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

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.

Salvage YERVOY® and OPDIVO® Combination after Prior Immune Checkpoint Inhibitor Therapy in Advanced RCC

SUMMARY: The American Cancer Society estimates that 73,750 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2020 and about 14,830 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.

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

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 Sunitinib, a multikinase inhibitor (CheckMate 214). Subsequently, two studies, a combination of BAVENCIO® (Avelumab), a PD-L1 targeted monoclonal antibody and INLYTA® (Axitinib), a Receptor Tyrosine Kinase inhibitor (JAVELIN Renal-101), and KEYTRUDA® (Pembrolizumab), a PD-1 targeted monoclonal antibody and INLYTA® (KEYNOTE-426), demonstrated superior OS, compared to Sunitinib, and for the first time set the stage for the use of a combination of Immune Checkpoint Inhibitor (ICI) and targeted therapy as first line treatment in this patient population.

The safety and activity of the combination of YERVOY® and OPDIVO® in patients with prior exposure to anti-PD-1 pathway targeted therapy, but no prior exposure to anti-CTLA-4 pathway targeted therapy, remains unknown. The rationale behind combining YERVOY® and OPDIVO® is that these two agents act in different phases of the immune response. Blocking the PD-1/PD-L1 pathway does not induce antitumor immunity if antigen-specific CD8-positive T cells are not present in cancer tissues. However, blocking the CTLA-4 pathway leads to increased activation of CD8-positive cells in the lymph nodes as well as increased infiltration of activated CD8-positive T cells into the tumor. This mechanistic difference between an anti-PD-1 antibody and an anti-CTLA-4 targeted therapy may allow activity of anti-CTLA-4 antibody in combination with anti-PD-1 antibody, upon treatment failure on prior anti-PD-1 targeted therapy.

The authors in this publication evaluated YERVOY® and OPDIVO® combination in patients with metastatic RCC, after prior treatment with anti-PD-1 pathway targeted therapy. This study included 45 patients with metastatic Renal Cell Carcinoma from 5 medical centers in the US and all patients had received prior therapy with Immune Checkpoint Inhibitors (ICIs) targeting the PD-1 pathway. The Primary objective of this study was to estimate the Objective Response Rate (ORR) to salvage YERVOY® and OPDIVO® combination, in patients with metastatic RCC, who received ICI as prior treatment.

The median number of prior lines of therapy was 3 and all patients had received at least one prior therapy targeting the PD-1 pathway. About 76% of patients received an anti-PD-1 antibody, and 24% received an anti-PDL-1 antibody before receiving YERVOY® and OPDIVO® combination. Of the 45 patients included in this study, 60% received monotherapy with prior anti-PD-1 or anti-PDL-1 antibody, 18% received PD-1 pathway targeted Immune Checkpoint Inhibitor (ICI) in combination with a VEGF receptor inhibitor (Axitinib,Sunitinib, or Cabozantinib), 9% received an ICI in combination with Bevacizumab, and 13% received an ICI in combination with another agent . Approximately 71% of the study patients received one line of prior ICI therapy and 29% of the study patients had received more than one prior ICI regimen. The best Objective Response Rate to prior ICI therapy was a Partial Response Rate of 53%, Stable disease in 27%, and Progressive disease in 20%. The median time on prior ICIs was 13 months. The median age at the time of initiation of YERVOY® and OPDIVO® combination was 62 years and all patients had more than one metastatic site, and 38% had brain metastasis. Twenty percent of the patients were favorable risk on the basis of IMDC criteria, 64% were intermediate risk, 7% were poor risk, and 9% were unknown risk.

At a median follow up of 12 months, the Objective Response Rate with the YERVOY® and OPDIVO® combination was 20% and the median Duration of Response was 7 months. An additional 16% of patients had stable disease. The median Progression Free Survival while on YERVOY® and OPDIVO® combination was 4 months. Immune-related Adverse Events of any grade with YERVOY® and OPDIVO® combination were noted in 64% of patients, and Grade 3 Immune-related Adverse Events were noted in 13% of the study patients.

It was concluded from this study that YERVOY® and OPDIVO® combination demonstrated antitumor activity with acceptable toxicity in patients with metastatic Renal Cell Carcinoma, who had prior treatment with Immune Checkpoint Inhibitors, suggesting that responses are possible in a subset of patients with metastatic Renal Cell Carcinoma who are naïve to therapy with anti-CTLA-4 antibody, and had prior exposure to therapy targeting the PD-1 pathway. Salvage YERVOY® and OPDIVO® therapy after single-agent OPDIVO® is currently being evaluated in multiple clinical trials.

Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors. Gul A, Stewart TF, Mantia CM, et al. J Clin Oncol 2020;38:3088-3094

High Tumor Mutational Burden Predicts Response to KEYTRUDA®

SUMMARY: Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High and less than 10 mutations/Megabase as Low. (A megabase is 1,000,000 DNA basepairs). 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, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the tumor-specific effector T cells.

The authors in this publication prospectively explored the association of high tissue TMB with outcomes, following treatment with KEYTRUDA®, in patients with selected, previously treated, advanced solid tumors. KEYNOTE-158 is a multicenter, multicohort, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. Eligible patients had advanced unresectable or metastatic solid tumors (Anal, Biliary, Cervical, Endometrial, Mesothelioma, Neuroendocrine, Salivary, Small-cell lung, Thyroid, and Vulvar), who had progressed on, or were intolerant to one or more lines of standard therapy, had measurable disease, as well as tumor sample available for biomarker analysis.

This study enrolled 1073 patients of whom 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients, with sufficient tissue for testing. Of these 790 patients, 102 patients (13%) had tumors identified as TMB-High, defined 10 or more mutations /Megabase. TMB status was assessed in Formalin-Fixed Paraffin-Embedded tumor samples using the FoundationOne® CDx assay. Patients received KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety. The median study follow up was 37.1 months.

In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. The ORR in the non-TMB-High group was 6%. The median duration of response was not reached in the TMB-H group and was 33.1 months in those without high TMB, at the time of data cutoff. There was low correlation between TMB and PD-L1 expression. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.

The authors concluded that high Tumor Mutational Burden status identifies a subgroup of patients who could have a robust tumor response to KEYTRUDA® monotherapy . They added that tissue TMB therefore could be a novel and useful predictive biomarker for response to KEYTRUDA® monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Marabelle A, Fakih MG, Lopez J, et al. Lancet Oncol. 2020;21:1353-1365.

FDA Approves KEYTRUDA® Plus Chemotherapy for Triple Negative Breast Cancer

SUMMARY: The FDA on November 13, 2020, granted accelerated approval to KEYTRUDA® (Pembrolizumab) in combination with chemotherapy for the treatment of patients with locally recurrent, unresectable or metastatic, Triple Negative Breast Cancer (TNBC), whose tumors express PD-L1 (Combined Positive Score-CPS 10 or more) as determined by an FDA approved test. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients and African American females. It is usually aggressive, and tumors tend to be high grade, and patients with TNBC are at a higher risk of both local and distant recurrence and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates, similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival (PFS) of only 2-3 months.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10% to 21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first-line treatment of TNBC.

KEYNOTE-355 is a randomized, double-blind, Phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2, IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (Yes versus No). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and Safety. The median follow up for patients assigned to receive KEYTRUDA® was 17.5 months and 15.5 months for the placebo group. The authors reported the results from an interim analysis conducted by an Independent Data Monitoring Committee (IDMC).

KEYTRUDA® in combination with chemotherapy, significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. Among patients with CPS of 1 or greater, the median PFS was 7.6 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for the placebo plus chemotherapy arm (HR= 0.74; P=0.0014). This however based on prespecified statistical criteria, was not considered statistically significant. Among the entire Intention-To-Treat (ITT) population, the median PFS was 7.5 months in the KEYTRUDA® plus chemotherapy group, compared with 5.6 months for chemotherapy plus placebo group (HR=0.82). Formal statistical significance was not tested in the ITT population. Overall Survival data are pending. Adverse Events (AEs) were similar in both treatment groups, although immune-related AEs occurred at a higher incidence in the KEYTRUDA® arm.

It was concluded that KEYTRUDA® in combination with several chemotherapy regimens, showed a statistically significant and clinically meaningful improvement in PFS, compared with chemotherapy alone, in patients with previously untreated locally recurrent, inoperable or metastatic TNBC, whose tumors expressed PD-L1 with a Combined Positive Score (CPS) of 10 or more. This data may be particularly relevant for patients who may have received a taxane in the adjuvant setting within a year, and could be more appropriately treated with a non-taxane regimen, in combination with KEYTRUDA®.

KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Cortes J, Cescon DW, Rugo HS. et al. J Clin Oncol 38: 2020 (suppl; abstr 1000)

Chemotherapy-Free First Line Induction and Consolidation Treatment for Acute Lymphocytic Leukemia

SUMMARY: It is estimated that 6150 individuals will be diagnosed with Acute Lymphocytic Leukemia (ALL) in the US and 1520 patients will die of the disease. ALL is more common in children, but can occur at any age and arises from malignant transformation of B- or T-cell progenitor cells. These cells express surface antigens that define their respective lineages. Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface, along with nuclear Terminal deoxynucleotide Transferase (TdT), whereas precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.

Philadelphia Chromosome (Chromosome 22) is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. Approximately 20% of adults and a small percentage of children with ALL are Philadelphia Chromosome (Ph) positive, and in the majority of children and in more than 50% of adults with Ph-positive ALL, the molecular abnormality (fusion protein) is different from that in Ph-positive Chronic Myelogenous Leukemia (p190 versus p210).

Adult patients with Ph-positive ALL are rarely cured with chemotherapy and the prognosis in these patients has markedly improved with the availability of BCR/ABL targeted Tyrosine Kinase Inhibitors (TKIs). Use of these TKIs with or without chemotherapy can result in a Complete Hematologic Remission in 94-100% of patients, irrespective of age. Eligible patients are then usually referred for allogeneic Hematopoietic Stem Cell Transplant (allo HSCT). To increase the chance of cure and decrease the likelihood of relapse, sustained decrease in Minimal Residual Disease is required, with a reduction in the tumor burden to less than 1 tumor cell in 10,000 bone marrow mononuclear cells.BLINATUMOMAB-(BLINCYTO)-(Engages-Two-Different-Targets-Simultaneously)

BiTE® technology (Bispecific T cell Engager antibody) engages the body’s immune system to detect and target malignant cells. These modified antibodies are designed to engage two different targets simultaneously, thereby placing the patient’s T cells within reach of the targeted cancer cell and facilitating apoptosis of the cancer cell. BiTE® antibodies are currently being investigated to treat a wide variety of malignancies. BLINCYTO® (Blinatumomab) is a BiTE® antibody designed to activate the patients T cells with its anti-CD3 group and then bind them to tumor cells with its anti-CD19 group, thus promoting cellular cytotoxicity. CD19 is a protein expressed on the surface of B-cell derived leukemias and lymphomas

The Italian GIMEMA investigators adopted a chemotherapy-free induction strategy and conducted a Phase II single-group trial, in which adults (no upper age limit) with newly diagnosed Ph-positive ALL, received first line therapy with SPRYCEL® (Dasatinib) plus glucocorticoids, followed by two cycles of BLINCYTO® (Blinatumomab). This study enrolled 63 patients with newly diagnosed Ph-positive ALL, and patients received prephase treatment with a glucocorticoid for 7 days before they received SPRYCEL®, and glucocorticoids were continued for an additional 24 days and discontinued on day 31. SPRYCEL® 140 mg orally once daily was administered as induction therapy for 85 days.

Patients who completed the induction phase received consolidation treatment with BLINCYTO® 28 mcg per day, and before each BLINCYTO® cycle, Dexamethasone 20 mg was administered. A minimum of two cycles of BLINCYTO® was mandatory and up to three additional cycles were allowed. Levetiracetam 500 mg twice daily was administered during treatment with BLINCYTO®, to prevent CNS adverse events. SPRYCEL® was continued during treatment with BLINCYTO®, and after BLINCYTO® administration, except in those patients in whom a T315I mutation was detected during the induction phase. Lumbar punctures were performed at diagnosis, at days 14, 22, 43, 57, and 85, and at the end of each BLINCYTO® cycle, for a total of 12 procedures. The choice of postconsolidation treatment, including allogeneic HSCT and subsequent administration of a Tyrosine Kinase Inhibitor, was at the discretion of the investigators. The median patient age was 54 years, 54% of the patients were women, and the median WBC was 13,000 per cubic millimeter. Of the 63 enrolled patients, 65% had the p190 fusion protein, 27% had the p210 fusion protein, and 8% had both. The most frequent molecular aberration was IKZF1 deletion (54%). The Primary endpoint was sustained molecular response in the bone marrow after this treatment.

Complete Hematologic Response was observed in 98% of the patients at the end of SPRYCEL® induction therapy (day 85), and the molecular response rate was 29%, and this percentage increased to 60% after two cycles of BLINCYTO®, with further increase in molecular responses after additional cycles of treatment with BLINCYTO®. At a median follow up of 18 months, Overall Survival was 95% and Disease Free Survival (DFS) was 88%. The probability of DFS among patients who had a molecular response at the end of induction therapy (day 85) was 100%, as compared with 85% among patients with a non-molecular response. There was no significant difference noted in the DFS between patients with p190 and those with p210. Patients who had an IKZF1 deletion along with additional genetic aberrations had lower Disease Free Survivals. Mutations in the ABL1 gene were detected in 6 patients who had increased Minimal Residual Disease during induction therapy, and all these mutations were cleared by BLINCYTO®. A total of 24 patients received an allogeneic HSCT, and the transplantation-related mortality was 4%. The most common adverse events of any grade were pyrexia, cytomegalovirus infection/reactivation and neutropenia.

The authors concluded that a chemotherapy-free induction and consolidation first-line treatment with SPRYCEL® and BLINCYTO®, that was based on a targeted and immunotherapeutic strategy respectively, was associated with high incidences of molecular response and survival, with fewer Grade 3 or higher adverse events, in adults with Philadelphia chromosome-positive ALL.

Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. Foà R, Bassan R, Vitale A, et al. for the GIMEMA Investigators. N Engl J Med 2020; 383:1613-1623

FDA Approves OPDIVO® plus YERVOY® for Malignant Pleural Mesothelioma

SUMMARY: The FDA on October 2, 2020, approved the combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), as first-line treatment for adult patients with unresectable Malignant Pleural Mesothelioma. It is estimated that about 3,000 new Malignant Mesothelioma cases are diagnosed each year. Mesothelioma is more common in Whites and Hispanics/Latinos than in African Americans or Asian Americans, and is also much more common in older people. Mesothelioma is more common in men than in women and the average age at the time of diagnosis for pleural mesothelioma is 72 years. The main risk factor for pleural mesothelioma is exposure to high levels of asbestos, usually in the workplace. Malignant Pleural Mesothelioma is relatively rare and has limited treatment options. The five-year survival rate for patients diagnosed with advanced disease is approximately 10 percent. There is currently only one FDA-approved first-line treatment, and there remains an unmet need for this patient group.

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 immune system T cells. 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.OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

The present FDA approval was based on a prespecified interim analysis of CheckMate 743 trial. This study is an open label, multi-center, randomized Phase III trial, evaluating OPDIVO® plus YERVOY® compared to chemotherapy (Pemetrexed and Cisplatin or Carboplatin), in patients with previously untreated Malignant Pleural Mesothelioma. This study enrolled 605 patients with unresectable pleural mesothelioma and patients were randomized 1:1 to receive either OPDIVO® 3 mg/kg IV once every 2 weeks, in combination with YERVOY® 1 mg/kg IV once every 6 weeks, for up to 2 years (N=303), or six cycles of combination chemotherapy with Cisplatin or Carboplatin plus Pemetrexed every 3 weeks (N=302). The Primary endpoint of the trial was Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and efficacy measures according to PD-L1 expression level.

Based on a pre-specified interim analysis conducted by the Independent Data Monitoring Committee (IDMC), at 22.1 months of follow up, the median OS was 18.1 months with the combination immunotherapy versus 14.1 months with combination chemotherapy (HR=0.74; P=0.002), suggesting a 26% reduction in the risk of death when treated with OPDIVO® plus YERVOY®. The 12- month OS rates were 68% and 58%, and 2-year OS rates were 41% and 27%, respectively. This OS benefit with combination immunotherapy was observed in both non-epithelioid and epithelioid Malignant Pleural Mesothelioma, regardless of PD-L1 expression.

The median PFS per Blinded Independent Central Review (BICR) was 6.8 months in the combination immunotherapy group, and 7.2 months in the combination chemotherapy group. However, combination immunotherapy resulted in a higher PFS rate at both 12 months and 24 months compared to the combination chemotherapy arm, at 30% versus 16%, and 24% versus 7%, respectively. The confirmed Objective Response Rate was 40% and 43% in the OPDIVO® plus YERVOY® and combination chemotherapy groups, respectively. The median Duration of Response was 11.0 months in the OPDIVO® plus YERVOY® group and 6.7 months in the combination chemotherapy group, with notable differences in response at 12 months (47% versus 26%) and 24 months (32% versus 8%) respectively. The most common adverse reactions in patients receiving the combination of OPDIVO® plus YERVOY® were fatigue, musculoskeletal pain, rash, pruritus, nausea, decreased appetite, diarrhea, cough and dyspnea.

The authors concluded that this is the first positive randomized trial of dual immunotherapy, in the first line treatment of patients with Malignant Pleural Mesothelioma, and the combination of OPDIVO® plus YERVOY® should be considered as the new standard of care.

First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Baas P, Scherpereel A, Nowak A, et al. Presented at the International Association for the Study of Lung Cancer 2020 Presidential Symposium; August 8, 2020; Virtual. Abstract 3.

Immune Checkpoint Inhibitors Associated with High Activity in MSI-H Cancers

SUMMARY: The DNA MisMatchRepair (MMR) system plays a crucial role in repairing DNA replication errors in normal and cancer cells. It 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 accumulation of mutations (hypermutation) and the generation of neoantigens, triggering an enhanced antitumor immune response.

MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system. Defective MMR can be a sporadic or heritable event. 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 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 Iinhibitors (ICIs). The positive outcomes following ICI treatment in MSI-H tumors may be related to the possible association with Programmed Death-Ligand 1 (PD-L1) expression and the high Tumor Mutational Burden (TMB) of these diseases.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.Testing-for-Micro-Satellite-Instability-and-MisMatch-Repair-Deficiency

MSI testing is performed using a PCR 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).

The authors in this publication conducted a systematic review and meta-analysis which included a total of 14 published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019. These articles were identified by searching the PubMed, EMBASE, and Cochrane Library databases. Overall, 939 patients in the 14 studies were analyzed, and the purpose of this study was to determine the outcomes in patients with advanced, MSI-H cancers, following treatment with ICIs. The selected studies for analysis had prospectively accrued patients with advanced or metastatic MSI-H/dMMR cancers, regardless of line of therapy, and data was available for Overall Response Rate (ORR) and/or survival analysis (Overall Survival and/or Progression Free Survival).

The studies included use of either, Avelumab (BAVENCIO®), Pembrolizumab (KEYTRUDA®), Ipilimumab (YERVOY®), Nivolumab (OPDIVO®), Atezolizumab (TECENTRIQ®) or Durvalumab (IMFINZI®). This analysis included a range of tumor types, and the Primary outcome of interest was Overall Response Rate (ORR). Secondary end points were median Progression Free Survival (PFS), median Overall Survival (OS), pooled rate of patients alive at 1, 2 and 3 years, and pooled rate of patients that attained Disease Control Rate (DCR), which is the sum of Stable Disease rate and ORR.

The pooled ORR was 41.5%, the pooled DCR was 62.8%, the pooled median PFS was 4.3 months and the pooled median OS was 24 months. The pooled 1 and 2-year OS were 75.6% and 56.5% respectively. Since only one study provided 3-year OS data, a formal pooled analysis for 3 years was not possible. The ORR was similar according to histologic analysis with the higher values for Gastric cancer (61.2%) and the lowest ORR associated with Colorectal cancer (47.1%), Endometrial (36.1%), and other tumors (35.5%).

It was concluded from this meta-analysis that Immune Checkpoint Inhibitors were associated with high activity, independent of tumor type and drug used, and molecular biomarkers such as MisMatch Repair proteins may have a predictive value for the activity of immunotherapy.

Outcomes Following Immune Checkpoint Inhibitor Treatment of Patients With Microsatellite Instability-High Cancers. A Systematic Review and Meta-analysis. Petrelli F, Ghidini M, Ghidini A, et al. JAMA Oncol. 2020;6:1068-1071.

Optimal Duration of Immune Checkpoint Inhibitors in Advanced Non Small Cell Lung Cancer

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response. The optimal duration of treatment with checkpoint inhibitors across tumor types is currently unknown and finding the balance between efficacy, toxicity and cost of therapy remains an ongoing challenge. There are presently no adequately powered, prospective, checkpoint inhibitor trials, comparing different treatment durations.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the T cells. The authors in this study explored the impact of duration of treatment with OPDIVO®, on outcomes, in patients with previously treated advanced NSCLC, in a randomized study.

CheckMate 153 is a largely community based, ongoing, Phase IIIb/IV study, reflecting a real-world population, designed to evaluate the efficacy and safety of OPDIVO® monotherapy treatment duration, in previously treated advanced NSCLC. In this study, patients with previously treated advanced or metastatic NSCLC received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression, unacceptable toxicity, or for 1 year. Treatment beyond initial progressive disease was permitted for patients with investigator-assessed clinical benefit, no rapidly progressive disease, and stable ECOG performance status, who were tolerating treatment. Patients who continued to receive treatment at 1 year were randomly assigned, regardless of response status to continue OPDIVO®, or to stop treatment (1-year fixed duration group), with the option of receiving OPDIVO® retreatment on study after disease progression. The Primary end point of safety was previously reported. Exploratory post-random assignment end points were added. Safety and tolerability, Progression Free survival (PFS), Overall Survival (OS), and Objective Response Rate (ORR) were assessed from the time of random assignment of those patients who continued to receive treatment at 1 year. The comparison was between a fixed 1-year treatment regimen and continuous therapy.

Of the 1,428 patients who received OPDIVO® in this study, 252 patients were randomly assigned to continuous treatment (N=127) or 1-year fixed-duration treatment (N=125). With minimum post-random assignment follow up of 13.5 months, median PFS was longer with continuous treatment versus 1-year fixed duration treatment (24.7 months versus 9.4 months; HR=0.56). Median Overall Survival from random assignment was also longer with continuous treatment versus 1-year fixed duration treatment in the Progression-Free Survival population (Not Reached versus 32.5 months; HR, 0.61), as well as in the Intent To Treat population (Not reached versus 28.8 months; HR, 0.62). New onset treatment-related Adverse Events occurred in a few patients and no new safety signals were identified.

The authors concluded that the above findings from an exploratory analysis represent the first randomized data on continuous versus fixed-duration immunotherapy, in previously treated patients with advanced NSCLC, and suggest that continuing OPDIVO® beyond 1 year improves outcomes.

Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non–Small-Cell Lung Cancer: CheckMate 153. Waterhouse DM, Garon EB, Chandler J, et al. DOI: 10.1200/JCO.20.00131 Journal of Clinical Oncology. Published online September 10, 2020.

OPDIVO® plus CABOMETYX® Combination Doubles Progression Free Survival in Newly Diagnosed Advanced Kidney Cancer

SUMMARY: The American Cancer Society estimates that 73,750 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2020 and about 14,830 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® is 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 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.MOA-of-CABOZANTINIB

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.

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 696O.

FDA Approves IO in Combination with Targeted Therapies for BRAF Positive Advanced Melanoma

SUMMARY: The FDA on July 30, 2020, approved TECENTRIQ® (Atezolizumab), in combination with COTELLIC® (Cobimetinib) and ZELBORAF® (Vemurafenib), for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Patients with locally advanced or metastatic melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.

ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF, demonstrated significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), compared to Dacarbazine. Squamous cell carcinomas were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. MEK gene is downstream from RAF in the MAPK pathway. The addition of a selective inhibitor of MEK gene such as COTELLIC® (Cobimetinib) to a BRAF inhibitor such as ZELBORAF® has addressed some of these limitations, in previously published studies, with improvement in Objective Response Rates (ORR) and decrease in the incidence of cutaneous secondary cancers. coBRIM is a multicenter, randomized, Phase III study in which the efficacy and safety of COTELLIC® combined with ZELBORAF®, was evaluated in previously untreated patients, with advanced BRAF-mutated melanoma. The final analysis of this trial evaluated the 5-year survival data, and the OS was over 30% in patients who received the combination therapy, with a Complete Response (CR) rate was about 20%.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells. The 5 year OS among patients receiving PD1 targeted immunotherapy is about 34%, with a median OS of 17-20 months. With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians, based on the long term data supporting the durability of responses with immunotherapies, but response rates are lower. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases, as the response rates are higher but are short lived. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear.

Preclinical studies suggested that combining these two targeted therapies with a checkpoint inhibitor might overcome the limitations of each class and potentially lead to more durable responses. The safety and efficacy of combining TECENTRIQ® with COTELLIC® (MEK inhibitor) and ZELBORAF® (BRAF inhibitor), in patients with BRAFV600-mutated metastatic melanoma, was evaluated in a Phase I study, with promising results, and a 28-day run-in period with COTELLIC® and ZELBORAF® was associated with an increase in proliferating CD4+ T-helper cells, without increasing the T-regulatory cells (Tregs). Tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response and Tregs remain a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. The aim of IMspire 150 trial was to determine if combining checkpoint inhibitor with two targeted therapies would improve efficacy.

IMspire150 is a pivotal, placebo-controlled, international, multicenter, double-blinded, Phase III trial, in which 514 treatment-naive patients with Stage IIIc and Stage IV, BRAF V600–mutant malignant melanoma were enrolled. Patients were randomly assigned 1:1 to treatment with the doublet combination or the triplet therapy. Doublet therapy given to the control group of patients consisted of ZELBORAF® 960 mg orally twice daily plus COTELLIC® at 60 mg orally, on days 1 to 21 of a 28 day cycle. In the experimental or triplet therapy group, there was a 28-day run-in with ZELBORAF® plus COTELLIC® alone, dosed similar to the control group (cycle 1), following which patients received TECENTRIQ® 840 mg IV on Days 1 and 15 of each 28 day cycle starting cycle 2, in combination with ZELBORAF® at a lower dose of 720 mg orally twice daily and COTELLIC® 60 mg orally once daily. Treatment was continued until disease progression, or unacceptable toxicity. Both treatment groups were well balanced, median patient age was 54 years, 58% were male and 94% of patients had Stage IV disease. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary end points included Objective Response Rates (ORR), Duration of Response (DOR), and Overall Survival (OS).

The combination of immunotherapy with targeted therapies was significantly superior to targeted therapies alone. At a median follow up of 18.9 months, the median PFS with the triplet combination was 15.1 months versus 10.6 months with the doublet therapy (HR=0.78; P=0.025). This represented a 22% reduction in the risk of disease progression. This benefit was observed across all subgroups including age, disease burden, LDH level, and extent of tumor involvement by organ site. Although Objective Response Rates were similar in both treatment groups, the median Duration of Response was 21.0 months with triplet combination versus 12.6 months for the doublet therapy. The OS data were not mature at the time of this analysis, but interim analysis however showed a median OS of 28.8 months with the triplet combination versus 25.1 months with doublet therapy. Both treatment groups had comparable toxicities. Among those patients receiving triplet combination, the most common toxicities were rash, fever, fatigue, nausea, pruritus, stomatitis, musculoskeletal pain, hepatotoxicity, edema, hypothyroidism, and photosensitivity.

It was concluded that in treatment-naive patients with advanced BRAF V600-mutant malignant melanoma, TECENTRIQ® in combination with ZELBORAF® and COTELLIC® significantly and clinically improved Progression Free Survival, when compared to placebo in combination with ZELBORAF® and COTELLIC®.

Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. McArthur GA, Stroyakovskiy D, Gogas H, et al. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.