Author: RR

HER2DX Genomic Assay Predicts Pathological Response in Early Stage HER2-Positive Breast Cancer

RR

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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence.

The HER or ERBB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes.

HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. PERJETA® (Pertuzumab) is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors, ie., HER3, HER1 and HER4. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways, which has been attributed to differing mechanisms of action and synergistic interaction.

In the NeoSphere Phase II trial, among patients with locally advanced, inflammatory, or early HER2-positive breast cancer, the addition of Pertuzumab to Trastuzumab and Docetaxel led to a statistically significant and clinically meaningful 16.8% increase in pathologic Complete Response rate (pCR) in the breast and a 17.8% increase in total pCR in the breast and axilla. Further, the addition of one year of Pertuzumab to Trastuzumab-based chemotherapy improved invasive Disease Free Survival, but this benefit was restricted to patients with node-positive disease and no Overall Survival benefit was observed. The benefits of Pertuzumab in early-stage HER2-positive disease were modest. Biomarkers beyond HER2 status are therefore needed, to guide the use of Pertuzumab in the treatment of early-stage HER2-positive breast cancer.

HER2DX (Reveal Genomics) is a novel clinically available genomic test that measures the expression of 27 genes from Formalin-Fixed, Paraffin-Embedded (FFPE) breast cancer tissues. This assay integrates biologic information such as Immune infiltration, luminal differentiation, tumor cell proliferation and HER2 amplicon expression from 4 gene signatures, with clinical data such as tumor stage and nodal stage.

The present study was conducted to determine if the use of HER2DX genomic assay in pretreatment baseline tissue samples of patients with early-stage ERBB2-positive breast cancer, predicted response to neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab. This analysis is a retrospective, multicenter, observational study conducted in Spain from 2018 to 2022. In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts, with results from the assay (DAPHNe and I-SPY2) was performed. All patients had Stage I-III ERBB2 (HER2) positive breast cancer, and clinical T1- T2 and node-positive disease was present in 72.9% and 63.9% patients, respectively, and 67.7% tumors were hormone receptor positive. The mean age was 50 years and all patients had Formalin-Fixed Paraffin-Embedded tumor specimens available prior to starting therapy. Patients received Trastuzumab, 8 mg/kg IV as a loading dose, followed by 6 mg/kg IV every 3 weeks in combination with Docetaxel, 75 mg/m2 IV every 3 weeks and Carboplatin AUC of 6 IV every 3 weeks for 6 cycles, or this regimen plus Pertuzumab, 840 mg IV as a loading dose, followed by an 420 mg IV every 3 weeks for 6 cycles. HER2DX genomic assay was evaluated in 155 patients with ERBB2-positive breast cancer. The main outcome measures were the association of baseline assay-reported pathologic Complete Response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to Pertuzumab.

The overall pCR rate was 57.4%. The assay-reported pathologic Complete Response (pCR) score showed statistically significant association with pCR in the breast and axilla following Trastuzumab-based chemotherapy independent of Pertuzumab use. The pCR rates in the breast and axilla in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (Odds Ratio=7.85; P<0.001). In the combined analysis of DAPHNe and I-SPY2 trials (N=282), assay-reported pCR-high tumors had an increase in pCR rate in the breast and axilla with the use of Pertuzumab (Odds Ratio=5.36; P<0.001), and this benefit was not seen in the assay-reported pCR-low tumors (Odds Ratio=0.86; P=0.77). A statistically significant interaction was observed between the assay-reported pCR score and the effect of Pertuzumab on pCR in the breast and axilla.

It was concluded that HER2DX genomic assay provides clinically meaningful information to guide therapeutic decisions, and can predict pCR following neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab, independent of known clinical-pathological variables and intrinsic subtype. This assay could guide therapeutic decisions regarding the use of neoadjuvant Pertuzumab and can reliably identify patients who might be ideal candidates for neoadjuvant taxane, Trastuzumab and Pertuzumab.

Assessment of a Genomic Assay in Patients With ERBB2-Positive Breast Cancer Following Neoadjuvant Trastuzumab-Based Chemotherapy With or Without Pertuzumab. Bueno-Muiño C, Echavarría I, López-Tarruella S, et al. JAMA Oncol. Published online April 27, 2023. doi:10.1001/jamaoncol.2023.0187

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline

RR

SUMMARY: The American Society for Radiation Oncology (ASTRO) and European Society for Radiotherapy and Oncology (ESTRO) convened a task force to review evidence and provide recommendations on the use of local therapy in the management of extracranial oligometastatic Non Small Cell Lung Cancer (NSCLC). Local therapy is defined as definitive comprehensive treatment of all known cancer (primary tumor, regional nodal metastases, and metastases). This joint guideline by ASTRO and ESTRO addressed 5 important questions focused on the use of local (radiation, surgery, other ablative methods) and systemic therapy in the management of oligometastatic NSCLC. The questions addressed clinical scenarios for using local therapy, sequencing and timing when integrating local with systemic therapies, radiation techniques critical for oligometastatic disease targeting and treatment delivery, and the role of local therapy for oligoprogression or recurrent disease.

Oligorecurrence refers to the general growth of limited numbers of metastatic deposits in patients off systemic therapy. For patients with oligometastates receiving active systemic treatment, they are considered as having oligoprogressive disease if current imaging establishes progression of disease in a limited number of existing and/or new sites, and oligopersistent disease if current imaging establishes stable disease or partial response to therapy, of the existing limited disease. The following recommendations were based on a systematic literature review, and created using ASTRO guidelines methodology. These recommendations focus on the management of extracranial disease with local therapy. This guideline and its recommendations with respect to the multimodally treatment strategy do not differentiate between patients with and without brain metastases.

Key Questions and Recommendations
What are the optimal patient/disease characteristics to select patients with oligometastatic NSCLC for definitive treatment combining systemic and local therapies?
1. Treatment decisions should be made using a patient-centered multidisciplinary team approach.
2. The integration of definitive local therapy is only recommended if technically feasible and clinically safe for all disease sites.
3. A discussion of definitive local therapy as a component of multimodality treatment approach is recommended irrespective of presence of activating driver mutations.
4. Definitive local therapy is recommended only for patients having up to 5 distant metastases, diagnosed with appropriate imaging. Implementation remark: Despite some prospective trials including patients with up to 5 extracranial metastases, most patients enrolled had 1-2 treated oligometastatic lesions, which should be factored into decision-making.
5. For patients with synchronous oligometastatic NSCLC, definitive local therapy to all cancer sites in addition to standard of care systemic therapy is conditionally recommended.
6. For patients with metachronous oligorecurrent NSCLC, definitive local therapy to all oligorecurrent cancer sites in addition to standard of care systemic therapy is conditionally recommended.
7. For patients with induced oligopersistent NSCLC, definitive local therapy to all persistent cancer sites in addition to standard of care systemic therapy is conditionally recommended.
8. For patients with induced oligoprogressive NSCLC receiving systemic therapy, definitive local therapy to all progressive cancer sites is conditionally recommended while continuing the current line of systemic therapy.

What are the selection criteria for choice of local treatment modality in the management of patients with oligometastatic NSCLC?
1. A patient-centered multidisciplinary discussion of the most appropriate local treatment strategy of RT and/or surgery, either alone or in combination, is recommended.
2. RT and/or surgery are recommended as definitive local treatment modalities for the locoregional primary and all oligometastases.
3. Highly conformal RT approaches and minimally invasive techniques for surgery are recommended to minimize morbidity.
4. Deciding between RT and surgery as the definitive local treatment modality should a) Favor RT when multiple organ systems are being treated b) Favor RT when the clinical prioritization is to minimize breaks from systemic therapy c) Favor surgery when large tissue sampling is needed for molecular testing, to guide systemic therapy.

What are the appropriate sequencing and timing of systemic therapy and definitive local therapies for patients with oligometastatic NSCLC?
1. For patients with synchronous oligometastatic NSCLC, 3 months or more of systemic therapy is recommended prior to definitive local therapy.
2. For patients with oligometastatic NSCLC, up-front definitive local treatment for symptomatic lesions should be prioritized. Implementation remark: Symptomatic disease sites (eg, brain metastases) are treated with up-front definitive local therapy.
3. For patients with synchronous oligometastatic NSCLC, the temporary pause of systemic therapy during definitive local therapy versus concomitant treatment should be discussed using a multidisciplinary team approach.
4. For patients with synchronous oligometastatic NSCLC, maintenance systemic therapy is conditionally recommended after completion of definitive local therapy.

What are the optimal dose-fractionation regimens, planning, and delivery technique of RT for patients with oligometastatic NSCLC?
1. Appropriate staging with FDG PET, cranial MRI, and MRI in cases of suspect or proven spine or liver metastases are recommended.
2. Individual assessment of respiratory motion for targets in the lungs and upper abdomen using 4-D CT, fluoroscopy, or MR-cine with appropriate motion compensation is recommended.
3. Highly conformal RT using inverse dose planning, appropriate motion management strategies and image-guided RT delivery are recommended.
4. A risk adapted approach using stereotactic RT (preferred), hypofractionated RT, or alternatively definitive chemoradiation based on the location and burden of disease is recommended.
5. Definitive local RT should use doses and fractionations which achieve durable local control.
Implementation remarks: a) Durable local control defined as minimum 85% local control at 2 years b) Higher BED10 (typically >75 Gy) with SBRT alone is associated with optimal local control c) Lower BED10 (50-75 Gy range) is associated with acceptable local control, typically in the setting of combination systemic therapy and SBRT.

After a definitive local therapy approach for oligometastatic NSCLC, what are the indications for additional local therapy upon disease progression?
1. Systemic therapy is recommended as the preferred treatment option.
2. Additional local therapy should be discussed using a multidisciplinary team approach.
3. Local therapy is conditionally recommended.
4. In patients previously treated with definitive local therapy for oligometastatic NSCLC who subsequently develop repeat oligoprogression or recurrence at sites previously treated with local therapy, re-treatment is conditionally recommended if systemic treatment options are limited, and local therapy can be delivered with toxicity acceptable to the multidisciplinary team and patient.

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline. Iyengar P, All S, Berry MF, et al. Published:April 25, 2023. https://doi.org/10.1016/j.prro.2023.04.004

ORSERDU® for ESR-1 Mutated Advanced Breast Cancer

RR

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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. In a previously published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%). It is estimated that 40% of ER-positive, HER2-negative advanced or metastatic breast cancer patients have tumors that harbor ESR1 mutations. It is best to test for ESR1 mutations with a liquid biopsy following progression on an AI and CDK 4/6 inhibitor.

Fulvestrant (FASLODEX®) is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.

ORSERDU® (Elacestrant) is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by ORSERDU® in the HR-positive xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, ORSERDU® was noted to have an acceptable safety profile and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with HR-positive metastatic breast cancer.

EMERALD trial is a multicenter, International, randomized, open-label, Phase III study, designed to evaluate the benefit of ORSERDU® in patients with ER+/HER2- advanced or metastatic breast cancer. In this study, 478 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either ORSERDU® 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=239). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain. In the study, 48% (N=228) had tumors with mutated ESR1 and 43% received two prior endocrine therapies. These patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.

This study met both co-Primary endpoints and treatment with ORSERDU® resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care treatment. In the group of patients whose tumors had ESR1 mutations, the median PFS was 3.8 months in the ORSERDU® group and 1.9 months in the Standard of Care group (HR=0.55; P=0.0005), reducing the risk of progression or death by 45%. A post-hoc analysis of the PFS results based on the duration of prior CDK4/6 inhibitors usage was presented at San Antonio Breast Cancer Symposium (SABCS) in December 2022. The median PFS was 8.6 months in the ORSERDU® group versus 1.9 months in the Standard of Care group, in those patients whose tumors harbored ESR1 mutations and had been treated with a CDK4/6 inhibitors for at least 12 months.

It can be concluded from this study that ORSERDU® is the first oral Selective Estrogen Receptor Degrader for ER-positive, HER2-negative advanced breast cancer patients with ESR1 mutations, and offers a novel therapeutic option for this patient group.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Bidard F-C, Kaklamani VG, Neven P, et al. J Clin Oncol, 1;40(28):3246-3256. DOI:10.1200/JCO.22.00338.

 

BRUKINSA® for First Line Treatment of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

RR

SUMMARY: The American Cancer Society estimates that for 2023, about 18,740 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4490 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.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling.

Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with Ibrutinib (IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

SEQUOIA is a randomized, multicenter, global Phase III trial, designed to evaluate the efficacy and safety of BRUKINSA® compared to Bendamustine plus Rituximab in patients with treatment naïve CLL or SLL. This trial consists of three cohorts:
Cohort 1 (N=479): Patients NOT harboring del(17p) were randomized 1:1 to receive BRUKINSA® (N=241) or Bendamustine plus Rituximab (N=238) until disease progression or unacceptable toxicity. Patients with del(17p) were not randomized to Bendamustine plus Rituximab, as they experience poor clinical outcomes and poor response to chemoimmunotherapy. Data from this group comprise the Primary endpoint
Cohort 2 (N=110): Patients WITH del(17p) received BRUKINSA® as a monotherapy.
Cohort 3 (enrollment ongoing): Patients WITH del(17p) or pathogenic TP53 variant receiving BRUKINSA® in combination with Venetoclax.

Treatment in Cohort 1 consisted of BRUKINSA® 160 mg orally twice daily as 28-day cycles or Bendamustine 90 mg/m2 IV on Days 1 and 2 for six cycles plus Rituximab 375 mg/m2 IV, the day before or on Day 1 of Cycle 1, and 500 mg/m2 IV on Day 1 of Cycles 2-6. Both treatment groups were well balanced, with more than 50% with unmutated IGHV gene and 18% with del(11q) in each group. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria, were 65 years or older, or 18 years or older with comorbidities, WITHOUT del(17p), and had an ECOG PS of 0-2. The Primary endpoint of the SEQUOIA trial was Progression Free Survival (PFS) per Independent Review Committee (IRC) assessment in the randomized Cohort 1 group of patients. Secondary endpoints included Overall Response Rates (ORR), Overall Survival (OS) and Safety.

At the interim analysis, with a median follow-up of 26.2 months, BRUKINSA demonstrated superiority in PFS over Bendamustine plus Rituximab. The median PFS was Not Reached in the BRUKINSA® group and was 33.7 months in the Bendamustine plus Rituximab group. The 24-month PFS rate was 85.5% in the BRUKINSA® group, compared to 69.5% in in the Bendamustine plus Rituximab group (HR=0.42; P<0.0001). This PFS benefit was consistently observed across key patient subgroups, including patients with del(11q), unmutated IGHV status, Binet Stage C, and bulky disease.

In a separate non-randomized group of patients in Cohort 2 of SEQUOIA trial, BRUKINSA® monotherapy was evaluated in 110 patients with previously untreated CLL/SLL, WITH 17p deletion. The Overall Response Rate (ORR) per IRC was 88% and the median Duration of Response (DOR) was not reached after a median follow-up of 25.1 months. The 18-month PFS in this group was 90.6%. Across clinical trials of BRUKINSA® the most common adverse events were neutropenia, upper respiratory tract infection, thrombocytopenia, hemorrhage, and musculoskeletal pain. Atrial fibrillation or flutter were reported in 3.7% of patients.

The researchers from this study concluded that BRUKINSA® significantly improved Progression Free Survival compared to Bendamustine plus Rituximab, in patients with untreated CLL and SLL with an acceptable safety profile, like what has been reported in other BRUKINSA® clinical trials, with consistently low rates of atrial fibrillation. They added that BRUKINSA® as a highly selective BTK inhibitor, can potentially provide a chemo-free treatment option for CLL patients.

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Tam CS, Brown JR, Kahl BS, et al. The Lancet Oncology 2022;23:1031-1043

FDA Approves POLIVY® for Untreated Diffuse Large B-Cell Lymphoma

RR

SUMMARY: The FDA on April 19, 2023, approved Polatuzumab vedotin-piiq (POLIVY®) with a Rituximab product, Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) for adult patients who have previously untreated Diffuse Large B-Cell Lymphoma (DLBCL), not otherwise specified (NOS), or High-Grade B-Cell Lymphoma (HGBL) and who have an International Prognostic Index (IPI) score of 2 or greater.

The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

CD79b is a B-cell specific surface protein, which is a component of the B-cell receptor and is ubiquitously expressed on the surface of malignant B cells. POLIVY® (Polatuzumab vedotin) is a CD79b-directed Antibody-Drug Conjugate (ADC) with activity against dividing B cells. It consists of three components: 1) the humanized ImmunoGlobulin G1 (IgG1) monoclonal antibody specific for human CD79b; 2) the small molecule anti-mitotic agent MMAE (monomethyl auristatin E) and 3) a protease-cleavable linker that covalently attaches MMAE to the Polatuzumab antibody. Upon binding to CD79b, POLIVY® is internalized, and the linker is cleaved by lysosomal proteases thus enabling intracellular delivery of MMAE. MMAE then binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis. POLIVY® demonstrated efficacy in patients with Relapsed or Refractory DLBCL, resulting in significantly longer Overall Survival when combined with Bendamustine and Rituximab, compared to Bendamustine and Rituximab alone. Based on these finding, the FDA granted accelerated approval to POLIVY® in June 2019.

In a Phase Ib-II study POLIVY® in combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) resulted in a 89% Overall Response rate and 77% Complete Responses when given as first line therapy, in patients with DLBCL. In this study, Vincristine was excluded from the regimen owing to the risk of overlapping neurotoxicities with POLIVY®. The present POLARIX trial was conducted to evaluate the efficacy and safety of pola-R-CHP as compared with R-CHOP, in patients with previously untreated DLBCL.

The POLARIX is a randomized, double-blind, placebo-controlled, International Phase III trial in which a total of 879 treatment naïve, CD20-positive, intermediate or high-risk DLBCL patients were randomly assigned in a 1:1 ratio to receive 6 cycles of either pola-R-CHP (N=440) or R-CHOP (N=439). Patients on Day 1 of each 21 day cycle, received POLIVY® 1.8 mg/kg IV and a placebo matching Vincristine IV (pola-R-CHP group) or a placebo matching POLIVY® and intravenous Vincristine at a dose of 1.4 mg/m2 (maximum of 2 mg) (R-CHOP group), along with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV and Doxorubicin 50 mg/m2 IV. All the patients also received Prednisone 100 mg orally once daily on Days 1-5 of each of the first six cycles. During cycles 7 and 8, patients in both treatment groups received Rituximab monotherapy at 375 mg/m2 IV. The median patient age was 65 years and stratification was based on IPI score and presence or absence of bulky disease, Subtypes of DLBCL were centrally evaluated and were balanced between the two treatment groups. Patients were eligible regardless of the Cell of Origin or the presence of rearrangements in MYC, BCL2, BCL6, or a combination of these. Approximately 84% of patients had de novo DLBCL, NOS and 11% had high grade B-Cell Lymphoma. Patients with known CNS involvement were excluded but CNS prophylaxis with intrathecal chemotherapy was permitted, in accordance with institutional practice guidelines. The use of Granulocyte Colony-Stimulating Factor (G-CSF) was required during the first six cycles of treatment for primary prophylaxis against neutropenia, and consolidative radiotherapy to initial sites of bulky disease or extranodal sites was allowed at the discretion of the investigator. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS) and Safety.

At a median follow up of 28.2 months, the PFS was significantly higher in the pola-R-CHP group compared to the R-CHOP group. The PFS at 2 years was 76.7% in the pola-R-CHP group versus 70.2% in the R-CHOP group (stratified HR=0.73; P=0.02). Treatment with pola-R-CHP resulted in a risk of disease progression, relapse, or death that was 27% lower, compared to R-CHOP. Patient subgroups that did not show a clear benefit with pola-R-CHP included patients 60 years of age or younger, patients with the Germinal Center B-cell-like subtype of DLBCL, patients who had bulky disease, and patients who had lower IPI scores. Overall Survival at 2 years did not differ significantly between the treatment groups and the researchers attributed the lack of a significant difference between the two groups in Overall Survival, to the availability of new, effective treatments for relapsed or refractory DLBCL, as well as short duration of follow up at the time of this reporting. The safety profile was similar in the two treatment groups.

The authors concluded that among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP.

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Tilly H, Morschhauser F, Sehn LH, et al. N Engl J Med 2022; 386:351-363.

Pembrolizumab Plus Chemotherapy Improves Overall Survival in Advanced Biliary Tract Cancer

RR

SUMMARY: Bile Tract cancer (Cholangiocarcinoma) is a rare and highly aggressive heterogenous cancer, and is the second most common type of primary liver cancer after Hepatocellular carcinoma. It comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. It is estimated that approximately 211,000 patients are diagnosed with Biliary Tract cancer and 174,000 patients will die of the disease each year globally. Biliary Tract cancer is most frequently diagnosed in patients between 50 to 70 years old, and 75% of patients are diagnosed at an advanced stage. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. Patients diagnosed with Biliary Tract cancer have a very poor prognosis, and the 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an urgent unmet need for new effective therapies.

Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by Biliary Tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival has been increasingly explored.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-966 is a multinational, randomized, double-blind, Phase III trial, conducted to determine whether adding the immune checkpoint inhibitor Pembrolizumab to first line standard chemotherapy, would impact survival outcomes in patients with metastatic or unresectable Biliary Tract cancers. In this study, 1069 patients (N=1069) with advanced and/or unresectable Biliary Tract cancers were randomly assigned to receive Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (N=533) or placebo (N=536). Both treatment groups received Gemcitabine 1000 mg/m2 IV on days 1 and 8 every 3 weeks without preset maximum number of cycles, and Cisplatin 25 mg/m2 IV on days 1 and 8 every 3 weeks for up to 8 cycles. The median age was 63.5 years, majority of patients had metastatic disease (88%) and more than half had intrahepatic disease. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response and Safety. The median follow up was 25.6 months.

The median OS was 12.7 months in the Pembrolizumab group and 10.9 months in the placebo group (HR=0.83; P=0.0034). This represented a 17% reduction in the risk of death in the Pembrolizumab group compared to the placebo group. The 12-month OS rate was 52% with the Pembrolizumab regimen versus 44% for chemotherapy alone and the 24-month OS rates were 24.9% versus 18.1%, respectively. The OS results were generally consistent across subgroups.

There was no significant difference in PFS between the treatment groups but there was a trend toward improved PFS with Pembrolizumab. The median PFS was 6.5 months in the Pembrolizumab arm and 5.6 months in the placebo group (HR=0.87; P=0.23). The estimated 12-month PFS was 25% and 20% respectively.The Objective Response Rates were similar between the two treatment groups – 28.7% in the Pembrolizumab group and 28.5% in the placebo arm.The safety profile of Pembrolizumab was consistent with that observed in previously reported studies and Grade 3-4 adverse events were similar between treatment groups.

The authors concluded that KEYNOTE-966 is the largest randomized Phase III trial in advanced Biliary Tract cancers to date, with more patients enrolled from non-Asian countries. First line treatment with Pembrolizumab plus chemotherapy significantly improved Overall Survival, when compared with chemotherapy alone. The researchers added that one of the limitations of this study is that patients with intrahepatic bile duct cancers were overrepresented in the study population compared with the incidence of the disease in the general population, resulting in smaller sample sizes of patients with extrahepatic and gall bladder sites of origin.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial. Kelley RK, Ueno M, Yoo C, et al. Lancet. Published online April 16, 2023. https://doi.org/10.1016/S0140-6736(23)00727-4.

Personalized mRNA Cancer Vaccine in Combination with KEYTRUDA® Improves Relapse Free Survival in Resected High Risk Melanoma

RR

SUMMARY: The American Cancer Society’s estimates that for 2023, about 97,610 new cases of melanoma of the skin will be diagnosed in the United States and 7,990 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma.
Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk resected melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab was 55.4% versus 38.3% with placebo. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab versus 41.2% for ipilimumab. Given the high relapse rates with the present adjuvant melanoma therapies, there is an unmet clinical need.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

mRNA-4157 (V940) is a novel messenger RiboNucleic Acid (mRNA)-based individualized neoantigen therapy consisting of a single synthetic mRNA coding for up to 34 neoantigens, that is designed and produced based on the unique mutational signature of the DNA sequence of the patients tumor. Individualized neoantigen therapies are designed to prime the immune system so that a patient can generate a tailored antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) was designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patient’s tumor. Early clinical studies demonstrated that combining mRNA-4157 (V940) with Pembrolizumab may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.

KEYNOTE-942 is a randomized Phase IIb trial, which assessed the efficacy of mRNA-4157/V940 in prolonging RFS in patients with resected, Stages IIIB/IIIC/IIID and IV melanoma, when given in combination with Pembrolizumab, the standard of care adjuvant therapy in this patient population. This study included 157 patients who were randomly assigned (2:1) to receive mRNA-4157/V940 in combination with Pembrolizumab (107 patients) or Pembrolizumab alone (50 patients). The vaccine was administered every three weeks for a total of nine doses, and Pembrolizumab was given at 200 mg IV every three weeks for up to 18 cycles (approximately one year). All patients had tumor sample (Formalin Fixed Paraffin Embedded-FFPE) available for Next Generation Sequencing and patients were stratified by disease stage. mRNA-4157/V940 was successfully prepared for more than 99% of patients in the combination arm. The median patient age was 62 years and 84% of patient had Stage IIIC disease. Approximately 64% of patients were PD-L1 positive and 74% had high Tumor Mutational Burden-TMB (10 or more mutations/Mb) in the combination treatment group, and 54% were PD-L1 positive and 60% had high TMB in the single agent Pembrolizumab group, respectively. The Primary endpoint was Relapse Free Survival (RFS), defined as the time from first dose of Pembrolizumab until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause. Secondary endpoints included distant Metastasis-Free Survival and Safety. Exploratory endpoints included distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint. The median follow up was 23 months for the mRNA-4157/V940 plus Pembrolizumab group and 24 months for Pembrolizumab alone group.

The Relapse Free Survival at 18 months was 78.6% for the immunotherapy combination versus 62.2% for Pembrolizumab alone (HR=0.56; P=0.0266), and this equated to a 44% reduction in the risk of recurrence or death with 2 years of follow up. mRNA-4157/V940 and Pembrolizumab combination treatment demonstrated an improvement in RFS, irrespective of PD-L1 status and TMB status. The immunotherapy combination was well tolerated without increased Grade 3-4 immune mediated or serious toxicities. The most common adverse events of any grade attributed to the combination immunotherapy were fatigue, injection site pain and chills.

The researchers concluded that this is the first randomized trial to demonstrate Relapse Free Survival improvement with an individualized neoantigen approach, compared to standard of care treatment with Pembrolizumab, among patients with high-risk resected melanoma.

A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial. Khattak A, Carlino M, Meniawy T, et al. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT001.

ctDNA Analysis in Resectable Colorectal Cancer and Efficacy of Adjuvant Chemotherapy

RR

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 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

It is estimated that approximately 30% of patients with Stage II or III CRC and 60–70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation. Even though 80% of patients with Stage II colon cancer are cured with surgery alone, adjuvant chemotherapy is recommended for patients who have Stage II colon cancer with high-risk clinicopathological features, including tumor penetration of the serosa (T4 disease). However, the benefit of adjuvant chemotherapy for patients with Stage II disease remains unclear, with less than 5% of patients benefiting from adjuvant chemotherapy. There is therefore an unmet need for more precise markers to predict risk of recurrence after surgery for resectable colon cancer, other than clinicopathological risk factors, and thus avoid exposure to unnecessary chemotherapy.

Circulating Tumor DNA (ctDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis, and can be detected in the cell-free component of peripheral blood samples (Liquid Biopsy) in almost all patients with advanced solid tumors including advanced colorectal cancer. ctDNA is a valuable biomarker and is directly evaluated for evidence of Minimal Residual Disease and allows early detection of relapse. Several studies have shown that detectable ctDNA following curative intent surgery for early stage cancers, including those with Stage II colon cancer, is associated with a very high risk of recurrence (more than 80%) without further adjuvant therapy. It has remained unclear whether adjuvant treatment is beneficial for these ctDNA-positive patients who are at high risk for recurrence.

The GALAXY study/cohort is a part of the CIRCULATE-Japan project, and is a large prospective, observational study that monitors ctDNA status for patients with clinical Stage II-IV or recurrent colorectal cancer following curative-intent surgery. In order to prospectively validate and build upon the previously published evidence, the authors conducted this cohort study to demonstrate that postsurgical ctDNA positivity is predictive of disease recurrence in early-stage CRC. In this publication the researchers reported on postsurgical ctDNA positivity and its associations with patient outcomes, as well as its implications for adjuvant chemotherapy selection, and the association between ctDNA dynamics and prognosis.

The GALAXY study/cohort included 1039 patients with clinical Stage II-III colon cancer or surgically resectable clinical Stage IV or recurrent colorectal cancer. Eligible patients had histologically confirmed colorectal adenocarcinoma, and curative resection planned for clinical Stage II or III, and R0 resection planned for relapsed or Stage IV colorectal cancer. The median age was 69 years. Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissue samples from surgical resection or biopsy were used for Whole Exome Sequencing (WES) to identify up to 16 patient-specific clonal, somatic Single-Nucleotide Variants (SNVs). These SNVs were then used to design personalized multiplex Polymerase Chain Reaction-based Next-Generation Sequencing assays (Signatera, Natera) for each study participant. Cell-free DNA was extracted from patient plasma at a given time point and was used to detect ctDNA. Plasma samples with at least 2 out of 16 tumor-specific variants detected above a predefined threshold were defined as ctDNA positive (tumor-informed ctDNA analysis. Overall, a total of 8,374 genes were selected for the 1,039 patients and the most frequently selected genes were TP53 (25.6%) and APC (17.5%). It was noted that more than 50% of genes were unique to each patient, suggesting large variability in the mutational landscape of colorectal cancer outside of known hotspot regions.

At a median follow-up of 16.74 months, postsurgical ctDNA positivity at 4 weeks after surgery was associated with higher recurrence risk compared to those patients who were ctDNA negative (61.4% versus 9.5%; HR=10.0, P< 0.0001) and the 18-month Disease Free Survival (DFS) was 38.4% versus 90.5%, respectively. This benefit was noted across all pathological stages. There was however no significant difference in recurrence risk by presurgical ctDNA status across all stages. In multivariate analysis for DFS in patients with pathological Stage II–III disease, ctDNA positivity 4 weeks after surgery was the most significant prognostic factor associated with increased risk for recurrence (HR=10.82, P< 0.001). Further, clinicopathological risk factors often used for staging and prognostication were nonsignificant. ctDNA was more valuable than CEA for relapse detection.

The researchers in this analysis examined the outcomes of ctDNA-positive and ctDNA-negative patients stratified by adjuvant chemotherapy status after adjusting for confounding variables such as age, sex, MSI status, pathological stage, and performance status in this analysis.

It was noted that patients with high-risk Stage II or Stage III disease and ctDNA-positive status 4 weeks after surgery derived significant benefit from adjuvant chemotherapy (adjusted HR=6.59; P< 0.001), and this trend was observed across all pathological stages. ctDNA-positive patients with Stage II–IV disease, not receiving adjuvant chemotherapy were noted to be at a higher risk for recurrence (adjusted HR=5.03; P< 0.001). Approximately 75% of ctDNA-positive patients with pathological Stage I or low-risk Stage II disease did not receive adjuvant chemotherapy and experienced recurrence.

Among the high-risk pathological Stage II or Stage III disease patients with ctDNA-negative status 4 weeks after surgery, there was no statistically significant benefit with adjuvant chemotherapy and the 18-month DFS was 94.9% and 91.5% for the adjuvant chemotherapy group and the observation group, respectively.

Among patients with available ctDNA status both 4 weeks and 12 weeks after surgery, there was a significantly higher risk of recurrence among patients who converted from ctDNA negative to positive, compared to those patients who were persistently negative (HR=14.0; P< 0.001).

Among the patients with ctDNA positivity 4 weeks after surgery, adjuvant chemotherapy was associated with a higher incidence of ctDNA clearance by week 24 after surgery compared with those who did not receive adjuvant therapy (68.48% versus 12.2%; adjusted HR=8.50, P< 0.0001). Among those who did not achieve ctDNA clearance, the DFS was inferior (adjusted HR=11; P< 0.0001).

Based on the results of this large and comprehensive prospective analysis of ctDNA in resectable colorectal cancer, the authors concluded that ctDNA status is a superior prognostic biomarker than the currently used high-risk clinicopathological features, and can identify patients who are at increased risk of recurrence and are likely to benefit from adjuvant chemotherapy.

Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Kotani D, Oki E, Nakamura Y, et al. Nature Medicine 2023; 29:127–134.

FDA Approves TRODELVY® for HR-Positive Breast Cancer

RR

SUMMARY: The FDA on February 3, 2023, approved TRODELVY® (Sacituzumab govitecan-hziy) for patients with unresectable, locally advanced or metastatic Hormone Receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer, who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.
Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.

TRODELVY® (Sacituzumab govitecan) is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38. TRODELVY® was approved by the FDA in 2021 for patients with unresectable, locally advanced or metastatic Triple Negative Breast Cancer, who have received two or more prior systemic therapies, at least one of them for metastatic disease.

In the IMMU-132 Phase I/II TRODELVY® study, the Hormone Receptor positive (HR+)/HER2-negative cohort of patients with metastatic breast cancer patients had an Objective Response Rate (ORR) of 31.5%, median Progression Free Survival (PFS) of 5.5 months and median Overall Survival (OS) of 12 months, with manageable toxicities.

The present new FDA approval is based on TROPiCS-02, a global, open-label, randomized, Phase III study, conducted to confirm the benefit of TRODELVY® in HR+/HER2- negative advanced breast cancer. In this study, 543 patients with HR+/HER2-negative, unresectable, locally advanced or metastatic breast cancer, were randomly assigned 1:1 to receive TRODELVY® 10 mg/kg IV on D1 and 8, every 21 days (N=272), or treatment of physician’s choice, which included single agent treatment with either Capecitabine, Eribulin, Vinorelbine, or Gemcitabine (N=271). Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced. Eligible patients had 3 median prior chemotherapy regimens for metastatic breast cancer, and one prior therapy for metastatic breast cancer was allowed if disease progressed in 12 months or less after neoadjuvant chemotherapy. Patients were required to have received endocrine therapy, a CDK4/6 inhibitor and at least one prior therapy with a Taxane in any setting. Majority of patients had visceral metastases (95%), 86% had prior endocrine therapy for metastatic breast cancer for at least 6 months, and 60% and 38% received prior CDK4/6 inhibitors for 12 months or less, and for more than 12 months, respectively. The Primary endpoint was Progression Free Survival (PFS) by Blinded Independent Central Review and key Secondary endpoint was Overall Survival (OS).

The median Progression Free Survival was 5.5 months with TRODELVY® versus 4 months with standard chemotherapy (HR=0.66; P=0.0003), representing a 34% improvement in PFS with TRODELVY®. This benefit was seen across all treatment subgroups including those who were 65 years or older, those who were heavily pretreated, as well as those with visceral metastases. The authors reported the planned TROPiCS-02 Overall Survival data at the 2nd interim analysis.

At a median follow up of 12.5 months, TRODELVY® significantly improved median Overall Survival compared to standard chemotherapy (14.4 months versus 11.2 months; HR=0.79; P=0.02). The Objective Response Rate (ORR) was 21% with TRODELVY® versus 14% with standard chemotherapy, and the median Duration of Response was 8.1 months versus 5.6 months, respectively. Treatment with TRODELVY® also resulted in an overall Health-Related Quality of Life benefit over chemotherapy, with delayed deterioration in fatigue and global health score/ Quality of Life. Grade 3 or more adverse events were observed in 74% of patients receiving TRODELVY® and in 60% of those receiving chemotherapy, and the most common toxicities associated with TRODELVY® were diarrhea neutropenia, nausea, alopecia and fatigue.

It was concluded from this landmark analysis that treatment with TRODELVY® resulted in a statistically significant and clinically meaningful improvement in Progression Free Survival, Overall Survival, Objective Response Rate and Quality of Life, compared to standard chemotherapy, in heavily pre-treated patients with HR+/HER2-negative, endocrine-resistant, unresectable, locally advanced or metastatic breast cancer. TRODELVY® should therefore be considered as a new treatment option for this patient population.

Overall survival results from the phase III TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in patients with HR+/HER2– metastatic breast cancer. Rugo HS, Bardia A, Marmé F, et al: ESMO Congress 2022. Abstract LBA76. Presented September 9, 2022.

FDA Approves Enfortumab vedotin with Pembrolizumab for Advanced Urothelial Carcinoma

RR

SUMMARY: The FDA on April 3, 2023, granted accelerated approval to Enfortumab vedotin-ejfv (PADCEV®) with Pembrolizumab (KEYTRUDA®) for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for Cisplatin-containing chemotherapy. The American Cancer Society estimates that in the United States for 2023, about 82,290 new cases of bladder cancer will be diagnosed and approximately 16,710 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic urothelial carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is a first-in-class Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, MonoMethyl Auristatin E (MMAE), which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-103 is an ongoing multi-cohort, open-label, global, multicenter Phase Ib/II study, investigating Enfortumab vedotin alone or in combination with Pembrolizumab and/or chemotherapy in first or second line settings, in patients with locally advanced or metastatic urothelial cancer, and in patients with muscle-invasive bladder cancer. The present FDA approval was based on Objective Response Rates (ORR) and median Duration of Response (DOR) in combined Dose Escalation/Cohort A and Cohort K of this study, also known as KEYNOTE-869 trial. The Dose Escalation Cohort and Cohort A were single-arm cohorts treating patients with Enfortumab vedotin plus Pembrolizumab, whereas patients in Cohort K were randomized to either Enfortumab vedotin monotherapy or Enfortumab vedotin in combination with Pembrolizumab. Patients had not received prior systemic therapy for locally advanced or metastatic urothelial cancer and were ineligible for Cisplatin-containing chemotherapy. Ineligibility for Cisplatin-based chemotherapy could be due to at least one of the following: Glomerular filtration rate (GFR) less than 60 mL/min, ECOG Performance Status of 2, Grade 2 or more hearing loss, or New York Heart Association Class III heart failure. In this analysis, a total of 121 patients (N=121) received Enfortumab vedotin plus Pembrolizumab. Patients received Enfortumab vedotin 1.25 mg/kg IV (up to a maximum of 125 mg for patients 100 kg or more) on days 1 and 8 and Pembrolizumab 200 mg IV on day 1, every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) determined by Blinded Independent Central Review.

Patients treated with a combination of Enfortumab vedotin and Pembrolizumab had an Objective Response Rate of 68%, with 12% of patients experiencing a Complete Response. The median Duration of Response for the Dose Escalation cohort plus Cohort A was 22 months and for Cohort K was Not Reached. The most common Treatment Related Adverse Events (TRAE) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Two thirds of patients had Grade 3 TRAEs, and the most common toxicities were increased lipase, maculopapular rash, and fatigue.

It was concluded that in Cisplatin-ineligible patients with unresectable locally advanced or metastatic urothelial cancer, treatment with Enfortumab vedotin and Pembrolizumab combination in chemo naïve patients, resulted in high Overall Response Rate, along with a safety profile that was tolerable. The authors added that Antibody-Drug Conjugates have the potential to make a greater impact in treating bladder cancer, especially in combination with checkpoint inhibitors, as shown in this trial and these data support ongoing investigations of first line Enfortumab vedotin and Pembrolizumab in patients with locally advanced or metastatic urothelial cancer.

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. Hoimes CJ, Flaig TW, Milowsky M, et al. DOI: 10.1200/JCO.22.01643 Journal of Clinical Oncology 41, no. 1 (January 01, 2023) 22-31.