Category: Immuno Oncology

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

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

RR

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)

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

FDA Approves KEYTRUDA® with Paclitaxel for Platinum-Resistant Epithelial Ovarian, Fallopian tube, or Primary Peritoneal Carcinoma

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SUMMARY: The FDA on February 10, 2026, approved Pembrolizumab (KEYTRUDA®) as well as Pembrolizumab and Berahyaluronidase alfa-pmph (KEYTRUDA QLEX®) in combination with Paclitaxel, with or without Bevacizumab (AVASTIN®), for adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) as determined by an FDA-authorized test, and who have received one or two prior systemic treatment regimens. The FDA also approved the PD-L1 IHC 22C3 pharmDx as a companion diagnostic device to identify patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) for treatment with Pembrolizumab.

It is estimated that in the United States, approximately 21,010 women will be diagnosed with ovarian cancer in 2026 and 12,450 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women. It accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%.

Platinum-resistant recurrent ovarian cancer therefore remains a significant therapeutic challenge, with historically limited options and modest improvements in survival. Previous studies, such as the Phase III AURELIA trial, established weekly Paclitaxel with Bevacizumab as an effective chemotherapy regimen. The potential for chemotherapy to enhance antitumor immune responses provided the rationale for combining Pembrolizumab, an anti–PD-1 antibody, with Paclitaxel, with or without Bevacizumab, in this patient population.

Trial Design

The ENGOT-ov65/KEYNOTE-B96 trial (NCT05116189) was a multicenter, randomized, double-blind, placebo-controlled Phase III study that enrolled 643 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Eligible patients had received one to two prior systemic therapies, including at least one platinum-based regimen, and had evidence of disease progression within six months after platinum therapy. Patients with primary platinum-refractory disease were excluded.

Participants were randomized 1:1 to receive Pembrolizumab 400 mg every six weeks or placebo, in combination with weekly Paclitaxel 80 mg/m² on days 1, 8, and 15 of each 3-week cycle, with or without Bevacizumab 10 mg/kg every 2 weeks. Prior use of PARP inhibitors, Bevacizumab, or PD-1/PD-L1 agents was allowed. Patients had an ECOG performance status of 0–1, with a median age of 61–62 years and predominance of high-grade serous histology (86%). Approximately one-third of patients had PD-L1 CPS ≥10.

Efficacy Results

The Primary endpoint was Progression-Free Survival (PFS) per RECIST v1.1, with Overall Survival (OS) as a key Secondary endpoint.

  • First interim analysis (median follow-up 15.6 months):
    • Overall population: median PFS 8.3 months with Pembrolizumab vs 6.4 months with placebo (HR 0.70; P<0.0001).
    • PD-L1 CPS ≥1 population: median PFS 8.3 months vs 7.2 months (HR 0.72; P=0.0014).
  • Second interim analysis (median follow-up 26.6 months):
    • PD-L1 CPS ≥1 population: OS improved to 18.2 months with Pembrolizumab vs 14.0 months with placebo (HR 0.76; P=0.0053).
    • Benefits were observed across subgroups, including older patients, prior PARP inhibitor exposure, and short platinum-free interval.
    • Objective Response Rates were higher with Pembrolizumab (53.0% vs 46.6% in PD-L1 CPS ≥1 patients) with longer Duration of Response.

The PFS and OS improvements were consistent regardless of Bevacizumab use, supporting both doublet and triplet strategies in routine practice.

Safety Profile

Pembrolizumab combined with weekly Paclitaxel, with or without Bevacizumab, demonstrated a manageable safety profile. Adverse events were consistent with known toxicities of checkpoint inhibitors and chemotherapy, including immune-mediated events, infusion reactions, and myelosuppression. No unexpected safety signals were reported, confirming the feasibility of this regimen in a platinum-resistant population.

Clinical Implications

KEYNOTE-B96 demonstrates a clinically meaningful improvement in both Progression-Free and Overall Survival, representing one of the longest reported OS durations in platinum-resistant ovarian cancer. The regimen leverages the immune-modulating effects of weekly Paclitaxel and the potential vascular-normalizing and immunosuppressive effects of Bevacizumab, addressing multiple barriers to effective immune activation.

These results support PD-L1 CPS as a predictive biomarker while emphasizing the importance of integrating immunotherapy with established chemotherapy backbones. The findings provide a foundation for sequencing this strategy alongside emerging therapies, including antibody-drug conjugates and other targeted agents, in this difficult-to-treat population.

Conclusion

KEYNOTE-B96 establishes Pembrolizumab plus weekly Paclitaxel, with or without Bevacizumab, as a viable and effective treatment option for patients with platinum-resistant ovarian cancer, delivering meaningful improvements in survival with a manageable safety profile. This trial highlights the potential of immunotherapy combinations in a disease historically considered immunologically “cold” and provides a new evidence-based option in a setting of high unmet need.

Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase 3 ENGOT-ov65/KEYNOTE-B96 study. Colombo N, Zsiros E, Sebastianelli A, et al. Presented at: European Society of Medical Oncology Congress 2025; October 17–20, 2025; Berlin, Germany. Abstract LBA3.

Late Breaking Abstract – ASH 2025: Teclistamab Plus Daratumumab Redefines Outcomes in Early Relapsed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Relapsed or Refractory Multiple Myeloma (RRMM) remains a complex clinical challenge, even as therapeutic options continue to expand. Progressive immune dysfunction, cumulative treatment toxicity, and repeated relapses often limit the durability of benefit with conventional salvage regimens. Moreover, the increasingly effective frontline landscape has raised the bar for second- and later-line therapy, leaving fewer highly active, well-tolerated options for patients early in relapse.

BCMA-directed therapies have transformed expectations in advanced disease, particularly with CAR-T cell approaches demonstrating deep responses and prolonged disease control. However, manufacturing timelines, resource intensity, and patient fitness requirements limit universal access. Consequently, there is a critical need for off-the-shelf, immunotherapy-based regimens that deliver CAR-T–like efficacy with broader applicability.

Teclistamab (TECVAYLI&reg;), a bispecific T-cell engaging antibody targeting CD3 on T cells and BCMA on myeloma cells, has previously shown meaningful and durable responses in heavily pretreated RRMM. Daratumumab (DARZALEX&reg;), an anti-CD38 monoclonal antibody, remains a foundational therapy across all disease stages, offering both direct antimyeloma activity and immune modulation. Preclinical and clinical observations suggest that Daratumumab-mediated depletion of immunosuppressive cellular subsets enhances T-cell fitness, providing a strong biological rationale for combination with BCMA-directed bispecific antibodies.

The MajesTEC-3 trial was designed to test whether combining Teclistamab with Daratumumab could improve outcomes compared with established Daratumumab-based regimens in patients with earlier-line RRMM.

Study Design and Patient Population

MajesTEC-3 (NCT05083169) is an ongoing, randomized, open-label, Phase 3 trial conducted across 150 centers in 20 countries. Eligible patients had relapsed or refractory multiple myeloma after one to three prior lines of therapy, including prior exposure to both an immunomodulatory agent and a proteasome inhibitor. Patients with prior BCMA-directed therapy or anti-CD38–refractory disease were excluded.

A total of 587 patients were randomized 1:1 to receive either:

  • Teclistamab plus subcutaneous Daratumumab, or
  • Investigator’s choice of standard Daratumumab-based therapy, consisting of Daratumumab and Dexamethasone combined with either Pomalidomide (DPd) or Bortezomib (DVd).

Randomization was stratified by choice of control regimen, International Staging System stage, prior exposure to anti-CD38 antibodies, and number of prior treatment lines. The median patient age was approximately 64–65 years, with a median of two prior lines of therapy. Importantly, more than one-third of enrolled patients had high-risk cytogenetic features, reflecting a clinically relevant population.

Treatment Administration: A Patient-Centered, Steroid-Sparing Approach

Patients in the investigational arm received subcutaneous Teclistamab using a step-up dosing strategy, followed by a progressively extended dosing interval, transitioning to monthly administration from cycle 7 onward. Daratumumab was administered subcutaneously according to its approved schedule.

Notably, the regimen became steroid-free after cycle 1, an important quality-of-life consideration for patients requiring long-term therapy. Infection prophylaxis, immunoglobulin supplementation, and monitoring of IgG levels were mandated, with protocol amendments reinforcing best practices for infection prevention during BCMA-directed therapy. The Primary end point was Progression-Free Survival (PFS), as assessed by an Independent Review Committee.

Primary Endpoint: Striking Improvement in Progression-Free Survival

At a median follow-up of 34.5 months, Teclistamab plus Daratumumab demonstrated a highly significant and clinically transformative improvement in PFS compared with DPd or DVd.

  • The estimated 36-month PFS rate was 83.4% with Teclistamab–Daratumumab versus 29.7% with standard Daratumumab-based therapy.
  • This translated into an 83% reduction in the risk of disease progression or death (HR 0.17; 95% CI, 0.12–0.23; P<0.001).
  • The prespecified boundary for superiority was crossed at the first interim analysis.

Importantly, the PFS advantage was consistent across all prespecified and clinically relevant subgroups, including patients with high-risk cytogenetics and those treated in earlier versus later relapse.

Depth and Durability of Response

Beyond delaying progression, Teclistamab–Daratumumab induced exceptionally deep and durable responses:

  • Complete Response or better was achieved in 81.8% of patients receiving the combination, compared with 32.1% in the control arm.
  • Overall Response Rates were also higher (89.0% vs. 75.3%).
  • Rates of Minimal Residual Disease negativity at a sensitivity of 10⁻⁵ were more than threefold higher with Teclistamab–Daratumumab (58.4% vs. 17.1%).

Responses occurred rapidly, with a median time to first response of just over one month, and deepened over time. At three years, nearly 90% of responders in the investigational arm remained in response, suggesting the emergence of a plateau in disease control.

Overall Survival and Symptom Outcomes

Although follow-up for overall survival continues, early analyses favored Teclistamab–Daratumumab, with a high proportion of patients remaining alive beyond two years. Improvements were also observed in time to worsening of myeloma-related symptoms, underscoring the regimen’s clinical and patient-reported benefit.

Safety and Tolerability: Manageable With Established Protocols

The safety profile of Teclistamab–Daratumumab was consistent with the known risks of BCMA-directed bispecific antibodies and Daratumumab. Serious adverse events occurred more frequently in the investigational arm, driven primarily by cytopenias and infections.

  • Cytokine Release Syndrome was common but predominantly low grade and largely confined to the step-up dosing period.
  • Importantly, the incidence of CRS was lower than that reported with Teclistamab monotherapy, supporting a favorable interaction between the two agents.
  • Fatal adverse events were infrequent and decreased following protocol-reinforced infection-prevention strategies.

The trial highlights the critical importance of early immunoglobulin replacement, antimicrobial prophylaxis, and vigilant monitoring, now well established in guidelines for patients receiving BCMA-targeted therapies.

Context Within the Evolving Treatment Landscape

The magnitude of benefit observed with Teclistamab–Daratumumab is particularly notable given the strong performance of the control arm, which exceeded historical expectations from prior DPd and DVd studies. Even in this context, the combination delivered superior depth, durability, and consistency of response. As CAR-T therapies move earlier in the disease course, off-the-shelf immunotherapies such as Teclistamab–Daratumumab offer a complementary strategy, one that combines accessibility, scalability, and sustained disease control. Monthly dosing after the initial treatment phase further supports feasibility in community oncology settings.

Clinical Implications

The MajesTEC-3 trial establishes Teclistamab plus Daratumumab as a highly effective immunotherapy-based option for patients with early relapsed multiple myeloma, delivering unprecedented Progression-Free Survival and deep molecular responses without the logistical barriers of cellular therapy. With appropriate supportive care and infection-prevention strategies, this regimen may meaningfully reset expectations for long-term disease control in a population historically characterized by inevitable relapse.

Conclusion

In patients with multiple myeloma who had received one to three prior lines of therapy, Teclistamab combined with Daratumumab significantly outperformed established Daratumumab-based regimens, offering durable disease control, deep responses, and a manageable safety profile. These findings position Teclistamab–Daratumumab as a potential new standard in earlier-line Relapsed or Refractory Multiple Myeloma, and signal continued progress toward prolonged survival in this traditionally incurable disease.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. Costa LJ,  Bahlis NJ, Perrot A, et al. for the MajesTEC-3 Trial Investigators. N Engl J Med. Published December 9, 2025. DOI: 10.1056/NEJMoa2514663

 

 

 

 

Late Breaking Abstract – ESMO 2025: Advancing First-Line Therapy in High-Risk NMIBC: Final Results from the Phase III POTOMAC Trial

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SUMMARY: The American Cancer Society estimates that 84,870 new cases of bladder cancer will be diagnosed in 2025 and 17,420 will die of the disease. Bladder cancer is the fourth most common cancer in men but is less common in women and the average age at the time of diagnosis is 73 years. Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Persistent Unmet Need in BCG-Naïve High-Risk NMIBC

High-risk Non–Muscle-Invasive Bladder Cancer (NMIBC) remains a clinically challenging disease despite decades of experience with intravesical Bacillus Calmette-Guérin (BCG). Standard management consists of complete TransUrethral Resection of Bladder Tumor (TURBT) followed by BCG induction and maintenance, However, up to 40% of patients experience early recurrence or progression within two years. For those with high-risk recurrence, radical cystectomy is frequently recommended, an intervention associated with substantial morbidity and quality-of-life implications. These limitations have driven interest in immunotherapy-based strategies aimed at improving disease control earlier in the treatment course and potentially delaying or avoiding radical surgery.

Rationale for Combining PD-L1 Blockade with BCG

Durvalumab (IMFINZI&reg;), a monoclonal antibody targeting Programmed Death-Ligand 1 (PD-L1), has demonstrated clinically meaningful benefit in bladder cancer, most notably in the perioperative setting for muscle-invasive disease. Biologic rationale for combining immune checkpoint inhibition with BCG includes immune priming within the bladder microenvironment and the observation that PD-L1 expression may increase with disease progression or BCG resistance. Introducing checkpoint blockade earlier, before immune escape is fully established, may therefore enhance the durability of response to BCG.

POTOMAC Trial Design and Patient Population

POTOMAC (NCT03528694) was a global, randomized, open-label Phase III trial evaluating whether adding Durvalumab to standard BCG therapy improves outcomes in patients with BCG-naïve, high-risk NMIBC. A total of 1,018 patients from more than 120 centers across 12 countries were randomized 1:1:1 following TURBT to one of three treatment arms:

  • Durvalumab plus BCG induction and maintenance (N=339)
  • Durvalumab plus BCG induction alone (N=339)
  • BCG induction and maintenance alone (control– N=340)

Durvalumab was administered at 1,500 mg IV every four weeks for 13 cycles (one year), while intravesical BCG induction therapy was weekly for 6 weeks and maintenance therapy consisted of three doses at weekly intervals at 3, 6, 12, 18, and 24 months. Patients were stratified by Carcinoma in Situ (CIS) and higher-risk papillary disease. The Primary endpoint was investigator-assessed Disease-Free Survival (DFS) comparing Durvalumab plus BCG induction and maintenance versus BCG alone.

Durable Improvement in Disease-Free Survival

At a median follow-up of 60.7 months, POTOMAC met its primary endpoint. The addition of one year of Durvalumab to BCG induction and maintenance resulted in a 32% reduction in the risk of high-risk disease recurrence or death compared with BCG alone (HR=0.68; P=0.015). Disease-free survival curves separated early and remained consistently apart over time, underscoring both early and sustained benefit. The median DFS was not reached in either arm. Importantly, Durvalumab combined with BCG induction alone, without maintenance BCG, did not improve outcomes, reinforcing the central role of adequate BCG exposure in disease control.

Overall Survival and Long-Term Follow-Up

Although the study was not powered to detect Overall Survival differences, extended follow-up showed no evidence of harm associated with Durvalumab. Descriptive analyses suggested numerically favorable survival outcomes with the combination regimen, providing reassurance regarding long-term safety in this curative-intent population.

Safety Profile and Treatment Tolerability

The safety profile of Durvalumab plus BCG was consistent with the known toxicities of each agent. Grade 3 or 4 treatment-related adverse events occurred more frequently with combination therapy than with BCG alone, but these events were generally manageable. No treatment-related deaths were reported. Common adverse effects reflected expected urinary and immune-related events, supporting the feasibility of integrating systemic immunotherapy into NMIBC management.

Context within the Evolving NMIBC Landscape

POTOMAC represents one of the longest follow-up datasets evaluating immune checkpoint inhibition in NMIBC and adds to a growing body of evidence supporting this strategy. Together with prior positive trials exploring PD-1/PD-L1 inhibitors alongside BCG, the data suggest that immune checkpoint blockade can meaningfully augment standard therapy when combined with full-course BCG. Differences among trials highlight the importance of patient selection, adequate maintenance therapy, and sufficient duration of treatment exposure.

Clinical Implications for Practice

The POTOMAC findings reinforce several key principles for clinicians:

  • Maintenance BCG remains essential and should not be replaced by systemic immunotherapy alone
  • Early integration of immune checkpoint blockade can improve disease control in carefully selected high-risk patients
  • Long-term follow-up matters, particularly in NMIBC where durable bladder preservation is a primary goal

Conclusion

For patients with BCG-naïve, high-risk NMIBC, the addition of one year of Durvalumab to standard BCG induction and maintenance delivers a statistically significant and clinically meaningful improvement in Disease-Free Survival with a manageable safety profile. POTOMAC raises the bar for first-line NMIBC therapy and positions combined systemic and intravesical immunotherapy as a compelling new option for this high-risk population.

Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial. De Santis M, Redorta JP, Nishiyama H, et al. The Lancet. 2025;406:2221-2234.

Durvalumab + FLOT Establishes New Benchmark in Curative-Intent Therapy for Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 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 gastric cancer. Additionally, one of the strongest risk factors for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI&reg;) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group.

In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates as well as Major Pathological Response, suggesting more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

The final Overall Survival results from the MATTERHORN trial were presented at the ESMO Congress 2025. In this definitive analysis, perioperative Durvalumab added to FLOT chemotherapy delivered a statistically significant and clinically meaningful survival advantage over placebo plus FLOT (HR=0.78; 95% CI, 0.63–0.96; P=0.021). Notably, the OS benefit was observed across PD-L1 expression levels, with comparable hazard ratios in both the TAP <1% and TAP ≥1% subgroups, suggesting that the activity of Durvalumab in the perioperative setting is not restricted to PD-L1–positive disease.

Durvalumab also enhanced pathological response metrics. Patients treated with Durvalumab achieved substantially higher nodal negativity rates (ypN0, 58.2% vs 44.8%), indicating deeper locoregional tumor clearance and supporting the biologic premise that checkpoint inhibition can potentiate chemotherapy-mediated cytoreduction. Improvements in Event-Free Survival were consistent across the spectrum of pathological response categories including partial, major, and complete responders, highlighting that meaningful clinical benefit extends beyond patients achieving ypCR.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite Instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications

The MATTERHORN findings reinforce that integrating Durvalumab into the perioperative FLOT regimen confers durable improvements in both Overall and Event-Free Survival for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. Importantly, the magnitude of benefit remained stable across key clinical and biological subgroups, including PD-L1 status and nodal involvement, underscoring the robustness and generalizability of the treatment effect.

Combined with the earlier JCO publication detailing significant gains in Event-Free Survival, these results strengthen the rationale for incorporating immunotherapy into curative-intent treatment pathways for early-stage upper gastrointestinal cancers. Durvalumab + FLOT is poised to emerge as a new global standard of care, reflecting the broader paradigm shift toward perioperative immune-checkpoint blockade in resectable solid tumors.

Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Tabernero J, Al-Batran, Wainberg ZA, et al. LBA81- Presented at ESMO Congress 2025, Berlin.

FDA Approves LIBTAYO® for Adjuvant Treatment of Cutaneous Squamous Cell Carcinoma

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SUMMARY: The FDA on October 8, 2025 approved Cemiplimab-rwlc (LIBTAYO®) for the adjuvant treatment of adults with Cutaneous Squamous Cell Carcinoma (CSCC) at high risk of recurrence after surgery and radiation.

Cutaneous Squamous Cell Carcinoma (CSCC) is the second most common skin cancer worldwide, with an estimated 2.4 million new cases annually. While surgery with or without adjuvant radiotherapy achieves cure in the vast majority of patients, approximately 5% experience locoregional or distant recurrence. Patients with high-risk features, such as nodal involvement, perineural invasion, or locally recurrent disease, remain particularly vulnerable to relapse following definitive local therapy.

Previous efforts to improve outcomes through systemic adjuvant approaches have been largely unsuccessful. Notably, the POST/TROG 05.01 trial demonstrated no additional benefit of adjuvant Carboplatin-based chemoradiation over radiotherapy alone, underscoring the unmet need for effective systemic adjuvant strategies in this population.

Trial Design

The C-POST (NCT03969004) is an ongoing, international, randomized Phase 3 study evaluating whether adjuvant immunotherapy with Cemiplimab, a PD-1 inhibitor previously approved for advanced and metastatic CSCC, could reduce recurrence risk following surgery and postoperative radiotherapy in patients with high-risk disease. A total of 415 patients were randomized 1:1 to receive Cemiplimab-rwlc or placebo after completing adjuvant radiation therapy (within 2–10 weeks before randomization). Eligible patients had either nodal high-risk features (e.g., extracapsular extension or 3 or more positive nodes) or non-nodal features (e.g., T4 tumors with bone invasion, in-transit metastases, perineural invasion, or locally recurrent tumors with additional risk factors). Cemiplimab was administered intravenously at 350 mg IV every 3 weeks for 12 weeks, then 700 mg every 6 weeks for up to 36 additional weeks (total of 48 weeks or less). The Primary endpoint was Disease-Free Survival (DFS). Secondary endpoints included freedom from locoregional and distant recurrence, Overall Survival (OS), and safety.

Efficacy Results

After a median follow-up of 24 months, Cemiplimab demonstrated a substantial DFS benefit over placebo.

  • Events: 24 with Cemiplimab vs. 65 with placebo
  • Hazard Ratio for disease recurrence or death: 0.32 (95% CI, 0.20–0.51; P<0.001)
  • Estimated 24-month DFS: 87.1% (95% CI, 80.3–91.6) vs. 64.1% (95% CI, 55.9–71.1)

The Kaplan–Meier curves separated early and remained distinctly apart over time, indicating both a rapid and durable treatment benefit.

Patterns of Recurrence

Cemiplimab significantly reduced both locoregional and distant recurrences:

  • Freedom from locoregional recurrence at 24 months: 94.6% vs. 76.7% (HR=0.20; 95% CI, 0.09–0.40)
  • Freedom from distant recurrence at 24 months: 94.3% vs. 83.8% (HR=0.35; 95% CI, 0.17–0.72)

The benefit was observed consistently across prespecified subgroups, including those stratified by PD-L1 tumor expression (<1% or ≥1%).

Safety Profile

Adverse events (AEs) of grade ≥3 occurred in 23.9% of Cemiplimab-treated patients compared with 14.2% in the placebo group. Treatment discontinuation due to AEs occurred in 9.8% versus 1.5%, respectively. The overall safety profile was consistent with known Cemiplimab toxicities, and quality-of-life scores remained largely stable throughout treatment. One treatment-related death was reported.

At the time of analysis, Overall Survival (OS) data were immature, with 25 deaths reported (12 in the Cemiplimab group, 13 in placebo). The 2-year OS was 94.8% vs. 92.3% (HR, 0.86; 95% CI, 0.39–1.90). Subsequent analyses will clarify whether the DFS advantage translates into a survival benefit.

Clinical Implications

The C-POST trial establishes adjuvant Cemiplimab as the first systemic therapy to significantly improve DFS in patients with high-risk CSCC following curative-intent surgery and radiotherapy. The 68% reduction in recurrence or death risk, coupled with a manageable safety profile, positions Cemiplimab as a potential new standard of care for this challenging population.

Notably, most recurrences occurred within the first year after local therapy, mirroring the known natural history of CSCC, and Cemiplimab’s early and sustained benefit suggests a durable immune-mediated effect.

While OS data are pending, these findings mark a major advance in the adjuvant management of high-risk CSCC. The results also stand in contrast to the KEYNOTE-630 trial of adjuvant Pembrolizumab, which was discontinued for futility, highlighting possible differences in trial design or patient selection.

Conclusion

Adjuvant therapy with Cemiplimab significantly prolongs Disease-Free Survival compared with placebo in patients with high-risk Cutaneous Squamous Cell Carcinoma after surgery and radiotherapy. The 24-month DFS benefit, 87% versus 64%, represents a meaningful reduction in recurrence risk and provides clinicians with the first evidence-based systemic option in this setting. Ongoing follow-up will determine the ultimate impact on Overall Survival.

Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. Rischin D, Porceddu S, Day F, et al. for the C-POST Trial Investigators. N Engl J Med 2025;393:774-785

FDA Approves ZEPZELCA® Plus TECENTRIQ® for First-Line Maintenance in Extensive-Stage Small Cell Lung Cancer

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SUMMARY: The FDA on October 2, 2025, approved Lurbinectedin (ZEPZELCA®)  in combination with Atezolizumab (TECENTRIQ®) or Atezolizumab and hyaluronidase-tqjs (TECENTRIQ HYBREZA®), for the maintenance treatment of adult patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with Atezolizumab or Atezolizumab and hyaluronidase-tqjs, Carboplatin, and Etoposide.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 10-15% of all lung cancers diagnosed annually in the US. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. While initial responses to chemotherapy are often dramatic, relapse occurs in most patients, and recurrent disease typically demonstrates resistance to previously effective regimens. Consequently, extending response durability through maintenance therapy remains a key therapeutic goal.

Lurbinectedin is a selective alkylating agent that binds to guanine residues within DNA, leading to inhibition of oncogenic transcription factors and impairment of DNA repair pathways. This disrupts the cell cycle and induces tumor cell death.
Atezolizumab is a monoclonal antibody targeting Programmed Death-Ligand 1 (PD-L1), blocking its interaction with PD-1 and B7.1 receptors. By inhibiting PD-L1–mediated immune evasion, Atezolizumab restores anti-tumor T-cell activity and enhances immune-mediated tumor elimination.

The IMforte Trial: Study Design

The IMforte Trial is a global, open-label, randomized Phase III study (NCT05091567) conducted to evaluate the efficacy and safety of Lurbinectedin plus Atezolizumab as first-line maintenance therapy for adults with Extensive-Stage SCLC (ES-SCLC). In this study, a total of 660 treatment-naïve patients received induction therapy with Atezolizumab, Carboplatin, and Etoposide for four 21-day cycles. Of these, 483 patients without disease progression were randomized 1:1 to receive either:

  • Lurbinectedin 3.2 mg/m² IV every 3 weeks with G-CSF prophylaxis plus Atezolizumab 1200 mg IV every 3 weeks, or
  • Atezolizumab alone 1200 mg IV every 3 weeks

Treatment was continued until disease progression, unacceptable toxicity, or withdrawal. Stratification factors included baseline liver metastases, ECOG performance status, LDH levels, and receipt of prophylactic cranial irradiation. The Primary endpoints were Independent Review Facility (IRF)–assessed Progression-Free Survival (PFS) and Overall Survival (OS) from the start of maintenance therapy.

Efficacy Outcomes

After a median follow-up of 15 months, the IMforte study achieved both of its Primary endpoints:

  • Median PFS: 5.4 months with Lurbinectedin plus Atezolizumab vs 2.1 months with Atezolizumab alone (HR=0.54; 95% CI: 0.43–0.67; P<0.0001)
  • Median OS: 13.2 months vs 10.6 months, respectively (HR=0.73; 95% CI: 0.57–0.95; P=0.0174)

These outcomes reflect a 46% reduction in the risk of disease progression or death and a 27% reduction in the risk of death with the combination regimen. Median maintenance treatment duration was 4.1 months for the combination arm and 2.1 months for the monotherapy arm.

Safety and Tolerability

The combination of Lurbinectedin and Atezolizumab demonstrated a manageable safety profile with no new safety signals.

  • Any-grade treatment-related adverse events (TRAEs):5% (combo) vs 40.0% (monotherapy)
  • Grade 3–4 TRAEs: 25.6% vs 5.8%
  • Grade 5 TRAEs: 0.8% vs 0.4%

The most common adverse reactions (≥30%) were lymphopenia, thrombocytopenia, anemia, leukopenia, neutropenia, nausea, and fatigue/asthenia. Discontinuations due to adverse events occurred in 6.2% and 3.3% of patients, respectively.

Clinical Interpretation

IMforte is the first global Phase III study to demonstrate significant improvement in both PFS and OS with a first-line maintenance approach in ES-SCLC. By integrating the DNA-damaging activity of Lurbinectedin with the immune reactivation potential of PD-L1 blockade, the combination offers a dual mechanism to counter both tumor proliferation and immune evasion. These results establish Lurbinectedin plus Atezolizumab as a new standard maintenance option for patients whose disease remains controlled after induction chemoimmunotherapy, an important milestone in a disease where long-term survival has historically been rare.

Key Takeaways for Oncology Practice

  • Unmet Need: SCLC remains an aggressive malignancy with limited long-term treatment options.
  • Clinical Significance: IMforte is the first Phase III trial to demonstrate both OS and PFS gains with a first-line maintenance regimen in ES-SCLC.
  • Mechanistic Synergy: Combines DNA-targeted cytotoxic activity (Lurbinectedin) with PD-L1 blockade (Atezolizumab) for enhanced and durable tumor control.
  • Practice Impact: Establishes Lurbinectedin plus Atezolizumab as an FDA-approved maintenance option for patients with ES-SCLC who respond to induction chemoimmunotherapy.
  • Safety: Manageable toxicity profile; regular hematologic and clinical monitoring recommended.

Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Paz-Ares L, Borghaei H, Liu SV, et al. The Lancet 2025;405:2129-2143.