Important clinical study results from one of Eli Lilly and Company's ongoing immuno-oncology collaborations with Merck (known as MSD outside the US and Canada) were announced at the ESMO 2016 Congress, the annual meeting of the European Society for Medical Oncology. 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 per cent objective response rate (ORR) compared to 29 per cent for pemetrexed-plus-carboplatin alone, and reduced the risk of disease progression or death by 47 per cent. 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.
"These randomized study data of Alimta and Keytruda in first-line nonsquamous non-small cell lung cancer build on the early results we've seen in this combination and are very encouraging," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "To see a near-doubling in the number of patients responding to this combination gives us hope for what may be able to be achieved above and beyond what is seen with the Alimta-containing standard-of-care regimen. These types of clinical advancements are truly exciting as we continue our pursuit to bring meaningful benefits to patients facing cancer."
Dr. Gaynor added, "These data also reflect the progress that Lilly is making in its oncology R&D strategy to develop cancer treatments across three key areas of disease modification: tumor cell signaling, tumor microenvironment and immuno-oncology. This approach allows for testing of combinations of internally derived agents to address tumor heterogeneity and drug resistance, through our own efforts and research collaborations."
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.
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.
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.
KEYNOTE-189, a randomized phase 3 study evaluating pemetrexed-plus-platinum chemotherapy (carboplatin or cisplatin) with and without pembrolizumab as initial therapy in NSCLC patients, is currently enrolling. The first results from this study could be available before the end of 2017.
Pemetrexed (marketed under the brand name Alimta) is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that 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.
Pembrolizumab (marketed under the brand name Keytruda) is a humanized monoclonal antibody that works by increasing the ability of the body's immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.
In 2004, Alimta received consecutive approvals: it was the first agent to be approved in combination with cisplatin as a treatment for patients with malignant pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for curative surgery, and then as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior treatment.
In 2008, Alimta, in combination with cisplatin, was approved as an initial chemotherapy treatment for locally advanced or metastatic NSCLC for patients with nonsquamous histology. At the time of this initial treatment approval, the FDA also approved a change to the indication for subsequent treatment. Alimta is now indicated as a single agent for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC after prior therapy.
In 2009, Alimta was approved as a maintenance therapy for locally advanced or metastatic NSCLC, specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based initial chemotherapy.
In 2012, Alimta was approved by the FDA as maintenance therapy for locally-advanced or metastatic NSCLC, following initial Alimta-plus-cisplatin treatment for locally advanced or metastatic nonsquamous NSCLC.
Alimta is not indicated for treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with Alimta therapy.