Category: Immuno Oncology

Five Year Outcomes with KEYTRUDA® Plus Chemotherapy in Metastatic Nonsquamous Non Small Cell Lung Cancer

RR

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

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. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-189 is a double-blind, Phase III trial in which 616 patients with untreated Stage IV non-squamous NSCLC, without sensitizing EGFR or ALK mutations, were randomly assigned in a 2:1 ratio to receive treatment with four cycles of KEYTRUDA®/Pemetrexed/Carboplatin (N=410) or placebo plus the same chemotherapy (N=206). Patients then received either KEYTRUDA® 200 mg or saline placebo, both administered IV every 3 weeks for up to 35 cycles. All the patients received four cycles of the investigator’s choice of Cisplatin 75 mg/m2 IV or Carboplatin AUC 5 along with Pemetrexed 500 mg/m2, all administered IV every 3 weeks, followed by maintenance Pemetrexed 500 mg/m2 every 3 weeks. Patients in the placebo combination group were allowed to crossover to KEYTRUDA® monotherapy upon disease progression. Patients with symptomatic brain metastasis were excluded and patients were stratified according to PD-L1 expression (Tumor Proportion Score, 1% or more versus less than 1%), choice of platinum-based drug (Cisplatin versus Carboplatin), and smoking history. Both treatment groups were well balanced and about 17% had brain metastasis and one-third were untreated. A PD-L1 Tumor Proportion Score of 1% or more was reported in 63% of the patients, Carboplatin was the preferred platinum-based drug in 72% of the patients, and 88% of the patients were current or former smokers. The co-Primary end points were Overall Survival (OS) and Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR) and Duration of Response (DOR) and Safety. Exploratory end points included PFS2 (time from random assignment to second/subsequent progressive disease on next-line treatment or death from any cause).

In the initial report from the trial, after a median follow-up of 10.5 months, the median PFS was 8.8 months in the KEYTRUDA® combination group and 4.9 months in the placebo combination group (HR=0.52; P<0.001) and the median OS was Not Reached with KEYTRUDA® combination and was 11.3 months in the placebo combination group (HR=0.49; P<0.001).

In this updated analysis, the researchers presented 5-year outcomes from the Phase III KEYNOTE-189 study. The median time from randomization to data cutoff (in March 2022) was 64.6 months. There was continued benefit in the Progression Free Survival and Overall Survival in the KEYTRUDA® group compared to the control group (HR=0.50 versus HR=0.60, respectively). The 5-year Progression Free Survival rates were 7.5% versus 0.6% and 5-year Overall Survival rates were 19.4% versus 11.3% respectively. The Objective Response Rate in the KEYTRUDA® group was 48.3% versus 19.9% in the control group, and the median Duration of Response was 12.7 and 7.1 months, respectively. Similar trends were observed across the PD-L1 subgroups analyzed. Among the 57 patients assigned to KEYTRUDA® combination and completed 35 cycles of KEYTRUDA®, the Objective Response Rate was 86% and the estimated Overall Survival rate 3 years after completion of 35 cycles (approximately 5 years from random assignment) was 71.9%. Sustained improvements in Overall Survival were observed in the KEYTRUDA® combination group, despite a crossover rate of 57% of patients from placebo plus chemotherapy to subsequent anti-PD1 therapy, further supporting the use of KEYTRUDA® plus chemotherapy as first-line treatment.

It was concluded that KEYTRUDA® in combination with Pemetrexed and Platinum chemotherapy continued to demonstrate prolonged survival and durable antitumor activity, compared to chemotherapy alone, regardless of PD-L1 expression. The authors added that these data continue to support the combination of first-line KEYTRUDA® plus a Platinum and Pemetrexed as a standard of care, in patients with previously untreated metastatic nonsquamous NSCLC, without EGFR/ALK alterations.

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. Garassino MC, Gadgeel S, Speranza G, et al. DOI: 10.1200/JCO.22.01989 Journal of Clinical Oncology. Published online February 21, 2023.

Overall Survival Benefit with Pembrolizumab in Advanced Gastric Cancer

RR

SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life. The efficacy of PD-1 inhibitors in combination with chemotherapy has been demonstrated in Gastric and GastroEsophageal cancer.

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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

KEYNOTE-859 was a double-blind, placebo-controlled, randomized Phase III trial, conducted to evaluate the benefit of adding Pembrolizumab to Fluoropyrimidine and Platinum-containing doublet chemotherapy in patients with advanced HER2-negative Gastric or GastroEsophageal cancer. In this study, 1,579 patients with locally advanced or metastatic HER2-negative Gastric or GastroEsophageal adenocarcinoma, with known a PD-L1 Combined Positive Score (CPS), were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=790) or placebo (N=789), every 3 weeks for 35 cycles or less, given along with investigator’s choice of 5-FU plus Cisplatin or Capecitabine plus Oxaliplatin (CAPOX). Baseline characteristics were balanced between treatment groups and randomization was stratified by region, PD-L1 CPS (less than 1 versus 1 or more), and choice of chemotherapy. At baseline, 78% of patients had PD-L1 CPS 1 or more, while 35% had tumors with CPS 10 or more.

The Primary end point was Overall Survival (OS) by blinded Independent Central Review. Secondary end points included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and Safety. The researchers provided the data from the interim analysis, at a median follow up of 31.0 months.

The median Overall Survival was 12.9 months with Pembrolizumab plus chemotherapy versus 11.5 months with chemotherapy alone (HR=0.78, P<0.0001). The median PFS was 6.9 months versus 5.6 months, respectively (HR=0.76, P<0.0001). The benefit with Pembrolizumab was consistent across subgroups, including those by PD-L1 CPS. The risk reduction was especially notable among patients with MicroSatellite Instability (MSI)-High status, who had a 66% relative reduction in the risk of death, and patients with PD-L1 CPS 10 or more, whose risk was reduced by 36%. The Objective Response Rate was 51.3% in the Pembrolizumab group and 42.0% in the control group (P=0.00009), and the median Duration of Response was 8.0 months versus 5.7 months, respectively. Immune-related toxicities, especially hypothyroidism, were more common with Pembrolizumab plus chemotherapy and no new safety signals were seen.

It was concluded that treatment with Pembrolizumab plus chemotherapy resulted in a statistically significant and clinically meaningful improvement in Overall Survival, Progression Free Survival and Objective Response Rate, among patients with locally advanced or metastatic, HER2-negative Gastric or GastroEsophageal adenocarcinoma of any PD-L1 expression level, thus providing a new treatment option for this patient group.

Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: Phase III KEYNOTE-859 study. Rha SY, Wyrwicz LS, Weber PEY, et al. ESMO Virtual Plenary Session Date: 16-17 February 2023. VP1-2023. Published: February 16, 2023. DOI: https://doi.org/10.1016/j.annonc.2023.01.006.

FDA Approves Adjuvant KEYTRUDA® in NSCLC Irrespective of PD-L1 Expression

RR

SUMMARY: The FDA on January 26, 2023, approved KEYTRUDA® (Pembrolizumab) for adjuvant treatment following resection and platinum-based chemotherapy for Stage IB (T2a ≥4 cm), II, or IIIA Non-Small Cell Lung Cancer (NSCLC). Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

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

KEYNOTE-091/EORTC-1416-LCG/ETOP-8-15 – PEARLS trial is a multicenter, randomized, triple-blind, placebo-controlled Phase III trial, which compared the efficacy of KEYTRUDA® with placebo, among patients with resected NSCLC. In this study, 1,177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC with negative margins, and with tumor tissue available for PD-L1 testing were included. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended. In the least, the subcarinal and 1 lobe-specific lymph node must have been examined. Eligible patients had not received neoadjuvant radiotherapy or chemotherapy, had ECOG PS of 0-1, and adjuvant chemotherapy for up to four cycles was optional. Adjuvant chemotherapy could be considered for those with Stage IB disease and was strongly recommended for those with Stage II and IIIA disease. Patients were randomized (1:1) to receive KEYTRUDA® 200 mg or placebo IV every three weeks and treatment was continued until disease recurrence, unacceptable toxicity, or up to 1 year. Both treatment groups were well balanced. The median patient age was 65 years, majority of patients (68%) were male, approximately 65% of patients had nonsquamous histology, 56% of patients had Stage II disease and 86% of patients had received adjuvant platinum-based chemotherapy following complete resection. Stratification factors included disease stage, receipt of adjuvant chemotherapy, PD-L1 Tumor Proportion Score and geographic region of the world. The median duration of exposure to KEYTRUDA® was 11.7 months and 68% of patients in the KEYTRUDA® group were exposed to KEYTRUDA® for at least 6 months. The major efficacy outcome measure was investigator-assessed Disease-Free Survival (DFS). An additional efficacy outcome was Overall Survival (OS).

The trial met its Primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population. In patients who received adjuvant platinum-based chemotherapy following surgical resection, KEYTRUDA® reduced the risk of disease recurrence or death by 27% (HR=0.73) versus placebo, regardless of PD-L1 expression. For patients who received adjuvant chemotherapy, median DFS regardless of PD-L1 expression was 58.7 months in the KEYTRUDA® group versus 34.9 months in the placebo group. In an exploratory subgroup analysis of the 167 patients who did not receive adjuvant chemotherapy, the DFS Hazard Ratio was 1.25. Overall survival Data were not mature.

It was concluded that these data support the benefit of KEYTRUDA® as a new adjuvant immunotherapy treatment option, for early-stage NSCLC following complete resection, and if indicated, adjuvant chemotherapy, regardless of PD-L1 expression.

EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study of pembrolizumab versus placebo for completely resected early-stage non-small cell lung cancer (NSCLC): Outcomes in subgroups related to surgery, disease burden, and adjuvant chemotherapy use.O’Brien M, Paz-Ares L, Jha N, et al. DOI: 10.1200/JCO.2022.40.16_suppl.8512 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 8512-8512.Published online June 02, 2022.

FDA Approves Bispecific Antibody LUNSUMIO® for Follicular Lymphoma

RR

SUMMARY: The FDA on December 22, 2022, granted accelerated approval to LUNSUMIO® (Mosunetuzumab-axgb), a bispecific CD20-directed CD3 T-cell engager for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after two or more lines of systemic therapy.

The American Cancer Society estimates that in 2022, about 80,470 people were diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals died 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 22% 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 Progression Free Survival of 6-8 years. However, approximately 30% of the patients will relapse in 3 years, and treatment options are limited for patients with relapses after multiple treatments. Patients with Follicular Lymphomas often experience a relapsing and remitting pattern of disease and may be exposed to multiple lines of therapy over the course of their disease. In spite of the availability of multiple systemic therapies for Follicular Lymphoma, the efficacy of these regimens drops off rapidly with later lines of therapy. Novel therapies are therefore being investigated to improve outcomes.

LUNSUMIO® is a first-in-class CD20 x CD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells.

This FDA approval was based on the positive results from the Phase II GO29781 study, which is a multicenter, open-label, dose-escalation and dose-expansion trial evaluating the safety, efficacy, and pharmacokinetics of LUNSUMIO® in patients with heavily pretreated Follicular Lymphoma, including those who were at high risk of disease progression or whose disease was refractory to prior therapies. The efficacy population consisted of 90 enrolled patients with Relapsed or Refractory FL (Grade 1-3a) who had received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.

LUNSUMIO® was administered IV in 21-day cycles with Cycle 1 step-up dosing of 1 mg on Cycle 1, Day 1, 2 mg on Cycle 1 Day 8, 60 mg on Cycle 1 Day 15, 60 mg on Cycle 2 Day 1, and 30 mg on Day 1 in subsequent cycles. Patients with a Complete Response discontinued therapy after 8 cycles. Patients with a Partial Response or Stable disease continued treatment for up to 17 cycles unless they experienced progressive disease or unacceptable toxicity. The Primary endpoint was Objective Response Rate (ORR) assessed by an Independent Review Committee according to standard criteria for Non-Hodgkins Lymphoma.

The ORR was seen in 80% of patients treated with LUNSUMIO® with 60% achieving Complete Responses. A majority of patients (57%) maintained responses for at least 18 months. With a median follow up of 14.9 months among responders, the estimated median Duration of Response was 22.8 months and the estimated Duration of Response at 12 months and 18 months was 62% and 57%, respectively. Among 218 patients with hematologic malignancies who received LUNSUMIO® at the recommended dose, the most common Adverse Event was Cytokine Release Syndrome (CRS) seen in 39% of patients, which can be severe and life-threatening. The median duration of CRS events was 3 days. Other common Adverse Events included fatigue, rash, fever and headache.

It was concluded from this study that in patients with heavily pretreated Follicular Lymphoma, chemotherapy-free, fixed-duration treatment with LUNSUMIO® induced high rates of Complete Remissions with favorable safety profile, allowing potential administration as an outpatient regimen.

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Budde LE, Sehn LH, Matasar M, et al. The Lancet Oncology 2022; 23:1055-1065.

Tumor-Infiltrating Lymphocyte Therapy in Advanced Refractory Melanoma

RR

SUMMARY: The American Cancer Society estimates that in 2022, about 99,780 new cases of melanoma of the skin were diagnosed in the United States and 7,650 people died of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

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 (ORR) 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. YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. They are therefore frequently used first-line treatment in patients with metastatic melanoma.

Over 50% of untreated patients receiving a combination of PD-1 and CTLA-4 inhibitors are alive after five years. However, combination immunotherapy with YERVOY® and OPDIVO® is associated with a high incidence of severe adverse events and is currently recommended primarily for a subgroup of patients with poor prognostic factors such as a high serum LDH levels or liver or brain metastases. Approximately 50% of melanomas harbor BRAF V600E mutation and are often treated with a combination of BRAF and MEK inhibitors. This combination is associated with a high response, but resistance develops in most patients over time. YERVOY® is presently often used as second line therapy, but only 15-30% of patients benefit from this intervention. There is an unmet need for this group of patients.

Adoptive immunotherapy, also known as cellular immunotherapy, is a form of treatment in which naturally occurring or gene-engineered T cells with antitumor activity are transferred to a tumor-bearing host to eliminate cancer. These killer T cells bind to antigens on the surface of cancer cells and destroy them. Cellular immunotherapies include Tumor-Infiltrating Lymphocyte (TIL) Therapy, Engineered T Cell Receptor (TCR) Therapy, Chimeric Antigen Receptor (CAR) T Cell Therapy and Natural Killer (NK) Cell Therapy.

Adoptive immunotherapy with Tumor-Infiltrating Lymphocytes (TILs) is a personalized autologous therapy in which lymphocytes which have infiltrated the tumor are expanded in vitro and administered intravenously following nonmyeloablative, lymphodepleting chemotherapy, and supported by the IV administration of Interleukin-2 (IL-2) to enhance the in vivo expansion of the cells and augment antitumor responses. In contrast to Lymphokine-Activated Killer cells (LAK), human TILs demonstrate cytolytic specificity against only the tumor from which they were derived or against closely related tumors, and in preclinical models have proved to be 50 to 100 times more potent than LAK cells. Evidence of clinical activity of TIL therapy in patients with advanced melanoma was initially reported by Rosenberg and colleagues in the 1990s and subsequent Phase 1-2 trials showed responses in 30-70% of patients, with responses noted even among those who had disease progression while receiving anti-PD1 treatment. Nonetheless, there has been no direct comparison of TILs with standard treatment.

This multicenter, open-label, Phase III, randomized trial was conducted to compared TILs with Yervoy® as first or second-line treatment in patients with advanced melanoma. In this study, a total of 168 patients with unresectable Stage IIIC or IV melanoma were randomly assigned in a 1:1 ratio to receive either TILs (N=84) or YERVOY® (N=84). Patients assigned to receive TILs underwent metastasectomy for the retrieval and expansion of TILs, followed by inpatient administration of nonmyeloablative, lymphodepleting chemotherapy, which consisted of Cyclophosphamide 60 mg/kg IV QD for 2 days and Fludarabine 25 mg/m2 IV QD for 5 days, single adoptive transfer of 5×109 to 2×1011 TILs intravenously, and subsequent high-dose IL-2, 600,000 IU/kg IV every 8 hours, for a maximum of 15 doses. Patients in the YERVOY® group received 3 mg/kg IV every 3 weeks, for a maximum of 4 doses. Administration of YERVOY® could be delayed or discontinued if adverse events occurred, and no dose reductions were allowed. Both treatment groups were well balanced and 86% of patients were refractory to PD-1 inhibitor therapy, mostly adjuvant or first line therapy. The median patient age was 59 years and patients were stratified according to BRAF V600-mutation status, line of treatment, and treatment center. The Primary end point was Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR), Complete Response (CR), Overall Survival (OS), Health-Related Quality of Life and Safety.The median follow-up was 33.0 months.

The median PFS was 7.2 months in the TIL group and 3.1 months in the YERVOY® group (HR=0.50;P<0.001).The Objective Response Rate was 49% in the TIL group and 21% in the YERVOY® group, with a Complete Response rate of 20% in the TIL group and 7% in the YERVOY® group, with durable Complete Responses in both treatment groups. The median Overall Survival was 25.8 months in the TIL group and 18.9 months in the YERVOY® group(HR=0.83). The 2-year OS was 54.3% in the TIL group and 44.1% in the YERVOY® group. Treatment-related adverse events of Grade 3 or higher occurred in all patients in the TIL group and in 57% of those in the YERVOY® group, and these events were mainly chemotherapy-related myelosuppression. Treatment-related serious adverse events occurred in 15% of the patients in the TIL group and 27% of those in the YERVOY® group.

It was concluded that in patients with advanced melanoma including those patients refractory to PD-1 inhibitor therapy, treatment with TILs was associated with significantly longer Progression Free Survival than treatment with YERVOY®.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. Rohaan MW, Borch TH, Van den Berg JH, et al. N Engl J Med 2022; 387:2113-2125

Landmark Five Year Overall Survival Rates for OPDIVO® and YERVOY® Combination in Advanced NSCLC

RR

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the 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® (Nivolumab) 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.

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. This study consisted of Part 1a/Part 1b and Part 2. In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere.

Part 1a: Patients received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks (N=396), OPDIVO® monotherapy 240 mg IV every 2 weeks (N=396) or chemotherapy alone given every 3 weeks for up to four cycles (N=397), in patients whose tumors had PD-L1 expression of 1% or more.
Part 1b: Patients received OPDIVO® plus YERVOY® (N=187), OPDIVO® 360 mg IV every 3 weeks plus chemotherapy IV every 3 weeks for up to four cycles (N=177), or chemotherapy alone IV every 3 weeks for up to four cycles (N=186), in patients whose tumors did not express PD-L1 (less than 1%)

Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or administered for 2 years for immunotherapy. It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.

There were two independent Primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Part 1a and Part 1b). Other assessments included Objective Response Rate (ORR), Duration of Response (DOR), and treatment-free interval. Treatment-free interval was measured in patients who discontinued study therapy and was defined as the time from last study dose to start of subsequent systemic therapy.

The Overall Survival (OS) data was previously reported at a minimum follow up of 29 months, and the median OS was of 17.1 months for the OPDIVO® plus YERVOY® group, compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007), with a 2-year OS rate of 40.0% and 32.8%, respectively. The researchers here in presented data after a minimum follow up of 61.3 months (5 years).

Patients whose tumors had PD-L1 expression of 1% or more continued to have sustained long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR=0.77), and the 5-year OS rates were 24% with OPDIVO® plus YERVOY® compared to 14% with chemotherapy alone.

Patients with a PD-L1 expression of less than 1% also demonstrated continued long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR = 0.65), and the 5-year OS rates were 19% for OPDIVO® plus YERVOY&reg compared to 7% for chemotherapy alone.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 months for PD-L1–negative patients who received OPDIVO® plus YERVOY®, compared to 9.5 months and 24.9 months respectively, for those who received chemotherapy.

Among those who responded to treatment, more patients who received OPDIVO® plus YERVOY® remained in response at five years, compared to chemotherapy, in both PD-L1 expression of 1% or more group (28% versus 3%) and PD-L1 expression of less than 1% group (21% versus 0%), respectively.

Among patients treated with OPDIVO® plus YERVOY® who were alive at five years, approximately two-thirds of patients did not receive any subsequent therapy for more than three years after stopping treatment, regardless of PD-L1 expression.

It was concluded that in this longest reported follow up of a Phase III trial of first line, chemotherapy free, combination immunotherapy, in metastatic Non Small cell Lung Cancer, a combination of OPDIVO® plus YERVOY® continued to provide long term durable clinical benefit and increased 5-year survivorship, when compared to chemotherapy, in previously untreated patients with metastatic NSCLC, regardless of PD-L1 expression.

Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. Brahmer JR, Lee J-S, Ciuleanu T-E, et al. DOI: 10.1200/JCO.22.01503 Journal of Clinical Oncology. Published online October 12, 2022.

Clinical considerations in 1L advanced renal cell carcinoma (aRCC)

RR

Written by Manojkumar Bupathi, MD, MS
Sponsored by Exelixis

The treatment of patients with aRCC is evolving rapidly, with new regimens being developed and approved for 1L therapy. When choosing a regimen for patients, there are a number of treatment components to assess, including but not limited to the patient’s clinical presentation, their ability to tolerate treatment, and potential impact on quality of life. In my practice, I look at the location of metastases in the patient, whether they have symptomatic disease, and whether treatment‐related adverse reactions can be managed with supportive care.

A 1L aRCC treatment I consider is the FDA‐approved combination of CABOMETYX® (cabozantinib) + OPDIVO® (nivolumab). I believe CABOMETYX + OPDIVO offers a balance of data including superior OS, safety and tolerability, and patient‐ reported QoL data.1‐3*

CheckMate‐9ER was a randomized (1:1), open‐label, Phase 3 trial vs sunitinib in 651 patients with previously untreated aRCC with a clear‐cell component.1,2,4

  • Dosing: CABOMETYX 40 mg (starting dose) PO once daily in combination with OPDIVO 240 mg flat dose IV every 2 weeks vs sunitinib 50 mg (starting dose) PO once daily for 4 weeks,      followed by 2 weeks off, per cycle.1
  • Starting dose: unlike the 60‐mg recommended starting dose for single‐ agent therapy, the starting dose of CABOMETYX is 40 mg when used in combination with OPDIVO1
  • Primary endpoint: PFS1
  • Secondary endpoints: OS, ORR, and safety1,4
  • Quality of life: evaluated as an exploratory endpoint using the FKSI‐19 scale, and the clinical significance of the results is unknown2,3
  • Additional exploratory endpoints: biomarkers, pharmacokinetics, immunogenicity, and PFS‐22,5
  • Updated efficacy analysis: conducted when 271 events were observed based on the pre‐specified number of events for the pre‐planned final analysis of OS1,6

Primary analysis results (median follow‐up time of 18.1 months; range: 10.6‐30.6 months)2:

Updated analysis of OS (median follow‐up: 32.9 months; range: 25.4‐45.4 months):

  • Median OS was 37.7 months for CABOMETYX + OPDIVO (95% CI: 35.5‐NR; n=323) compared with 34.3 months for sunitinib (95% CI: 29.0‐NR; n=328); HR=0.70 (95% CI: 0.55‐0.90).1,6,7

When selecting a 1L treatment for my patients with aRCC, I review all the efficacy endpoints along with tolerability and safety data, as well as dosing. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving CABOMETYX+ OPDIVO (n=320).1 Serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia.1 Fatal intestinal perforations occurred in 3 (0.9%) patients.1 The most common adverse reactions (≥20%) in patients receiving CABOMETYX + OPDIVO were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar‐plantar erythrodysesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), upper respiratory tract infection (20%), and cough (20%).1

  • CABOMETYX may be interrupted or reduced due to adverse events to 20 mg daily or 20 mg every other day.1
    • If previously receiving 20 mg once every other day, resume at same dosage. If not tolerated, discontinue CABOMETYX.1
    • Adverse reactions leading to discontinuation of either CABOMETYX or OPDIVO occurred in 20% of patients, which included 8% (CABOMETYX only) and 7% (OPDIVO only). It is important to note that 6% of patients in the CheckMate‐9ER trial discontinued both CABOMETYX and OPDIVO due to adverse events, compared with 16.9% of patients in the sunitinib arm who permanently discontinued their treatment.1,8
  • CABOMETYX should be permanently discontinued for Grade 3 or 4 hemorrhage, development of a GI perforation or Grade 4 fistula, acute myocardial infarction or Grade 2 or higher cerebral infarction, Grade 3 or 4 arterial thromboembolic events or Grade 4 venous thromboembolic events, Grade 4 hypertension/hypertensive crisis or Grade 3 hypertension/hypertensive crisis that cannot be controlled, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome1
  • For patients being treated with CABOMETYX in combination with OPDIVO, if ALT or AST >10x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN, both CABOMETYX and OPDIVO should be permanently discontinued1

With these data, I feel comfortable using CABOMETYX + OPDIVO as a first‐line treatment for appropriate aRCC patients. I’d like to add that, according to the NCCN guidelines, CABOMETYX + OPDIVO is a category 1 preferred regimen in clear cell aRCC, which gives me additional confidence to prescribe this regimen for appropriate patients.9‡

Dr Bupathi received a fee for participating in this program, and his comments reflect his opinions and are not intended to constitute medical advice for individual patients.

[Footnotes]
*Superior OS vs sunitinib in patients with previously untreated aRCC. Primary analysis OS results: 40% reduction in risk of death with CABOMETYX + OPDIVO vs sunitinib (HR=0.60 [98.89% CI: 0.40‐0.89]; P=0.001); median OS was not reached in either arm. The primary endpoint was PFS, and secondary endpoints included OS, ORR, and safety. Quality of life was evaluated as an exploratory endpoint using the FKSI‐19 scale, and the clinical significance is unknown.1-3
†PFS and ORR were assessed by BICR.1
‡The trial population size of CheckMate‐9ER was 651 patients.1

1L=first‐line; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BICR=blinded independent central review; CI=confidence interval; FDA=Food and Drug Administration; FKSI‐19=Functional Assessment of Cancer Therapy‐Kidney Symptom Index 19; HR=hazard ratio; IO=immunotherapy; IV=intravenous; NR=not reached; ORR=objective response rate; OS=overall survival; PFS=progression‐free survival; PFS‐2=PFS after subsequent therapy; PO=by mouth; QoL=quality of life; TKI=tyrosine kinase inhibitor; ULN=upper limit of normal.

INDICATIONS
CABOMETYX® (cabozantinib), in combination with nivolumab, is indicated for the first‐line treatment of patients with advanced renal cell carcinoma (RCC).
CABOMETYX is indicated for the treatment of patients with advanced RCC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti‐hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.
Palmar‐Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0‐1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.
Withhold and resume at a reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.
Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.
Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.
In COSMIC‐311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.
Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.
Embryo‐Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.
CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information by clicking here.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1‐800‐FDA‐1088.

References
1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2022.
2. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma. N Engl J Med. 2021;384(9):829‐841.
3. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma [supplementary appendix]. N Engl J Med. 2021;384(9):829‐841.
4. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma: outcomes by sarcomatoid histology and updated trial results with extended follow‐up of CheckMate 9ER. Poster presented at Genitourinary Cancers Symposium; February 11‐ 13, 2021.
5. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma [protocol]. N Engl J Med. 2021;384(9):829‐841.
6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ‐specific target lesion assessments with 2‐year follow‐up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. Poster presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium; February 17‐19, 2022.
7. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first‐line treatment for advanced renal cell carcinoma (CheckMate 9ER): long‐term follow‐up results from an open‐label, randomized, phase 3 trial. Lancet Oncol. 2022;23(7):888‐898.
8. Data on file. Final Clinical Study Report for Study CA2099ER. Bristol Myers Squibb.
9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.3.2023. © National Comprehensive Cancer Network, Inc. 2022.

All rights reserved. Accessed September 29, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

©2022 Exelixis, Inc. CA‐2644 12/22
OPDIVO® and the related logo are registered trademarks of Bristol‐Myers Squibb Company.

FDA Approves LIBTAYO® in Combination with Chemotherapy for Non-Small Cell Lung Cancer

RR

SUMMARY: The FDA on November 8, 2022, approved LIBTAYO® (Cemiplimab-rwlc) in combination with platinum-based chemotherapy for adult patients with advanced Non-Small Cell Lung Cancer (NSCLC) with no EGFR, ALK, or ROS1 aberrations. The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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 and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immuno-Oncology (IO) therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation, and a therapeutic response. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced NSCLC. It is now standard therapy for patients with lung cancer.

KEYTRUDA® (Pembrolizumab; anti PD-1) and TECENTRIQ® (Atezolizumab; anti PD-L1) are both approved in combination with platinum-based chemotherapy for the first-line treatment of patients with metastatic NSCLC. The FDA approval of TECENTRIQ® with platinum-doublet chemotherapy is however limited to non-squamous histology.

LIBTAYO® is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1. LIBTAYO® monotherapy was approved by the FDA in 2021 after it demonstrated significantly improved Overall Survival and Progression Free Survival compared with chemotherapy, in patients with advanced Non-Small Cell Lung Cancer with PD-L1 of at least 50%. The researchers in EMPOWER-Lung 3 evaluated the efficacy of first line LIBTAYO® in combination with investigator’s choice of platinum-doublet chemotherapy, among patients with advanced NSCLC, with either squamous or non-squamous histology, and any level of PD-L1 expression.

EMPOWER-Lung 3 is a randomized, multicenter, multinational, double-blind, active-controlled Phase III trial in which 466 patients with advanced NSCLC who had not received prior systemic treatment were randomized (2:1) to receive either Cemiplimab 350 mg IV once every 3 weeks (N=312) or placebo (N=154) every 3 weeks, in combination with four cycles of chemotherapy. Investigators’ choice of histology-specific chemotherapy options included Paclitaxel plus Carboplatin, Paclitaxel plus Cisplatin, Pemetrexed plus Carboplatin and Pemetrexed plus Cisplatin. Patients were treated for a maximum of 108 weeks, or until disease progression or unacceptable toxicity. For patients with non-squamous histology assigned to a Pemetrexed-containing regimen, maintenance Pemetrexed was mandatory. Patients were enrolled irrespective of PD-L1 expression or tumor histology and had advanced or metastatic NSCLC, with no ALK, EGFR or ROS1 aberrations. Among those enrolled, 43% had tumors with squamous histology, 67% had tumors with less than 50% PD-L1 expression, 15% had inoperable locally advanced disease not eligible for definitive chemoradiation, and 7% had pretreated and clinically stable brain metastases. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR).

The trial was stopped early upon recommendation by the Independent Data Monitoring Committee (IDMC) after the LIBTAYO® combination demonstrated a statistically significant and clinically meaningful improvement in Overall Survival, compared to placebo plus chemotherapy. The median OS was 21.9 months in the LIBTAYO® plus chemotherapy group and 13.0 months in the placebo plus chemotherapy group (HR=0.71; P=0.0140). This represented a 21% relative reduction in the risk of death in the LIBTAYO® plus chemotherapy group. The 12-month probability of survival was 66% for the LIBTAYO® combination versus 56% for chemotherapy.

The median PFS per BICR was 8.2 months in the LIBTAYO® plus chemotherapy group and 5.0 months in the placebo plus chemotherapy group (HR=0.56; p<0.0001). This represented a 44% reduction in the risk of disease progression in the LIBTAYO® plus chemotherapy group. The 12-month probability of PFS for the LIBTAYO® combination was 38%, versus 16% for chemotherapy. The confirmed ORR per BICR was 43% and 23% in the respective treatment groups and the median Duration of Response was 16 months versus 7 months respectively. The most common (15% or more) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

It was concluded that LIBTAYO® is only the second anti-PD-1/PD-L1 agent to show efficacy in advanced Non-Small Cell Lung Cancer either as monotherapy in those with PD-L1 expression 50% or more, or in combination with chemotherapy, irrespective of PD-L1 expression or tumor histology.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Gogishvili M, Melkadze T, Makharadze T, et al. Nature Medicine 2022;(28):2374-2380.

TAFINLAR® and MEKINIST® versus OPDIVO® plus YERVOY® for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial

RR

SUMMARY: The American Cancer Society estimates that for 2022, about 99,780 new cases of melanoma of the skin will be diagnosed in the United States and 7,650 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

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 results in constitutive activation of the MAPK pathway.

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 (ORR) 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. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. TAFINLAR® plus MEKINIST® led to long-term survival benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, from two randomized Phase III COMBI-d and COMBI-v trials.

A combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab) showed durable improved outcomes among patients with unresectable or metastatic melanoma and approximately 50% of patients were alive at 6.5 years (J Clin Oncol 39, 2021. suppl 15; abstr 9506). The FDA granted approval for this combination in 2015 for the treatment of patients with metastatic melanoma, regardless of tumor BRAF mutation status.

It has been noted that BRAF/MEK inhibitor therapy tends to produce high tumor response rates and prolonged median Progression Free Survival (PFS), whereas OPDIVO® /YERVOY® tends to have its major impact on Duration of Response. However, the optimal treatment sequence for patients with treatment-naive BRAFV600-mutant metastatic melanoma, between combination OPDIVO®/YERVOY® checkpoint inhibitor immunotherapy and combination TAFINLAR® plus MEKINIST® molecularly targeted therapy, has remained unclear. Recently published tumor biology studies have suggested that resistance to BRAF/MEK-inhibitor therapy results in an immunosuppressive tumor microenvironment that is void of functional CD103+ dendritic cells, preventing effective antigen presentation to the immune system, and that immunotherapy may enhance BRAF-mutated melanoma responsiveness to targeted therapy.

DREAMseq (EA6134) is a two-arm, two-step, open-label, randomized Phase III trial, which investigated the anti PD-1/CLTA-4 immunotherapy combination of OPDIVO® plus YERVOY® followed by the anti-BRAF/MEK targeted therapy combination of TAFINLAR® plus MEKINIST®, versus the reverse sequence, in patients with advanced BRAF V600-mutant melanoma. This study was conducted to determine which treatment sequence produced the best efficacy.

In this study, 265 patients with treatment-naive BRAF V600-mutant metastatic melanoma were randomly assigned to receive either combination OPDIVO® plus YERVOY® (arm A=133) or TAFINLAR® plus MEKINIST® (arm B=132) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, TAFINLAR® plus MEKINIST® (arm C=27) or OPDIVO® plus YERVOY® (arm D=46). The two initial treatment arms were balanced and more patients on arm B had BRAF V600K-mutant tumors than those on arm A (25.2% versus 12.1%). The median patient age was 61 years and eligible patients had histologically confirmed, BRAF V600-mutant unresectable Stage III or IV melanoma with measurable disease. The Primary end point was 2-year Overall Survival (OS). Secondary end points included 3-year OS, Objective Response Rate (ORR), Duration of Response, Progression Free Survival (PFS), crossover feasibility, and Safety.

The study was stopped early by the Independent Data Safety Monitoring Committee because statistical significance was achieved for the Primary endpoint. The 2-year OS for those starting on arm A was 71.8% and arm B was 51.5% (P=0.01). Step 1 Progression Free Survival favored arm A (P=0.054). The Objective Response Rates were arm A: 46%, arm B: 43%, arm C: 47.8%, and arm D: 29.6%. The median Duration of Response was not reached for arm A, and 12.7 months for arm B (P<0.001). Crossover occurred in 52% of patients following documented disease progression. Grade 3 or more toxicities occurred with similar frequency between treatment groups and adverse events related to regimens were as expected.

It was concluded from this study that for patients with advanced BRAF V600-mutant metastatic melanoma, the treatment sequence beginning with the immune checkpoint inhibitor combination of OPDIVO® plus YERVOY® resulted in superior Overall Survival and longer Duration of Response, compared with the treatment sequence beginning with TAFINLAR® plus MEKINIST®, and should therefore be the preferred treatment sequence for most of these patients.

Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134. Atkins MB, Lee SJ, Chmielowski B, et al. J Clin Oncol. Published online September 27, 2022. doi:10.1200/JCO.22.01763

Association of Gut Microbiome with Immune Checkpoint Inhibitor Response in Advanced Melanoma

RR

SUMMARY: The American Cancer Society estimates that in 2022, there will be an estimated 1.92 million new cancer cases diagnosed and 609,360 cancer deaths in the United States. 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. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years. Nonetheless, less than 50% of the patients respond to single-agent ICI and a higher response to targeting both PD-1 and CTLA-4 is associated with significant immune-related Adverse Events.

Biomarkers predicting responses to ICIs 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- Interferon-gamma, Neutrophil-to-ratio, and peripheral cytokines, have also been proposed as predictors of response. It has been postulated that concomitant medications during therapy with ICIs such as baseline steroid use as well as treatment with antibiotics may negate or lessen the efficacy of ICIs.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The gut microbiome is unique in each individual, including identical twins. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. It should be noted however that the relationship between gut bacteria and immune response is influenced by several factors and may be partially cancer type specific and it is unlikely that the same microbiome features can reflect the uniqueness of the genetic and immune characteristics of each tumor.

Even though the composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, there is a lack of consistency of results between the published studies, and there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. The Predicting Response to Immunotherapy for Melanona with Gut Microbiome and Metabolomics (PRIMM) studies are two separate prospective observational cohort studies that has been recruiting patients in the UK (PRIMM-UK) and the Netherlands (PRIMM-NL) since 2018. These cohorts of previously ICI-naive patients with advanced melanoma have provided extensive biosamples, including stool, serum and peripheral blood mononuclear cells, before and during ICI treatment, with detailed clinical and dietary data collected at regular intervals longitudinally.

The authors therefore performed a meta-analysis on existing publicly available datasets to produce the largest study to date. In order to study the role of the gut microbiome in ICI response, the researchers recruited ICI-naive patients with advanced cutaneous melanoma from the PRIMM cohorts, as well as three additional cohorts of ICI-naive patients with advanced cutaneous melanoma, originating from Barcelona, Leeds and Manchester (N = 165), and performed shotgun metagenomic sequencing on a total of 165 stool microbiome samples collected before initiating ICI treatment. Shotgun sequencing is a laboratory technique for determining the DNA sequence of an organism’s genome. This dataset was integrated with 147 metagenomic samples from smaller publicly available datasets. This methodology provided the largest assessment of the potential of the gut microbiome as a biomarker of response to ICI, in addition to allowing for investigation of specific microbial species or functions associated with response. Patient demographics including age, gender, BMI, previous non-immunotherapy treatments, previous drug therapies such as antibiotics, Proton Pump Inhibitors (PPIs) and steroids, as well as dietary patterns, were collected in these cohorts for the majority of patients, and were considered in the multivariate analysis.

The researchers used machine learning analysis to understand the association between gut microbiome and response to ICIs. This analysis confirmed the link between the microbiome and Overall Response Rates (ORRs), as well as Progression Free Survival (PFS) with ICIs. This analysis also revealed limited reproducibility of microbiome-based signatures across cohorts. A panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansiamuciniphila were associated with responders, but no single species could be regarded as a fully reliable biomarker across studies. Based on these findings from this large set of real-world cohorts, the authors noted that the relationship between human gut microbiome and response to ICIs is more complex than previously understood, and extends beyond the presence or absence of different microbial species in responders and nonresponders.

It was concluded that future studies should include large samples and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course. Until then, the authors recommend high-quality, diverse, whole-foods diet to optimize gut health, rather than consumption of commercial probiotics.

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Lee KA, Thomas AM, Bolte LA, et al. Nat Med. 2022;28:535-544.