Date: 2016-10-09
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
Company: Eli Lilly (USA - IN) Merck&Co (USA - NJ)
Product: Alimta® (pemetrexed) plus carboplatin in combination with Keytruda® (pembrolizumab)
Action
mechanism: antifolate/monoclonal antibody/immune checkpoint inhibitor. Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Keytruda® (pembrolizumab - MK-3475) is an investigational, highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system. In April 2013, MK-3475 has received a Breakthrough Therapy designation for advanced melanoma from the FDA. In October 2014, the FDA has gralso anted Breakthrough Therapy Designation to Keytruda® (pembrolizumab) for the treatment of patients with Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease has progressed on or following platinum-based chemotherapy. In November 2015, the FDA has granted Breakthrough Therapy Designation to Keytruda® for the treatment of patients with microsatellite instability high (MSI-H)metastatic colorectal cancer. Keytruda® is the first approved drug that blocks the PD-1 cellular pathway. The Keytruda® clinical development program includes patients with more than 30 tumor types in more than 160 clinical trials, including more than 80 trials that combine Keytruda® with other cancer treatments. Registration-enabling trials of Keytruda® are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer, Hodgkin lymphoma, multiple myeloma and other tumors, with further trials in planning for other cancers.
Disease: non-small cell lung cancer (NSCLC)
Therapeutic area: Cancer - Oncology
Country: USA, Taiwan
Trial
details: Cohort G of the multicenter, open-label, phase 1/2 multi-cohort KEYNOTE-021 study evaluated the efficacy and safety of pembrolizumab in combination with pemetrexed and carboplatin compared with pemetrexed and carboplatin in patients with advanced, nonsquamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting. Patients were randomized 1:1 to four cycles of pembrolizumab (200 mg) plus pemetrexed (500 mg/m2 every three weeks) plus carboplatin AUC 5 (5 mg/mL/min), or pemetrexed plus carboplatin alone, followed by maintenance pemetrexed with or without pembrolizumab. Randomization was stratified by PD-L1 expression (positive expression defined as TPS of one percent or more; negative expression defined as TPS of less than one percent). Patients randomized to the control arm were allowed to cross over to pembrolizumab monotherapy if they experienced disease progression. Response was assessed by blinded, independent central review using RECIST 1.1 every six weeks for the first 18 weeks, every nine weeks through the first year, and every 12 weeks in the second year. The primary endpoint was ORR; secondary endpoints included PFS, duration of response, and OS.(NCT02039674)
Latest
news: * On October 9, 2016, Eli Lilly and Merck&Co have presented results from their ongoing immuno-oncology collaborations at the ESMO 2016 Congress. Specifically, data released from KEYNOTE-021, Cohort G, which evaluated Alimta® (pemetrexed) plus carboplatin in combination with Merck's Keytruda® (pembrolizumab) in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), showed that the combination of Alimta®, Keytruda® and carboplatin demonstrated superior efficacy compared to Alimta® and carboplatin - standard of care - alone. In KEYNOTE-021, Cohort G, which included patients with advanced nonsquamous NSCLC regardless of PD-L1 expression level, the combination of pemetrexed, pembrolizumab and carboplatin achieved a 55 percent objective response rate (ORR) compared to 29 percent for pemetrexed-plus-carboplatin alone, and reduced the risk of disease progression or death by 47 percent. Median progression-free survival (PFS) was 13.0 months with the pemetrexed-pembrolizumab-carboplatin combination. To date, this combination of pemetrexed-pembrolizumab-carboplatin is the only anti-PD-1-containing regimen to demonstrate superior efficacy compared to chemotherapy alone in NSCLC patients receiving first-line treatment. KEYNOTE-021, Cohort G, included 123 previously untreated patients with advanced nonsquamous NSCLC regardless of PD-L1 expression and whose tumors did not have EGFR mutations or ALK translocations. Patients were randomized to receive the pemetrexed-pembrolizumab-carboplatin combination (n=60) or pemetrexed-plus-carboplatin (n=63). Patients randomized to the pemetrexed-plus-carboplatin control arm had the option of crossing over to pembrolizumab monotherapy upon disease progression. The median follow-up was 10.6 months (range, 0.8-19.3). The findings demonstrated that ORR nearly doubled with the pemetrexed-pembrolizumab-carboplatin combination, with an ORR of 55 percent (n=33/60), compared to 29 percent (n=18/63) for the control arm alone (treatment difference 26%, 95% CI, 9-42% p=0.0016); all responses were partial. Median duration of response was not reached in either group (range, 1.4+-13.0+ for the pemetrexed-pembrolizumab-carboplatin combination; 1.4+-15.2+ for the control arm). Responses in both groups were durable, with 88 percent (n=29/33) of responders in the pemetrexed-pembrolizumab-carboplatin combination group and 78 percent (n=14/18) of responders in the control arm group experiencing ongoing response at the time of data cut-off. Additionally, the pemetrexed-pembrolizumab-carboplatin combination significantly reduced the risk of disease progression or death compared to the control arm (hazard ratio 0.53, 95% CI, 0.31-0.91, p=0.0102). Median PFS was 13.0 months with the pemetrexed-pembrolizumab-carboplatin combination compared to 8.9 months in the control arm. Overall survival (OS) was similar between the two arms, with 92 percent survival at six months in both, and 75 percent and 72 percent survival at 12 months in the pemetrexed-pembrolizumab-carboplatin combination and control arm, respectively. Of treated patients on the pemetrexed-pembrolizumab-carboplatin combination arm, 47 percent remained on treatment as of the cut-off date, compared to 31 percent on the control arm. Of the treated patients who discontinued treatment on the control arm, 52 percent (n=32/62) subsequently received anti-PD-L1 therapy, with 32 percent crossing over to pembrolizumab monotherapy as allowed by the study protocol and 19 percent receiving it outside of study crossover. Additional Safety Information from KEYNOTE-021, Cohort G: The most common treatment-related adverse events (occurring in at least 15% of patients) for the pemetrexed-pembrolizumab-carboplatin combination were fatigue, nausea, anemia, rash, vomiting, diarrhea, increased AST, constipation, decreased appetite, increased ALT, dysgeusia, and decreased neutrophils. Grade 3-4 treatment-related adverse events in this arm included fatigue, nausea, anemia, rash, vomiting, increased AST, increased ALT, and decreased neutrophils. The most common immune-mediated adverse events in patients receiving the pemetrexed-pembrolizumab-carboplatin combination were hypothyroidism and hyperthyroidism. Additionally, pneumonitis, infusion reactions, and severe skin toxicity were noted. These immune-mediated adverse events occurred at similar rates to patients receiving pembrolizumab as a single agent. There was one treatment-related death from sepsis in a patient receiving the pemetrexed-pembrolizumab-carboplatin combination, and two (one from sepsis and one from pancytopenia) in patients on the control arm.
