
  • CapCar: Capecitabine 1000 mg/m2 plus Carboplatin AUC5 every 3 weeks
  • CapOx: Capecitabine 1000 mg/m2 plus Oxaliplatin 130 mg/m2 every 3 weeks

Before the regulatory approval of Nivolumab (OPDIVO®) in this setting (through August 2022), patients were randomized in a 2:2:1 ratio to F-Nal-Iri, CapCar, or CapOx. After immunotherapy became available, treatment allocation incorporated PD-L1 status as measured by the Combined Positive Score (CPS):

  • CPS <5 or contraindication to Nivolumab: randomized to chemotherapy alone (F-Nal-Iri, CapCar, or CapOx; 2:2:1).
  • CPS ≥5: randomized to CapCar or CapOx combined with Nivolumab (2:1).

The trial employed a predefined “pick-the-winner” strategy to determine the most favorable regimen. The co–Primary endpoints were:

  • Incidence of Grade 2–4 neurotoxicity
  • Progression-Free Survival (PFS)

Between September 2019 and January 2025, 320 patients were enrolled. The median age was 65 years and 81% of participants were male. Treatment distribution included:

  • F-Nal-Iri: 83 patients
  • CapCar: 157 patients (including 74 receiving Nivolumab)
  • CapOx: 80 patients (including 36 receiving Nivolumab)

The median PFS follow-up was 24.1 months.

Neurotoxicity Outcomes

The most striking finding from LyRiCX was the dramatic difference in neurotoxicity rates across treatment arms.

Grade 2–4 neurotoxicity occurred in:

  • 0% of patients receiving F-Nal-Iri
  • 2.5% of patients receiving CapCar ± Nivolumab
  • 46.3% of patients receiving CapOx ± Nivolumab

Statistical analysis showed no significant difference in neurotoxicity between CapCar and F-Nal-Iri. In contrast, neurotoxicity was significantly higher with CapOx compared with both alternative regimens (P<0.001 for both comparisons).

These findings highlight the substantial neurologic toxicity burden associated with oxaliplatin-based therapy in this patient population.

Efficacy Results

Despite marked differences in neurotoxicity, efficacy outcomes were broadly comparable across treatment arms.

Median Progression-Free Survival was:

  • 4.5 months with F-Nal-Iri
  • 5.7 months with CapCar ± Nivolumab
  • 5.9 months with CapOx ± Nivolumab

Among patients who did not receive immunotherapy, statistical analyses showed no significant differences in PFS between:

  • F-Nal-Iri and CapCar
  • F-Nal-Iri and CapOx

Similarly, comparisons between CapCar ± Nivolumab and CapOx ± Nivolumab did not demonstrate a statistically significant difference in PFS.

Taken together, these data indicate that non-Oxaliplatin regimens reduce neurotoxicity without significantly compromising disease control

Safety and Adverse Events

Overall safety profiles were generally comparable across treatment groups, and no unexpected safety signals were identified. Grade 3–4 adverse events occurred at similar frequencies among the regimens, with the notable exception of neurotoxicity. Anemia was observed across all treatment arms and appeared somewhat more frequently in the CapCar-based group, although this difference did not translate into a clear safety disadvantage.

Importantly, neurotoxicity remained the dominant differentiating toxicity, occurring at markedly higher rates in the CapOx arm relative to the other regimens.

Clinical Implications

The LyRiCX study provides important insight into the optimization of chemotherapy backbones for metastatic esophagogastric adenocarcinoma. While Oxaliplatin-containing regimens remain widely used, the substantial risk of cumulative neuropathy may have significant downstream consequences for quality of life and treatment sequencing.

Both CapCar and F-Nal-Iri demonstrated dramatically lower rates of clinically significant neurotoxicity while maintaining similar Progression-Free Survival compared with CapOx. Among the evaluated regimens, CapCar emerged as the most practical and favorable option, offering several advantages:

  • Minimal risk of treatment-limiting neuropathy
  • Comparable efficacy outcomes
  • No requirement for central venous access
  • Use of widely available off-patent agents, supporting cost efficiency

As treatment strategies continue to evolve with the integration of immunotherapy and additional targeted therapies, selecting chemotherapy backbones that preserve patient function and enable subsequent treatment options will remain a critical component of clinical decision-making.

Key Takeaway for Oncology Practice:

The LyRiCX trial suggests that Capecitabine plus Carboplatin may represent a highly favorable first-line chemotherapy backbone for HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, providing comparable disease control to Oxaliplatin-based therapy while substantially reducing the risk of neurotoxicity.

Liposomal irinotecan, carboplatin or oxaliplatin (LyRICX) with or without nivolumab in the first-line treatment of metastatic or irresectable esophagogastric adenocarcinoma: A randomized phase 2 study. Kamp D, van Velzen M, Kessels R, et al. J Clin Oncol 44, LBA287(2026): DOI: 10.1200/JCO.2026.44.2_suppl.LBA287 

Late Breaking Abstract – 2026 ASCO GU Symposium: Advancing Adjuvant Therapy in Clear Cell Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 80,450 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2026 and about 15,160 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

Adjuvant immunotherapy has become an important component of treatment for patients with clear cell Renal Cell Carcinoma (ccRCC) who are at elevated risk for recurrence following nephrectomy. The role of adjuvant immune checkpoint blockade was established by the Phase 3 KEYNOTE-564 study, which demonstrated that adjuvant Pembrolizumab (KEYTRUDA®) significantly improves outcomes in this patient population.

Updated results from KEYNOTE-564 with a median follow-up of approximately 57 months confirmed a statistically significant Overall Survival (OS) benefit with adjuvant Pembrolizumab compared with placebo. Median OS was not reached in either group, but treatment with Pembrolizumab reduced the risk of death by 38% (HR 0.62; P=0.0024). At 48 months, the estimated OS rate was 91.2% among patients treated with Pembrolizumab versus 86.0% for those receiving placebo. The survival advantage was consistent across clinically relevant subgroups, including patients with M0 disease, those with M1 disease rendered no evidence of disease (M1 NED), and across PD-L1 expression levels and sarcomatoid histology status.

Building upon these findings, investigators have explored whether combining immunotherapy with other targeted agents could further reduce recurrence risk. The Phase 3 LITESPARK-022 trial evaluated the addition of the Hypoxia-Inducible Factor-2α inhibitor Belzutifan (WELIREG®) to adjuvant Pembrolizumab in patients with high-risk ccRCC following surgery.

Study Design

LITESPARK-022 is a randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 1,841 patients with ccRCC at increased risk of recurrence after nephrectomy.

Eligible patients included those with:

  • Intermediate-to-high risk M0 disease
    • pT2 tumors with grade 4 or sarcomatoid features, N0
    • pT3 tumors of any grade, N0
  • High-risk M0 disease
    • pT4 tumors of any grade, N0
    • Any pT stage with nodal involvement (N+)
  • M1 NED disease
    • Patients with metastatic disease who had undergone surgery and achieved no radiographic evidence of disease

Participants were randomized in a 1:1 ratio to receive either Pembrolizumab plus Belzutifan (N=921), Pembrolizumab plus placebo (N=920). Treatment consisted of Pembrolizumab 400 mg IV every 6 weeks for 9 cycles (approximately 1 year) and Belzutifan 120 mg orally once daily or placebo. Randomization was stratified according to risk category and tumor grade. The Primary endpoint was Disease-free survival (DFS) assessed by investigators and Secondary endpoints included Overall Survival (OS), Safety and tolerability.

Results discussed here represent the first interim analysis, conducted after a median follow-up duration was 28.4 months. Treatment completion rates were similar between groups (about 70%)

Efficacy Outcomes

The addition of Belzutifan to Pembrolizumab resulted in a statistically significant improvement in Disease-Free Survival, compared to Pembrolizumab plus placebo, meeting the Primary endpoint of the study (HR=0.72; 95% CI: 0.59–0.87; P=0.0003. This corresponds to a 28% reduction in the risk of recurrence or death with the combination regimen. The Median DFS had not yet been reached in either arm at the time of analysis. The estimated 24-month DFS rates were 80.7% in the Pembrolizumab plus Belzutifan group and 73.7% in the Pembrolizumab plus placebo group.

This represents the first Phase 3 adjuvant RCC trial demonstrating superiority of a combination therapy over active immunotherapy alone.

Overall Survival

Overall survival results remain immature. At the time of the interim analysis, only 29% of the events required for the final OS analysis had occurred, preventing definitive conclusions regarding survival benefit.

Safety Profile

As expected with the addition of Belzutifan, the combination regimen was associated with higher rates of treatment-related toxicity. Grade ≥3 Adverse Events for Pembrolizumab plus Belzutifan combination was 52.1% versus 30.2% for the Pembrolizumab plus placebo group. The most frequently reported grade ≥3 events included Anemia (12.1% vs 0.4%), Elevated ALT (6.4% vs 2.0%) and Hypoxia (4.6% vs 0%). Despite increased toxicity, grade 5 adverse events were rare and similar between arms, and no new safety signals were identified.

Clinical Implications

The findings from LITESPARK-022 suggest that combining Belzutifan with Pembrolizumab may further improve outcomes for patients with high-risk ccRCC following nephrectomy. However, the improved DFS must be balanced against the increased toxicity profile. Experts emphasize that careful patient selection will be essential if this regimen is adopted in clinical practice. Patients with baseline pulmonary or cardiovascular comorbidities, who may be more vulnerable to Belzutifan-associated hypoxia or anemia, may require additional consideration.

Furthermore, longer follow-up will be necessary to determine whether overall survival benefit emerges, as well as the impact on quality of life, and long-term safety of the combination regimen

Key Takeaways for Clinical Practice

  • Adjuvant Pembrolizumab remains a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy.
  • The LITESPARK-022 trial demonstrated a significant improvement in DFS when Belzutifan was added to Pembrolizumab.
  • The combination reduced the risk of recurrence or death by 28% compared with Pembrolizumab alone.
  • Toxicity was higher, particularly with respect to anemia and hypoxia, but was generally manageable with dose modification and supportive care.
  • Ongoing follow-up will determine whether Overall Survival and Patient-Reported Outcomes support broader adoption of this strategy.

Conclusion

The Phase 3 LITESPARK-022 trial represents an important step forward in the adjuvant treatment landscape for clear cell Renal Cell Carcinoma. By demonstrating a clinically meaningful improvement in Disease-Free Survival with the addition of Belzutifan to Pembrolizumab, the study introduces a promising new therapeutic approach for patients at high risk of recurrence after nephrectomy. Continued follow-up will clarify the long-term survival benefit and help define the role of this combination in routine clinical practice.

Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study. Choueiri TK, Motzer RJ, Karam JA, et al. 2026 ASCO Genitourinary Cancers Symposium. J Clin Oncol 44, 2026 (suppl 7; abstr LBA418)

Expanding Targeted First-Line Options in BRAF V600E–Mutant Metastatic Colorectal Cancer: Insights From the BREAKWATER Trial

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 158,850 new cases of CRC will be diagnosed in the United States in 2026 and about 55,230 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as Panitumumab (VECTIBIX®) and Cetuximab (ERBITUX®), as well as anti VEGF agent Bevacizumab (AVASTIN®), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency.

Metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation represents a biologically aggressive subtype associated with poor prognosis, higher rate of peritoneal metastasis, and historically limited responsiveness to conventional chemotherapy. Approximately 8% to 12% of patients with mCRC carry this mutation, and outcomes with traditional first-line regimens have been suboptimal. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Historically, patients with these mutations experienced shorter survival when treated with chemotherapy with or without biologics such as Bevacizumab, compared to their BRAF wild-type counterparts. While the BEACON CRC trial established the Encorafenib plus Cetuximab (EC) doublet as standard in the previously treated setting, the optimal first-line strategy remained undefined.

The global Phase III BREAKWATER trial was designed to evaluate whether combining targeted agents with standard chemotherapy could improve outcomes for patients with previously untreated BRAF V600E–mutant mCRC. Earlier analyses from the study demonstrated that the combination of Encorafenib and Cetuximab with modified FOLFOX6 (mFOLFOX6) significantly improved Response Rates and Progression-Free Survival compared with chemotherapy with or without Bevacizumab. These findings ultimately led to accelerated FDA approval in December 2024 for the targeted triplet regimen in the first-line setting.

However, Oxaliplatin-based therapy is not suitable for all patients. Cumulative exposure to Oxaliplatin is frequently associated with peripheral neuropathy, prompting clinicians to consider Irinotecan-based regimens such as FOLFIRI as an alternative chemotherapy backbone in the first-line setting. It is estimated that 20% to 25% of patients with newly diagnosed BRAF V600E–mutant mCRC receive FOLFIRI as part of their initial treatment strategy. To address this clinical reality, investigators expanded the BREAKWATER trial to evaluate whether targeted therapy could also enhance outcomes when combined with Irinotecan-based chemotherapy.

Study Design and Patient Population

Cohort 3 of the BREAKWATER study specifically examined the combination of Encorafenib plus Cetuximab with FOLFIRI, compared with FOLFIRI with or without Bevacizumab, representing standard care in this setting. Eligible patients had previously untreated BRAF V600E–mutant mCRC, measurable disease according to RECIST 1.1 criteria, and an ECOG Performance Status of 0 or 1.

A total of 147 patients were randomized in a 1:1 ratio to receive either the targeted therapy combination plus FOLFIRI (N=73) or the control regimen (N=74). Baseline characteristics were balanced between treatment arms, with a median patient age of 62 years, 46% male, and 60% with ECOG performance status 0. The Primary endpoint was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review, while Progression-Free Survival (PFS) served as the key Secondary endpoint. Additional endpoints included Overall Survival (OS), Duration of Response (DOR), Time To Response (TTR), and Safety.

Significant Improvement in Objective Response Rate

At the time of the March 1, 2025 data cutoff, the combination of Encorafenib, Cetuximab, and FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed Objective Response Rate compared with the control regimen.

The confirmed ORR reached 64.4% with the targeted therapy combination, compared with 39.2% in the control arm, corresponding to an odds ratio of 2.76 (P=0.0011). Responses included Complete Responses in 4.1% of patients receiving the targeted regimen versus 1.4% in the control group, while Partial Responses occurred in 60.3% and 37.8% of patients, respectively.

Importantly, the responses observed with the targeted regimen were rapid and durable. The median time to response was similar between groups, occurring at approximately 6.9 weeks with Encorafenib plus Cetuximab and FOLFIRI and 7.1 weeks with the control regimen. Although the median Duration of Response had not yet been reached in either group, a greater proportion of patients receiving the targeted combination experienced sustained responses lasting at least six months (57.4% vs 34.5%). Responses lasting 12 months or longer were observed only in the experimental arm.

Clinical benefit with the targeted regimen was consistent across prespecified patient subgroups, further supporting the robustness of the treatment effect.

Early Signals for Survival Benefit

While Overall Survival data remain immature, early findings suggest a potential survival advantage with the targeted regimen. At the time of analysis, 15.1% of patients in the Encorafenib–Cetuximab–FOLFIRI group had died, compared with 27.0% in the control arm, translating to a hazard ratio of 0.49. Longer follow-up will be required to confirm the durability of this emerging survival signal.

Treatment exposure also favored the experimental arm. Nearly 70% of patients receiving the targeted regimen remained on treatment, compared with approximately one-third of patients in the control group, with a median treatment duration of 9.9 months versus 7.4 months, respectively.

Manageable Safety Profile

The safety profile of the triplet regimen was consistent with the known effects of each agent, and the addition of Encorafenib and Cetuximab did not substantially compromise treatment tolerability. The most frequently reported adverse events with the combination regimen included nausea, diarrhea, and vomiting. Serious treatment-emergent adverse events occurred in 39.4% of patients in the experimental arm vs 36.8% in the control arm. Importantly, the incorporation of targeted therapy did not lead to a meaningful increase in chemotherapy discontinuation, with FOLFIRI discontinuation rates of 9.9% in the experimental arm versus 8.8% in the control group. Investigators also reported no new safety signals, reinforcing the feasibility of combining targeted therapy with an Irinotecan-based chemotherapy backbone.

Clinical Implications

The results from BREAKWATER Cohort 3, build on the earlier success of Encorafenib and Cetuximab combined with Oxaliplatin-based chemotherapy, and provide important new insights for clinical practice. For patients who may not be optimal candidates for Oxaliplatin due to concerns such as cumulative neurotoxicity, the Encorafenib–Cetuximab–FOLFIRI regimen represents a compelling alternative.

Taken together, the findings support the growing role of targeted therapy- based combinations in the first-line treatment of BRAF V600E–mutant mCRC, offering both improved response rates and the potential for durable disease control.

Looking Ahead

The BREAKWATER trial remains ongoing, and continued follow-up will clarify the long-term durability of responses and the ultimate impact on Overall Survival. Nonetheless, the current analysis highlights the expanding therapeutic landscape for patients with this challenging molecular subtype of colorectal cancer.

If confirmed with longer follow-up, the combination of Encorafenib, Cetuximab, and FOLFIRI may emerge as another frontline standard-of-care option, providing clinicians with greater flexibility to tailor treatment strategies based on patient characteristics and toxicity considerations.

BREAKWATER: Primary analysis of first-line encorafenib + cetuximab + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer. Kopetz S, Wasan HS, Yoshino T, et al: 2026 ASCO GI Cancers Symposium. J Clin Oncol 44, 2026 (suppl 2; abstr 13)

FDA Approves First Line HERNEXEOS® for HER2-mutant Advanced NSCLC

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SUMMARY: The FDA on February 26, 2026, granted accelerated approval to Zongertinib (HERNEXEOS®), a kinase inhibitor, for an expanded indication for adults with unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) whose tumors have HER2 (ERBB2) Tyrosine Kinase Domain (TKD) activating mutations, as detected by an FDA-authorized test.

The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein, and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases.

The FDA in 2022 granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan), for adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) mutations. This is the first drug approved for HER2-mutant NSCLC. Trastuzumab deruxtecan, however, can be associated with toxicities including Interstitial Lung Disease (ILD). Similarly, Pan-HER TKIs such as Poziotinib and Pyrotinib have shown limited efficacy and are frequently associated with EGFR-related adverse events, underscoring the urgent need for more targeted, better-tolerated therapies.

Zongertinib (HERNEXEOS®) is a novel, oral, irreversible Tyrosine Kinase Inhibitor designed to selectively target HER2 while sparing EGFR, thus minimizing common toxicities such as rash and diarrhea.

Beamion LUNG-1 is an ongoing Phase 1a/1b multicenter, multi-cohort trial, evaluating Zongertinib in  patients with HER2-altered advanced or metastatic solid tumors (Phase 1a) and those with HER2-mutant advanced or metastatic NSCLC across multiple clinically relevant patient cohorts (Phase 1b). In the Phase 1a dose-escalation trial, Zongertinib showed encouraging preliminary activity at the recommended expansion doses of 120 mg and 240 mg once daily, with a low incidence of Grade 3 or higher adverse events.

The Phase 1b portion is an ongoing study of Zongertinib in three key Cohorts (Cohort 1, 2 and 5) and three exploratory Cohorts (Cohorts 3, 4 and 6)

  • Cohort 1: Pretreated NSCLC patients with tumors harboring HER2 mutations in the TKD (Tyrosine Kinase Domain), the most common category of HER2 mutations encountered in the clinic.
  • Cohort 2: Treatment-naïve NSCLC with HER2 TKD mutation
  • Cohort 3: NSCLC patients whose tumor had HER2 mutations outside the TKD or HER2 TKD mutation-positive squamous NSCLC, pretreated
  • Cohort 4: NSCLC with active brain metastases with a HER2 TKD mutation
  • Cohort 5: NSCLC patients whose tumors had HER2 mutations within the TKD and had previously received HER2-directed ADCs, including Trastuzumab deruxtecan.
  • Cohort 6: NSCLC patients with HER2 TKD mutation and prior systemic treatment including HER2-directed ADCs.

(Some reports define Cohort 5 as the post-ADC cohort. However, clinical trial documentation indicates Cohort 6 specifically addresses the requirement for previous HER2-directed ADC treatment in specific phases of the study)

Cohorts 3, 4 and 6 are exploratory

Patients were initially treated at 120 mg or 240 mg daily and following interim analysis, 120 mg was selected as the optimal dose based on a favorable efficacy and safety balance.

The FDA in August 2025, granted accelerated approval to Zongertinib, for adults with unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) whose tumors have HER2 (ERBB2) Tyrosine Kinase Domain (TKD) activating mutations and who have received prior systemic therapy. This was based on Objective Response Rate (ORR) and Duration of Response (DOR). This cohort study also suggested that Zongertinib may offer a viable treatment option even in patients who have progressed on ADCs or harbor atypical HER2 alterations.

The present accelerated approval was based on the efficacy of Zongertinib in unresectable or metastatic, non-squamous NSCLC with HER2 TKD mutation, who had not received systemic therapy for advanced disease (Cohort 2). The efficacy analysis included 72 patients (N=72) and the major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) as determined by Blinded Independent Central Review (BICR)

The ORR was 76%, with Complete Response seen in 11% and Partial Response noted in 65% of patients. Sixty four percent (64%) of responders had a DOR of 6 months or more and 44% had a DOR of 12 months or more. The researchers added that the present efficacy reinforces the existing efficacy data for Zongertinib in previously treated NSCLC tumors with HER2  TKD activating mutations.

Safety and Tolerability

In a pooled safety population, which included 292 patients with HER2-mutant NSCLC, both treatment-naïve and previously treated, the most common adverse reactions were diarrhea (54%), rash (27%), hepatotoxicity (26%), fatigue (25%), nausea (23%), and musculoskeletal pain (21%), and upper respiratory tract infection (20%). No cases of drug-related interstitial lung disease were observed. The safety profile compares favorably with existing HER2-targeted agents, including Trastuzumab deruxtecan, which has reported interstitial lung disease rates of up to 26% in earlier trials.

Clinical Context and Future Directions

Compared with other HER2-targeted agents including Trastuzumab deruxtecan and investigational pan-HER TKIs, Zongertinib stands out as the first targeted therapy for treatment naïve patients with HER2-mutant advanced NSCLC, with its high response rates, durability, and manageable toxicity, and once daily oral administration. While cross-study comparisons have inherent limitations, these results support Zongertinib as a promising, HER2-selective oral agent for patients with HER2-mutant NSCLC. The ongoing Phase 3 Beamion LUNG-2 trial (NCT06151574) will further assess Zongertinib in the first-line setting, providing critical data on its role relative to current standard-of-care therapies.

Conclusion

Zongertinib has emerged as a strong candidate in the evolving landscape of HER2-mutant NSCLC. With high response rates, durable outcomes, and a favorable safety profile, it may soon offer oncologists a powerful new tool for treating this difficult-to-manage patient population.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-unresectable-or-metastatic-non-squamous-non-small-cell

 

Adjuvant Nivolumab for Resected Melanoma: 9 Year Outcomes

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SUMMARY: The American Cancer Society estimates that in the US, approximately 112,000 new cases of melanoma will be diagnosed in 2026 and about 8510 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades.

Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease specific survival rates of 59% and 40% respectively.

Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoint proteins (“gate keepers”) suppress antitumor immunity. Antibodies targeting these membrane bound, inhibitory, immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc., block the immune checkpoint proteins and unleash T cells, resulting in T cell proliferation, activation and a therapeutic response.

Ipilimumab (YERVOY®) was approved by the FDA for the adjuvant treatment of patients with completely resected Stage III melanoma, based on an improvement in Relapse Free Survival, when compared to placebo, in a randomized Phase III trial. In this study however, over 50% of the patients treated with the recommended high dose Ipilimumab experienced Grade 3/4 toxicities. There is therefore an unmet need for adjuvant therapies, with improved benefit-risk ratio, for this patient group.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. Monotherapy with Nivolumab, in heavily pretreated advanced melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment.

Study Details

CheckMate 238 trial is a double-blind Phase III study that included 906 patients with completely resected, Stage IIIB/C or Stage IV melanoma. Patients were randomized in a 1:1 ratio to receive either Nivolumab 3 mg/kg IV, every 2 weeks (N=453) or Ipilimumab 10 mg/kg IV, every 3 weeks (N=453) for 4 doses, then every 12 weeks beginning at week 24, for up to 1 year. Both treatment groups were well balanced. Patients were stratified according to disease stage and PD-L1 status (positive vs. negative or indeterminate according to tumor-cell PD-L1 expression with a 5% cutoff). The Primary end point was Recurrence Free Survival (RFS).

Data from the primary analysis showed that adjuvant Nivolumab was superior to Ipilimumab with respect to RFS and Distant Metastasis–Free Survival (DMFS), and had a more favorable safety profile. This benefit was seen regardless of BRAF mutational status with Nivolumab, and was sustained at a minimum follow-up of up to 7 years. The Overall Survival at 4 years and 7 years was 71% with Nivolumab and 69% with Ipilimumab, and was not significantly different.

In this publication, the researchers provided the final results from CheckMate 238, with a minimum follow-up of 9 years (107 months).

Efficacy at 9 Year Follow-up

The median duration of RFS was 61.1 months with Nivolumab and 24.2 months with Ipilimumab (HR for recurrence or death=0.76) and the 9-year RFS was 44% and 37%, respectively. This benefit was seen across nearly all subgroups analyzed.

The median duration of DMFS in Stage III melanoma patients was more than 9 years with Nivolumab and 83.8 months with Ipilimumab, with 9-year survival of 54% and 48%, respectively (HR for distant metastasis or death=0.81).

The median OS was more than 9 years in both treatment groups, with 9-year survival of 69% in the Nivolumab group and 65% in the Ipilimumab group (HR for death=0.88). The rates of death from melanoma at 9 years were 26% with Nivolumab and 30% with Ipilimumab (HR=0.87; 95% CI, 0.67 to 1.13). It is still uncertain whether OS is improved when treatment is administered in the adjuvant setting compared with initiation at the time of metastatic disease. These outcomes indicate that, similar to trends in metastatic therapy, many patients receiving adjuvant treatment now live long enough to succumb to causes unrelated to melanoma.

Fewer patients in the Nivolumab group required subsequent systemic therapy compared to those in the Ipilimumab group (37.3% vs. 44.6%), with no new late-onset adverse events reported.

Conclusion

Final 9-year data from the CheckMate 238 trial confirms that adjuvant Nivolumab provides sustained improvements in Recurrence-Free Survival (RFS) and Distant Metastasis–Free Survival compared to Ipilimumab, in high-risk melanoma patients, maintaining a safer profile. The results highlight the need for ongoing long-term monitoring.

Nivolumab for Resected Stage III or IV Melanoma at 9 Years. Ascierto PA, Vecchio MD, Merelli B, et al. N Engl J Med 2026;394:333-342