Category: Hem/Onc Updates

FDA Approves LIBTAYO® for Advanced Basal Cell Carcinoma

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SUMMARY: The FDA on February 9, 2021, granted regular approval to LIBTAYO® (Cemiplimab-rwlc) for patients with locally advanced Basal Cell Carcinoma (laBCC) previously treated with a HedgeHog pathway Inhibitor (HHI) or for whom a HHI is not appropriate, and granted accelerated approval to LIBTAYO® for patients with metastatic BCC (mBCC) previously treated with a HHI or for whom a HHI is not appropriate.

BCC is the most common type of skin cancer in the U.S., with approximately two million new cases diagnosed every year. Exposure to UltraViolet rays is a significant risk factor. Majority of BCCs are diagnosed early and cured with surgery and radiation. However, a small proportion of tumors can become locally advanced or progress to metastatic disease and can be painful and disfiguring. The primary systemic treatment options for these patients with advanced BCC are oral HedgeHog pathway inhibitors such as ERIVEDGE® (Vismodegib) and ODOMZO® (Sonidegib). There are however no FDA-approved treatment options available, for patients who progress on, or are intolerant to HedgeHog Inhibitors (HHIs).

LIBTAYO® is a fully human IgG4, high affinity anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor on tumor-infiltrating T cells and blocks its interaction with tumor derived ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. LIBTAYO® was previously approved by the FDA in 2018 as the first systemic treatment for adults with metastatic Cutaneous Squamous Cell Carcinoma (CSCC) or locally advanced CSCC, who are not candidates for curative surgery or curative radiation.

The present FDA approval of LIBTAYO® was based on results from an interim analysis of an ongoing open-label, multi-center, non-randomized Phase II trial (Study 1620), involving patients with unresectable locally advanced BCC or metastatic BCC (nodal or distant). This was the first and largest prospective clinical trial (N=132) among this patient population, with 112 patients included in the efficacy analysis. Patients in both cohorts (locally advanced and metastatic) had either progressed on HHI therapy, had not had an objective response after 9 months on HHI therapy, or were intolerant of prior HHI therapy. Eligibility required that locally advanced BCC patients were not candidates for curative surgery or curative RT, per multidisciplinary assessment. All patients received LIBTAYO® 350 mg IV over 30 minutes every 3 weeks for up to 93 weeks, until disease progression, unacceptable toxicity, or completion of planned treatment. No PD-L1 or Tumor Mutational Burden (TMB) testing was required before starting treatment with LIBTAYO®. The Primary efficacy endpoint was confirmed Objective Response Rate (ORR) and a key Secondary endpoint was Duration of Response (DOR), as assessed by Independent Central Review.

Among the 84 patients with locally advanced BCC, the confirmed ORR was 29% with a median DOR not reached, and 79% of responders maintained their response for at least 6 months. Among 28 patients with metastatic BCC, the confirmed ORR was 21%, with a median DOR not reached, and all responders maintained their responses for at least 6 months. The most common adverse reactions (incidence 20% or more) were fatigue, musculoskeletal pain, diarrhea, rash, and pruritis.

It was concluded from this study that LIBTAYO® is the first agent to provide clinically meaningful anti-tumor activity including durable responses, in patients with advanced BCC, after progression or intolerance on HHI therapy.

Interim Analysis of Phase 2 Results for Cemiplimab in Patients with Metastatic Basal Cell Carcinoma (mBCC) who Progressed on or are Intolerant to Hedgehog Inhibitors (HHIs). Lewis KD, Peris K, Sekulic A, et al. Presented at the 2021 Winter Clinical Dermatology Conference, January 16–24, Virtual Conference (encore of SITC 2020 poster presentation).

Key Breast Cancer Risk Genes Identified from Two Large Studies

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence.

Genetic testing for cancer susceptibility with multigene testing panels is now becoming widely available and affordable. Identification of pathogenic variants in predisposition genes such as BRCA1 and BRCA2 among carriers has provided benefit through early intervention. However, the evidence of an association with cancer is often weak for many other genes on multigene testing panels, and estimates of the cancer risks associated with such variants are often not available. Further, estimates of the prevalence of pathogenic variants in predisposition genes in the general population are lacking.

Two large breast cancer case-control studies analyzed the associations between a number of commonly accepted cancer susceptibility genes and breast cancer risk.

The multinational study by Dorling et al. used a panel of 34 commonly accepted cancer susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls (unaffected woman) from 25 countries participating in the Breast Cancer Association Consortium. The authors estimated odds ratios for breast cancer overall and tumor subtypes and evaluated missense-variant associations and classification of pathogenicity. The researchers found strong evidence of an association with breast cancer risk for Protein-Truncating Variants (genetic variants) caused by frameshift mutations in 9 genes, with a significant risk for breast cancer and P value of less than 0.0001 for 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2 – Odds Ratios ranging from 2.1 for ATM to 10.6 for BRCA1), and a P value of less than 0.05 for the other 4 genes (BARD1, RAD51C, RAD51D, and TP53 – Odds Ratio ranging from 1.8 for RAD51D to 3.06 for TP53). Further, it was noted that for the genetic variants in most of these genes, the Odds Ratio differed according to breast cancer subtype. Protein-Truncating Variants in ATM and CHEK2 were more strongly associated with ER-positive disease than with ER-negative disease, whereas genetic variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D were more strongly associated with ER-negative disease than with ER-positive disease. It was also found that rare missense variants in CHEK2 overall, as well as variants in specific domains in ATM, were associated with moderate breast cancer risk. The researchers also noted that none of the other 25 genes in the panel were informative for the prediction of breast cancer risk. This study places Protein-Truncating Variants in BRCA1, BRCA2, and PALB2 in the high-risk category and Protein-Truncating Variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D in the moderate-risk category.

The US study by Hu et al. used a panel of 28 cancer predisposition genes to perform sequencing on samples from 32,247 women with breast cancer and 32,544 controls (unaffected women) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. The researchers assessed the associations between pathogenic variants in each gene and the risk of breast cancer.
The researchers noted that pathogenic variants in 12 established breast cancer predisposition genes were detected in 5% of breast cancer patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with Odds Ratios of 7.62 and 5.23 respectively and pathogenic variants in PALB2 were associated with a moderate risk (Odds Ratio 3.83). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of ER-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of ER-positive breast cancer. Pathogenic variants in the other 16 candidate breast cancer predisposition genes were not associated with an increased risk of breast cancer.

Taken together, the results from these two large case-control studies suggested that variants in 8 genes – BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2, had a significant association with breast cancer risk and majority of the other genes tested did not have a significant association with disease. Further, the distribution of mutations among women with breast cancer was different from the distribution among controls (unaffected women). Among breast cancer patients, the majority of mutations were in BRCA1, BRCA2, and PALB2, and among controls, the majority of mutations were in CHEK2 and ATM.

It can be concluded that, these two studies define the genes that are of utmost clinical value for inclusion on sequencing panels, for the prediction of breast cancer risk, and provides estimates of the prevalence of the pathogenic variants in the unaffected population. The authors added that these estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.

Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. Breast Cancer Association Consortium; Dorling L, Carvalho S, Allen J, et al. N Engl J Med 2021;384:428-439.

A Population-Based Study of Genes Previously Implicated in Breast Cancer. Hu C, Hart SN, Gnanaolivu R, et al. N Engl J Med 2021;384:440-451.

FDA Approves UKONIQ® for Relapsed or Refractory Marginal Zone and Follicular Lymphomas

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SUMMARY: The FDA on February 5, 2021 granted accelerated approval to UKONIQ® (Umbralisib), a kinase inhibitor including PI3K-delta and Casein Kinase CK1-epsilon, for adult patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and adult patients with Relapsed or Refractory Follicular Lymphoma (FL) who have received at least three prior lines of systemic therapy. The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas (FL).

Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median PFS of 6-8 yrs and a median OS of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments.

UKONIQ® is an oral, once-daily, dual inhibitor of Phosphatidylinositol-3-Kinase-delta (PI3Kδ) and Casein Kinase 1-epsilon (CK1-epsilon) that exhibits improved selectivity for the delta isoform of PI3K. In contrast with other PI3K inhibitors, there was a low incidence of immune-mediated toxicities with UKONIQ® possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1-epsilon.

The present FDA approval was based on the UNITY-NHL trial (NCT02793583), which is global, multicenter, open-label, multicohort, Phase IIb registration study, designed to evaluate the safety and efficacy of UKONIQ® in previously treated NHL patients. This study had a total 208 patients with indolent NHL and included 69 patients with MZL (splenic, nodal, extranodal), 117 patients with FL (grade 1, 2, 3a), and 22 patients with Small Lymphocytic Lymphoma (SLL). MZL patients were Relapsed/Refractory to 1 or more prior lines of treatment, which included an anti-CD20, while FL and SLL patients were Relapsed/Refractory to 2 or more prior lines of therapy, which included an anti-CD20 and an alkylating agent. UKONIQ® was administered at 800 mg orally once daily in 28-day treatment cycles until disease progression or unacceptable tolerability. The median age was 66 years and the median duration of treatment exposure was 8.4 months. Pneumocystis jiroveci Pneumonia (PCP) and anti-viral prophylaxis were mandated for all patients. The Primary endpoint of the study was Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and Secondary endpoints included Duration of Response (DoR), Progression Free Survival (PFS), Time To Response (TTR), and Safety.

With a median follow up of 27.8 months, the ORR for patients with MZL was 49%, with a 16% Complete Response (CR) rate and a Disease Control Rate (CR+PR+SD) of 82.6%. The ORR was consistent amongst MZL subtypes and no patients who achieved CR had experienced disease progression to date. Additionally, the median DoR and median PFS was not reached for this patient population.

Among patients with FL, with a median follow up of 27.5 months, the ORR was 45%, with 5% achieving a CR, and a DCR of 79.5%. The median TTR was 4.6 months and the median DoR was 11.1 months. The median PFS was 10.6 months.

Among SLL patients, with a median follow up of 29.3 months, the ORR was 50%, with 4.5% achieving a CR, and a DCR of 86.4%. The median TTR was 2.7 months and the median DoR was 18.3 months. The median PFS was 20.9 months.

The most common toxicities included increased creatinine, diarrhea/colitis, fatigue, transaminase elevation, musculoskeletal pain, neutropenia, anemia, thrombocytopenia, upper respiratory tract infection, nausea, vomiting, abdominal pain, reduced appetite, and cutaneous reactions.

It was concluded from this study that UKONIQ® has a favorable benefit-risk profile and achieved meaningful clinical activity in a heavily pretreated population of patients with indolent NHL. The authors added that the safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and treatment discontinuations.

Umbralisib, the Once Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients with Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results from the Phase 2 Global Unity-NHL Trial. Zinzani PL, Samaniego F, Jurczak W, et al. Presented at the 62nd ASH Annual Meeting and Exposition, December 5-8, 2020. Abstract # 2934.

TIBSOVO® Improves Survival in IDH1 Mutated Advanced Cholangiocarcinoma

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SUMMARY: Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. 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. The 5-year survival is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia (AML) and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic Cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

TIBSOVO® (Ivosidenib) is an oral, targeted, small-molecule inhibitor of mutant IDH1. The FDA in July, 2018, approved TIBSOVO® for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. A previously published Phase I study demonstrated the safety and activity of TIBSOVO® in patients with IDH1 mutated advanced Cholangiocarcinoma.MOA-of-Ivosidenib

ClarIDHy is an international, randomized, double-blind, Phase III study, in which 187 previously treated patients with advanced Cholangiocarcinoma with an IDH1 mutation were randomly assigned 2:1 to receive TIBSOVO® 500 mg orally once daily (N=126) or matched placebo (N=61). All patients had advanced unresectable Cholangiocarcinoma. The median age was 62 years, 91% had intrahepatic Cholangiocarcinoma, 93% of patients had metastatic disease and 47% had received two prior therapies. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Safety, Objective Response Rate (ORR) and Overall Survival (OS). Crossover from placebo to TIBSOVO® was permitted upon radiographic disease progression.

This study met its Primary endpoint and the median PFS was 2.7 months for patients treated with TIBSOVO® compared to 1.4 months with placebo (HR=0.37; P<0.0001). More importantly, the median PFS at 6 and 12 months were 32% and 22% in the TIBSOVO® group, whereas no patients randomized to the placebo group were progression-free for 6 or more months, at the time of data cutoff.

The authors now reported the results of final analysis which showed an improvement in the secondary endpoint of OS, favoring patients randomized to TIBSOVO® compared to those randomized to placebo. However, statistical significance was not reached. The median OS for patients in the TIBSOVO® arm was 10.3 months compared to 7.5 months for patients in the placebo arm (HR=0.79; 1-sided P=0.093). A high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO®. After adjusting for crossover from placebo to TIBSOVO®, the median OS for patients in the placebo arm was 5.1 months (HR=0.49; 1-sided P<0.0001).

The 6-month survival rate for patients in the TIBSOVO® arm was 69% compared to 57% of patients in the placebo arm, not adjusted for crossover. The 12-month survival rate for patients in the TIBSOVO® arm was 43% compared to 36% for patients in the placebo arm, not adjusted for crossover. Treatment with TIBSOVO® preserved patients’ physical functioning from baseline, as assessed by the EORTC QLQ-C30 questionnaire, whereas patients in the placebo arm experienced decline from baseline starting cycle 2. The most common Adverse Events of any grade for TIBSOVO® were nausea (38%), diarrhea (33.1%) and fatigue (28.9%). Adverse Events leading to discontinuation were more common with placebo compared with total TIBSOVO® (8.5% versus 6.6%).

It was concluded that treatment with TIBSOVO® in patients with advanced Cholangiocarcinoma with an IDH1 mutation, resulted in significant improvement in Progression Free Survival as well as favorable Overall Survival trend, when compared to Placebo, despite a high rate of crossover. This is the first pivotal study demonstrating the clinical benefit of targeting IDH1 mutation in this patient group. This new oral, non-cytotoxic, targeted treatment option, with a tolerable safety profile, will be a welcome addition to treat this aggressive disease, for which there is an unmet need for new therapies.

Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. Zhu A, Macarulla T, Javle MM, et al. J Clin Oncol 39, 2021 (suppl 3; abstr 266)

Real-World Data: Surgery Improves Survival in Treatment Responsive Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene and about 50% of HER2-positive breast cancers are Hormone Receptor positive. Patients with HER2-positive metastatic 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. Not all HER2-positive, Hormone Receptor positive metastatic breast cancer patients, are candidates for chemotherapy. These patients however may benefit from anti-HER2 targeted therapy given along with endocrine therapy.

Approximately 6% of newly diagnosed breast cancer patients present with Stage IV disease. Systemic therapy has been the cornerstone of treatment for patients with metastatic breast cancer. Breast surgery is often not a consideration for patients with metastatic breast cancer. However, breast surgery can be offered for palliation of symptoms, taking into consideration the risks and benefits of such intervention, in a patient with an ulcerated, bleeding, or a fungating tumor mass, that cannot be controlled with systemic therapy.

Surgical resection of metastatic disease is not a new concept. Previously published results from randomized controlled trials among patients with metastatic breast cancer concluded that there was no survival advantage with surgical intervention. However these results have been questioned because of the small number of participants, and did not take into account either the Hormone Receptor, HER-2 status or the sequence of chemotherapy in relation to the surgical intervention. It therefore remains unclear whether surgery, in addition to systemic treatments and radiation therapy, improves survival for certain patients with metastatic breast cancer.

The authors in this real-world study identified 12,838 patients with HER-2 overexpressing and Hormone Receptor positive, Stage IV breast cancer, from the NCI database. They then studied patients who had either systemic therapy alone, systemic therapy and surgery, or had systemic therapy, surgery and radiation, and evaluated whether certain biologic subtypes and timing of chemotherapy were associated with survival advantages. Specifically, they evaluated whether the Hormone Receptor status had an influence on surgical benefit, in these treatment-responsive breast cancer patients, understanding that triple negative breast cancers are not very responsive to treatment. The researchers excluded patients who died within six months of their diagnoses, in order to ensure that only treatment-responsive cancers were being studied. The goal of this study was to understand if surgery made a difference in metastatic breast cancers that were responsive to treatment.

The researchers noted that patients with a surgical intervention tended to have a longer survival, compared to patients with other treatment plans. Patients whose cancers were HER2-positive saw prolonged survival, especially when their treatment plan included surgery. Further, in addition to the benefit of surgery among treatment-responsive metastatic breast cancer patients, the authors noted that systemic therapy before surgery (preoperative systemic therapy which included chemotherapy and targeted therapies) had the greatest survival advantage in patients with positive HER-2 and Estrogen and Progesterone Receptor status.

It was concluded from this study that patients with Stage IV breast cancer responsive to systemic therapy may be able to benefit from the addition of surgery, regardless of their biologic subtype. The authors added that clinicians should evaluate real-world evidence, including this study, when choosing the optimal treatment for their patients with metastatic breast cancer, as it may be difficult to conduct randomized clinical trials in this patient population.

ASO Author Reflections: Surgery Offers Survival Advantage in Treatment-Responsive Metastatic Breast Cancer. Stahl K, Dodge D, and Shen C. Annals of Surgical Oncology, 2020; DOI: 10.1245/s10434-020-09286-9

FDA Approves OPDIVO® plus CABOMETYX® in Newly Diagnosed Advanced Kidney Cancer

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SUMMARY: The FDA on January 22,2021, approved the combination of OPDIVO® (Nivolumab) and CABOMETYX® (Cabozantinib) as first line treatment for patients with advanced Renal Cell Carcinoma (RCC). The American Cancer Society estimates that 76,080 new cases of kidney cancers will be diagnosed in the United States in 2021 and about 13,780 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is significant unmet need for improved therapies for this disease. SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/smooth vessel cell wall, and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® has been the standard first line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, Phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival (OS) was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.

The FDA in 2018, approved combination immunotherapy, OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), for the treatment of intermediate or poor-risk, previously untreated advanced Renal Cell Carcinoma (RCC), based on significantly higher Overall Survival (OS) and Objective Response Rates (ORR), compared with SUTENT® (CheckMate 214). Subsequently, two studies, a combination of BAVENCIO® (Avelumab) and INLYTA® (Axitinib) – JAVELIN Renal 101, and KEYTRUDA® (Pembrolizumab) and INLYTA® (KEYNOTE-426), demonstrated superior OS, compared to SUTENT®, and for the first time set the stage for the use of a combination of checkpoint inhibitor and targeted therapy in this patient population.MOA-of-CABOZANTINIB

OPDIVO®, an anti-PD-1 checkpoint inhibitor and CABOMETYX® (Cabozantinib), a small-molecule Tyrosine Kinase Inhibitor, are both approved as single agents, for the second-line treatment of Renal Cell Carcinoma. The rationale for combining these two agents is that OPDIVO® unleashes the immune system and restores antitumor immune response, whereas CABOMETYX® has both antiangiogenic and immunomodulatory properties and may counteract tumor-induced immunosuppression.

CheckMate 9ER study is a multinational, randomized, Phase III trial, in which a combination of OPDIVO® plus CABOMETYX® was compared with single agent SUTENT®, in treatment naïve patients with advanced clear cell Renal Cell Carcinoma. This study included 651 treatment naïve patients with advanced Renal Cell Carcinoma with a clear cell component, who were randomly assigned in a 1:1 ratio to receive OPDIVO® 240 mg IV every 2 weeks along with CABOMETYX® 40 mg orally daily (N=323) or SUTENT® 50 mg orally daily in 4-week-on, 2-week-off cycles (N=328). Treatment was continued until disease progression or unacceptable toxicity. Patients with any IMDC (International Metastatic RCC Database Consortium) risk score were included. Patients with sarcomatoid tumor features were allowed. Patients were stratified by IMDC risk score and tumor PD-L1 expression. The median patient age was 62 years, 58% of patients were in the IMDC intermediate risk category and 75% of patients had tumor PD-L1 expression of less than 1%. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and safety.

At a median follow up of 18.1 months, the median PFS was 16.6 months with OPDIVO® plus CABOMETYX® combination versus 8.3 months with single agent SUTENT® (HR=0.51; P<0.0001), suggesting a doubling of PFS, with a 49% reduction in the risk of disease progression or death. The median Overall Survival, a secondary endpoint, was not reached in either treatment group, but at this first analysis, patients randomized to the OPDIVO® plus CABOMETYX® combination had significantly longer OS, than those receiving SUTENT® (median Not Reached; HR=0.60; P=0.001), suggesting a 40% reduction in the risk of death. These benefits were seen consistently across pre-specified subgroups defined according to IMDC risk categories and PD-L1 expression. The Objective Response Rate (ORR) was also significantly higher and doubled among patients receiving the OPDIVO® plus CABOMETYX® combination, compared to those receiving SUTENT® (55.7% versus 27.1%, P<0.0001). Complete response rates were also higher among those receiving the OPDIVO® plus CABOMETYX® combination (8.0% versus 4.6%), with a shorter median time to response, and longer duration of response. Grade 3 or more Adverse Events were higher among those receiving OPDIVO® plus CABOMETYX® combination, compared to those receiving SUTENT® (60.6% versus 50.9%).

It was concluded that a combination of OPDIVO® plus CABOMETYX® demonstrated superior Progression Free Survival, Overall Survival and Overall Response Rate, compared to SUTENT®, in treatment naïve patients with advanced Renal Cell Carcinoma, and provides a new treatment option for this patient group.

Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Choueiri TK, Powles T, Burotto M, et al. Ann Oncol. 2020;31(4). Abstract 6960.

Maintenance Therapy with NINLARO® in Transplantation Ineligible Multiple Myeloma Patients

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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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction and consolidation, can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Transplant (ASCT) and to date is the only drug approved for this indication. REVLIMID® maintenance however is associated with the development of second new primary malignancies and tolerability issues.

Proteasomes are enzymes found in cells and they enable the breakdown of abnormal or mutant proteins. The amino acids from these proteins are recycled to make new proteins. Just like normal cells make proteins, so do cancerous cells. But the proteins made by the cancerous cells are ineffective and in excess. Myeloma cells depend on the Proteasomes to facilitate this metabolic function, to regulate their growth and survival. Proteasome Inhibitors (PIs) inhibit Proteasome function and are a backbone of multiple myeloma treatment. VELCADE® (Bortezomib), a Proteasome Inhibitor has shown promising activity in early clinical trials, as maintenance treatment post-ASCT. The limitations with VELCADE® as maintenance therapy include, parenteral administration and tolerability. There is therefore an unmet need for an effective oral PI maintenance therapy that is convenient for the patients, with acceptable toxicities. NINLARO® (Ixazomib) unlike VELCADE® is a second generation, oral, Proteasome Inhibitor, which disrupts protein metabolism in myeloma cells, by inhibiting Proteasomes and has an antiproliferative and pro-apoptotic effect. In the TOURMALINE-MM3 Phase III trial study, weekly NINLARO® maintenance treatment in responding patients after ASCT resulted in a significant reduction in the risk of progression and death, and was associated with a favorable safety profile.

TOURMALINE-MM4 is an International, randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate the efficacy and safety of NINLARO® as maintenance therapy in transplant-ineligible patients after standard-of-care induction therapy. In this study, patients were randomly assigned 3:2 to receive NINLARO® 3 mg orally (N=425) or matching placebo (N=281) on days 1, 8, and 15 of 28-day cycles, as maintenance treatment for 24 months. The dose of NINLARO® was increased to 4 mg from cycle 5, if tolerated during cycles 1-4. Eligible patients had newly diagnosed multiple myeloma, not undergoing Autologous Stem Cell Transplantation (ASCT) and had achieved better than or equal to Partial Response after 6-12 months of standard induction therapy. The median patient age was 73 years and enrolled patients were stratified by induction regimen (PI-containing versus non-PI therapy), preinduction disease Stage (I or II versus III), age at randomization (less than 75 years versus 75 years or older) and response to initial therapy at screening (Complete Response-CR or Very Good Partial Response-VGPR versus Partial Response-PR). About 62% were in CR or VGPR at study entry. The Primary endpoint was Progression Free Survival (PFS). The key Secondary endpoint was Overall Survival (OS).

With a median follow up for PFS of 21.1 months, the median PFS since randomization was 17.4 versus 9.4 months (HR=0.659; P<0.001), suggesting a 34.1% reduction in risk of progression or death with NINLARO® versus placebo. Patients who achieved Complete or Very Good Partial Response postinduction benefitted the most with NINLARO® maintenance treatment, with a median PFS of 25.6 versus 12.9 months with placebo (HR=0.586; P<0.001). NINLARO® maintenance was well tolerated in this elderly population of transplantation-ineligible patients and 70.7% of patients tolerated the 3 mg dose of NINLARO® sufficiently well to escalate the dose to 4 mg. Overall rates of adverse events were similar between groups, and adverse events in the NINLARO® group were mostly grade 1-2 severity and included GI toxicities, rash, and peripheral neuropathy. No new safety signals were seen. There was no increase in new primary malignancies and there was no impact on patients’ self-reported quality of life.

It was concluded that TOURMALINE-MM4 is the first randomized Phase III trial to specifically investigate an induction-agnostic maintenance option for transplantation-ineligible patients with NDMM, and oral NINLARO® maintenance treatment prolonged Progression Free Survival with no unexpected toxicity in this patient population.

Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial. Dimopoulos MA, Spicka I, Quach H, et al. J Clin Oncol. 2020;38:4030-4041.

Adjuvant VERZENIO® with Endocrine Therapy in High Risk Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-ABEMACICLIB-A-CDK4-and-CDK6-Inhibitor

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

VERZENIO® is presently approved by the FDA as monotherapy as well as in combination with endocrine therapy for patients with HR-positive, HER2- negative advanced breast cancer. The addition of VERZENIO® to FASLODEX® resulted in a statistically significant improvement in Overall Survival among patients with HR-positive, HER2-negative advanced breast cancer, who had progressed on prior endocrine therapy. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk early breast cancer.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5 to 10 years of physicians choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease Free Survival (IDFS), and Secondary end points included distant Relapse Free Survival, Overall Survival, and safety. At a preplanned interim analysis, the addition of VERZENIO® to endocrine therapy resulted in a 25% reduction in the risk of developing a Invasive Disease Free Survival (IDFS) event, relative to endocrine therapy alone. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and Overall Survival. The current study describes outcomes following an extended follow up of this trial, with a median follow up time of 19 months.

At the time of this primary outcome analysis, 1,437 patients (25.5%) had completed the two-year treatment period and 3,281 patients (58.2%) were in the two-year treatment period. The combination of VERZENIO® plus endocrine therapy continued to demonstrate superior Invasive Disease Free Survival (IDFS) compared to endocrine therapy alone, with a 28.7% reduction in the risk of developing invasive disease (P=0.0009; HR=0.713). The 2-year IDFS in the combination group was 92.3% and 89.3% in the endocrine therapy alone treatment group. This IDFS benefit with VERZENIO® was consistently noted in all prespecified subgroups. Further, there was an improvement in the 2-year distant Relapse Free Survival rate among patients who received the combination treatment compared with those who received endocrine therapy alone (93.8% versus 90.8%, respectively). Overall Survival data was immature at the time of analysis.

The researchers also evaluated outcomes among 2,498 patients with centrally assessed high tumor Ki-67 status. Among patients in this cohort, those who received the combination treatment had a 30.9% decreased risk of invasive disease compared with those who received endocrine therapy alone (P=0.01; HR=0.691) and the 2-year IDFS rates in the combination group and the endocrine therapy alone group were 91.6% and 87.1%, respectively. There were no new safety signals observed with VERZENIO®.

It was concluded that at the time of this primary outcome analysis, VERZENIO® combined with endocrine therapy continued to demonstrate a clinically meaningful improvement in Invasive Disease Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer.

Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. O’Shaughnessy JA, Johnston S, Harbeck N, et al. Presented at the 2020 San Antonio Breast Cancer Symposium, December 8-11. Abstract. GS1-01.

PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common Non-Hodgkin Lymphoma diagnosed in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 yrs or older at the time of diagnosis and the incidence is likely to increase with the 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 five 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 (RITUXAN®-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. The MInT trial (MabThera International Trial Group) published in The Lancet Oncology in 2006 established that for a subgroup of young DLBCL patients with favorable prognosis (age-adjusted International Prognostic Index (aaIPI) of 0 and no bulky disease, 6 cycles CHOP-like chemotherapy plus RITUXAN® resulted in a 3-year Event Free Survival of 89%, Progression Free Survival of 95% and Overall Survival of 98% (Lancet Oncol 2006;7:379-391).

Approximately 25-30% of DLBCL present as limited stage. Three cycles of Rituximab (RITUXAN®) along with CHOP plus Radiation Therapy (RT) is the standard treatment approach for limited stage DLBCL based on SWOG S0014 study. Data from retrospective studies suggested that 80% of patients were PET negative after 3 cycles of R-CHOP (defined as Deauville score 1-2), on a mid-treatment interim PET/CT scan, and only 8% of them relapsed after receiving 1 additional cycle of R-CHOP without RT.

S1001 is a prospective, Phase II, Intergroup, National Clinical Trials Network, PET-directed study, designed to tailor therapy for patients with limited-stage DLBCL after 3 cycles of R-CHOP. The goal of this study was to eliminate toxicities associated with RT, for the majority of patients with a negative PET scan after 3 cycles of R-CHOP and to improve the outcome in the minority of patients with a positive interim PET scan.

This study included 132 eligible, treatment naïve, Stage I/II, CD20-positive, DLBCL patients, with nonbulky (less than 10 cm) disease. All patients received 3 cycles of standard R-CHOP treatment given every 3 weeks, with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m2 IV, Vincristine 1.4 mg/m2 (capped at 2 mg) IV, and Prednisone 100 mg orally daily for 5 days. Patients had an interim PET scan between days 15 and 18 of cycle 3, which was centrally reviewed in real time. Patients with a negative PET, defined as Deauville score 1-3, proceeded with 1 additional cycle of R-CHOP. Patients with a positive PET (Deauville score 4-5) initiated 36 Gy of involved field radiation therapy, plus an additional boost of up to 9 Gy to FDG-avid areas, within 5 weeks of cycle 3 of R-CHOP. Three to 6 weeks after completing radiation therapy, patients received ZEVALIN® (Ibritumomab tiuxetan) administered per standard protocol, with Rituximab 250 mg/m2 IV given on day 1 and day 7, 8, or 9, and ZEVALIN® 0.4 mCi/kg on day 7, 8, or 9, after Rituximab. A final PET scan was performed 12 weeks after treatment completion. Patients were followed up with clinical examination and testing, including CT scans every 6 months for the first 2 years and then annually for up to 7 years or death.

The median age was 62 years, 62% of patients had Stage I disease, 17% had B symptoms, 43% had extranodal involvement, 66% had exclusive involvement of the head and neck region, and 10% had fully resected disease at baseline. Stage-modified IPI score was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the patients. Overall, 72% of the patients had DLBCL-Not Otherwise Specified, 17% had high-grade B-cell lymphoma–Not Otherwise Specified, and 3% had high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit lymphoma or triple-hit lymphoma). Among 87 patients for whom Cell of Origin could be assessed, 68% had Germinal Center B-cell (GCB), 23% had Activated B-Cell (ABC), and 9% were unclassifiable.

With a median follow up of 4.92 years, only 6 of 132 eligible patients progressed, and 3 died as a result of lymphoma, for a 5-year Progression Free Survival (PFS) estimate of 87% and an Overall Survival (OS) estimate of 89%. Eighty-nine percent of the patients with a negative interim PET/CT received R-CHOP × 4, whereas only 11% had a positive interim PET/CT and required radiation-based therapy, with both groups having excellent outcomes.

The authors concluded that, this largest prospective study in the US of limited-stage DLBCL establishes R-CHOP × 4 alone as the new standard treatment for the absolute majority of patients.

Positron Emission Tomography–Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. Persky DO, Li H, Stephens DM, et al. J Clin Oncol. 2020;38:3003-3011

First Line KEYTRUDA® Superior to Chemotherapy in Metastatic MSI-H/dMMR Colorectal Cancer

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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 147,950 new cases of CRC were diagnosed in the United States in 2020 and about 53,200 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have family histories of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA in 2017 granted accelerated approval to KEYTRUDA® for patients with advanced MSI-High or dMMR solid tumors, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors.

KEYNOTE-177 is an International, multicenter, randomized open-label, Phase III trial conducted, to evaluate the efficacy and safety of KEYTRUDA® versus Standard-of-Care (SOC) chemotherapy, as first-line therapy for dMMR or MSI-H metastatic ColoRectal Cancer (mCRC). In this study, a total of 307 patients with MSI-H/dMMR mCRC as determined locally, and with ECOG PS of 0 or 1 were randomly assigned 1:1 to first-line treatment with KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=153) or investigator’s choice of mFOLFOX-6 or FOLFIRI every 2 weeks, with or without Bevacizumab or Cetuximab (N=154). Chemotherapy regimens were chosen prior to randomization. Treatment was continued until disease progression, unacceptable toxicity or completion of 35 cycles (for KEYTRUDA® only). The median patient age was 63 years and both treatment groups were well balanced. The co-Primary endpoints of the study were Progression Free Survival (PFS) and Overall Survival (OS). Key Secondary endpoints included Overall Response Rate (ORR) and Safety. Patients with confirmed disease progression on chemotherapy were given the option to crossover, to receive treatment with KEYTRUDA®.

At the second interim analysis, after a median follow up of 32.4 months, it was noted that KEYTRUDA® was superior to chemotherapy with a median PFS of 16.5 months versus 8.2 months for chemotherapy (HR=0.60; P=0.00002). The estimated restricted mean survival time after 24 months of follow up was 13.7 months in the KEYTRUDA® group as compared with 10.8 months in the chemotherapy group. Progression Free Survival was consistently longer with KEYTRUDA® than with chemotherapy across prespecified subgroups. The confirmed ORR was 43.8% with KEYTRUDA® versus 33.1% with chemotherapy, with Complete Responses in 11% and 4%, respectively. Among patients with an Overall Response, 83% in the KEYTRUDA® group had ongoing responses, as compared with 35% in the chemotherapy group at 24 months. The median Duration of Response was not reached in the KEYTRUDA® group and was 10.6 months in the chemotherapy group. Following disease progression, 36% of patients assigned to the chemotherapy group crossed over to the KEYTRUDA® group. This study is being continued to evaluate OS. Grade 3-5 treatment related Adverse Event rates were 22% in the KEYTRUDA® arm and 66% in the chemotherapy group.

The authors concluded that when compared to chemotherapy, first-line therapy with KEYTRUDA® provided a clinically meaningful and statistically significant improvement in Progression Free Survival, among patients with MSI-H/dMMR metastatic colorectal cancer, with fewer treatment-related Adverse Events. The authors added that KEYTRUDA® should be the new standard of care for this patient group.

Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer. Andre T, Shiu K-K, Kim TW, et al. for the KEYNOTE-177 Investigators. N Engl J Med 2020;383:2207-2218.