Category: Hem/Onc Updates

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

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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

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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

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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

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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

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 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

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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

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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.

Tremelimumab in Combination with Durvalumab and Chemotherapy in Metastatic Non Small Cell Lung Cancer: The Phase III POSEIDON Study

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) 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. IMJUDO® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses. The concurrent addition of chemotherapy to checkpoint inhibitors causes tumor cell death and release of neoantigens, which increases immune priming, important for early disease control.

POSEIDON is a global, randomized, open-label, three-arm, Phase III study, which evaluated the efficacy of Tremelimumab plus Durvalumab along with chemotherapy, and Durvalumab along with chemotherapy, compared to chemotherapy alone, in first-line treatment of metastatic NSCLC. In this trial, 1013 patients (N=1013) with EGFR/ALK wild-type metastatic NSCLC were randomly assigned (1:1:1) to receive either Tremelimumab 75 mg IV plus Durvalumab 1,500 mg IV along with chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, with one additional Tremelimumab dose after chemotherapy at week 16 (fifth dose), Durvalumab 1500 mg IV plus chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, or chemotherapy alone for up to six 21-day cycles. Chemotherapy options for treatment groups included Carboplatin plus nab-Paclitaxel regardless of histology, Cisplatin or Carboplatin plus Gemcitabine for patients with squamous histology, and Cisplatin or Carboplatin plus Pemetrexed for patients with nonsquamous histology. Patients with nonsquamous histology who received Pemetrexed-Platinum doublet could receive Pemetrexed maintenance therapy if eligible. Patients continued treatment until progressive disease or unacceptable toxicity. Patients were stratified by PD-L1 expression (50% or more versus less than 50%), disease Stage (IVA versus IVB), and histology (squamous versus nonsquamous). The median age was 64 yrs, 63% had nonsquamous histology, and approximately a third of the patients had PD-L1 expression less than 1%. The treatment groups were well balanced. The Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) for the Durvalumab plus chemotherapy group, compared to the chemotherapy alone group. Key Secondary end points were PFS and OS for Tremelimumab plus Durvalumab along with chemotherapy, compared to chemotherapy alone.

The coPrimary end point of PFS benefit with Durvalumab plus chemotherapy compared to chemotherapy alone was met (HR=0.74; P=0.0009), and the median PFS was 5.5 versus 4.8 months respectively and the 12-month PFS rates were 24.4% versus 13.1%. However, OS did not reach statistical significance (HR=0.86; P=0.075). When Secondary end points were formally evaluated, Tremelimumab plus Durvalumab and platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared to chemotherapy alone (HR=0.77; P=0.003). The median OS was 14 months versus 11.7 months respectively and 2 year OS was 32.9% versus 22.1% respectively. The median PFS was 6.2 months and 4.8 months in the treatment arms, respectively (HR=0.72; P=0.0003) and the 1-year PFS rate was 26.6% and 13.1% respectively. Treatment benefit was seen across all PD-L1 subgroups, particularly in tumors with PD-L1 expression of 50% or more. Patients with tumor PD-L1 expression less than 1% appeared to gain improved survival benefit from the addition of Tremelimumab to Durvalumab and chemotherapy.

Based on this study, the FDA approved Tremelimumab in combination with Durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC, with no sensitizing EGFR mutation or ALK genomic tumor aberrations.

It was concluded that Durvalumab plus chemotherapy significantly improved Progression Free Survival when compared to chemotherapy alone. A limited course of Tremelimumab added to Durvalumab and chemotherapy significantly improved Overall Survival and Progression Free Survival when compared to chemotherapy, and the clinical benefit extended to patients who had tumor PD-L1 expression less than 1%.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study. Johnson ML, Cho BC, Luft A, et al. DOI: 10.1200/JCO.22.01737 Journal of Clinical Oncology 41, no. 6 (February 20, 2023) 1176-1179.

Real World Experience of Anti-BCMA CAR T-Cell Therapy in 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, 35,730 new cases will be diagnosed in 2023 and 12,590 patients will 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 CD 38 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 2023 remains an incurable disease. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median progression-free survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR) by transducing with a gene encoding the engineered CAR via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

ABECMA® (Idecabtagene vicleucel) is the first FDA approved cell-based gene therapy for multiple myeloma and was based on results from the pivotal, open-label, single-arm, multicenter, multinational, Phase II study (KarMMa trial), in which the efficacy and safety of ABECMA® was evaluated in adults with Relapsed and Refractory multiple myeloma. The KarMMa trial however had stringent eligibility criteria, which was likely not representative of real-world population.

The researchers conducted this study to evaluate safety and efficacy of Standard of Care ABECMA® for the treatment of Relapsed and Refractory multiple myeloma in a real-world population. This retrospective, multicenter, observational study included 196 patients planned for Standard of Care ABECMA® for Relapsed and Refractory multiple myeloma from 11 US medical centers. Unlike the KarMMa trial which had stringent eligibility criteria, not representative of real-world patient population, the present study included patients with comorbidities that would have made them ineligible for the KarMMa trial. A total of 159 patients successfully received ABECMA®. The median age was 64 years, and 35% of patients had high-risk cytogenetics (del(17p), t(4;14) and t(14;16), the median number of prior lines of therapy was seven and 44% of patients had penta-refractory disease. In this real-world experience study, 21% had prior anti-BCMA therapy, 84% had prior Autologous Stem Cell Transplant and 6% had Allogeneic Stem Cell Transplant. Approximately 75% of patients in this study would not have met KarMMa eligibility criteria. Further, relative to KarMMa trial, this real-world cohort had more patients with extramedullary and penta-refractory disease.

The median time from leukapheresis to ABECMA® infusion was 47 days. The CAR T-cells manufacturing failure rate in real-world patients was higher than that seen in KarMMa trial and this was attributed to poor bone marrow reserve among patients in this study, probably related to prior treatment, including alkylators, which can result in T-cell depletion. Nonetheless, 90% of eligible patients were administered ABECMA®, which is comparable with 91% in the KarMMa trial. The median follow up from infusion was 6.1 months.

Overall, the efficacy of ABECMA® in the real-world population was comparable with that in the KarMMa trial group of patients. The Overall Response and Complete Response rates with Standard of Care ABECMA® were 84% and 42%, which are comparable with 73% and 33% noted in the KarMMa trial. The median DOR was 8.6 months in the present study versus 10.7 months in the KarMMa trial and the median time to response was 1 month. The median PFS in this study was 8.5 months, similar to that observed in the KarMMa trial and the median Overall Survival was 12.5 months. In a multivariable analysis of this study, prior use of BCMA targeted therapy, high-risk cytogenetics, ECOG PS 2 or more, lymphodepletion, and younger age were independent predictors of inferior Progression Free Survival. Any grade and Grade 3 or more Cytokine Release Syndrome and neurotoxicity occurred in 82%/3% and 18%/6%, respectively.

It was concluded from this trial that safety and efficacy of ABECMA® in patients with Relapsed and Refractory multiple myeloma in the Standard of Care setting were comparable with those in the Phase II pivotal KarMMa trial, even though majority of patients in this study did not meet KarMMa trial eligibility criteria. This real-world population study also suggested that if BCMA chimeric antigen receptor-T-cell treatment is planned, prior exposure to BCMA-targeted therapy should be avoided.

Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium. Hansen DK, Sidana S, Peres LC, et al. DOI: 10.1200/JCO.22.01365 Journal of Clinical Oncology. Published online January 09, 2023.

Zolbetuximab Plus Chemotherapy Improves Survival in CLDN18.2 Positive Metastatic Gastric and Gastroesophageal Junction Cancer

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SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 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 factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.
Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 6%.

These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6. Patients with HER2-positive disease are usually treated with chemotherapy plus trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor or checkpoint inhibitor alone if the tumors express PD-L1.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed and accessible to targeted therapies with antibodies as gastric tumors develop. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death. About 30-40% of patients with gastric cancer have CLDN18.2 expression.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. In this study, 565 enrolled patients were randomly assigned 1:1 to receive the combination of Zolbetuximab and mFOLFOX6 (N=283) or placebo and mFOLFOX6 (N=282). Zolbetuximab was given at 800 mg/m2 IV on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1, and days 1 and 22 of subsequent cycles, every 3 weeks. mFOLFOX6 (Oxaliplatin, 5-Fluorouracil and Leucovorin) was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, Zolbetuximab was given at the same dosing schedule in combination with 5-Fluorouracil and Leucovorin IV every 2 weeks. Those in the placebo arm were given placebo at the every 3-week schedule and chemotherapy was administered at the same dosing schedule. Treatment was continued until disease progression or discontinuation criteria were met. Enrolled patients had moderate-to-strong CLDN18 staining intensity in at least 75% of tumor cells based on a validated ImmunoHistoChemistry assay, had HER2-negative disease, and an ECOG performance status of 0 or 1. Patients were stratified by region (Asian versus non-Asian), number of organs with metastases (0-2 versus 3 or more), and prior gastrectomy. The median age was 61 years and 31.4% of patients were from Asia. Majority of patients had 0-2 organs with metastases, 30% had prior gastrectomy. Approximately 13% of patients had tumors with a PD-L1 CPS of at least 5. The primary disease site was stomach in 76% of patients and was GastroEsophageal Junction in 24%. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and Safety.

This study met the Primary endpoint and the median PFS was 10.61 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The OS was also significantly improved (18.23 versus 15.54 months, HR=0.750; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population. The most common Adverse Events with Zolbetuximab plus mFOLFOX6 were nausea, vomiting and decreased appetite. The incidences of serious Adverse Events were similar between the two treatment groups.

The authors concluded that Zolbetuximab plus mFOLFOX6 is a new potential Standard-of-Care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic Gastric/GE Junction adenocarcinoma. It is unclear if this regimen is superior to chemotherapy plus a checkpoint inhibitor in patients with PD-L1–positive and CLDN18.2-positive disease.

Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Shitara K, Lordick F, Bang Y-J, et al. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292