Merck carried off the prize in 1st Line NSCLC with KEYNOTE-021G and KEYNOTE-024 data
Keytruda showed impressive results in 1L NSCLC both as a monotherapy and in combination with chemo. In the monotherapy study (KEYNOTE-024) focused on high PD-L1 expressors (TPS ≥50%), Keytruda gave superior results versus chemotherapy (mPFS: 10.3 vs 6 mos.). These results led to Keytruda’s approval as a 1L treatment (FDA approval on 24th Oct 2016, 2 months ahead of the original PDUFA date: Dec 24, 2016) making it the only approved immunotherapy in 1L treatment setting. MSD has a >2 years of competitive advantage over next set of immunotherapies such as Tecentriq® and Avelumab whose launch are estimated by Q3-Q4 2018.
Also, the data from the combination study KEYNOTE-021 (Cohort G) in 1L was impressive with an ORR of 55% with pembro + chemo vs. 29% with chemo. The ORR difference, observed across the PD-L1 expression levels, reached as high as 80% in PD-L1 (≥ 50%). The addition of pembrolizumab improved the PFS to 13 vs 8.9 months (HR 0.53), but it also added to the toxicity (Gr. >3 AEs 39% in pembro + chemo vs 26% in chemo). These results warrant a larger investigation of the combination in a Phase III study.
Roche flexed OAK (atezo vs. doce) results as unambiguously positive, in 2nd Line NSCLC
Tecentriq won big in 2L NSCLC with data from Phase 3 OAK study in chemo pretreated NSCLC. The survival benefits were observed regardless of PD-L1 status or histology (median ITT OS: 13.8 mos. for atezo vs 9.6 mos. for doce). This is the first phase III study of atezolizumab, a PD-L1 inhibitor, and it confirms the efficacy seen in the POPLAR phase II study, presented at ESMO 2015. Tecentriq received a broad approval from FDA on 19th Oct’ 2016. Tecentriq has now become the 3rd I/O agent in a broad 2L PD-L1+ NSCLC population.
BMS feels the heat on the back of the failure of its CHECKMATE-026 study in 1st Line NSCLC
The results from CHECKMATE-026 (Opdivo in 1L NSCLC) were probably the biggest disappointment at ESMO. Patient selection (n=541) was broad – Patients with TPS ≥1% were eligible. The trial did not meet its primary PFS endpoint. Interestingly, the PFS curves separated early (with the chemotherapy arm performing better than the Opdivo arm) but then later converged after ~seven months, post-randomization. No ORR, PFS or OS benefits were seen in Opdivo patients, versus chemotherapy in patients whose tumors expressed PD-L1 at ≥5% (ORR=26.1% vs. 33.5%; PFS=4.2 vs. 5.9 months, HR 1.15; OS=14.4 vs. 13.2 months, HR 1.02). The toxicity profile was improved with Opdivo, as there were fewer adverse events of any grade (71.2% versus 92.4%) and fewer Grade 3-4 adverse events (17.6% versus 50.6%).
The discussant, Dr. Rizvi couldn´t explain the disparity between KEYNOTE-024 and CHECKMATE-026 results. It could be that the molecules are ultimately just different – which is hard to justify given the similarity of efficacy/safety in relapsed lung cancer and other tumors. Furthermore, in CHECKMATE-026, patients with TPS ≥ 50% also did not benefit from Opdivo. Dr. Rizvi shed some light on the trial design that warrants further investigation e.g. ~38% of patients had received radiation prior to trial enrolment, long time from diagnosis to treatment initiation (two months). Other differences were also cited between the two trials – number of patients with squamous histology (19% in KEYNOTE-024 and 24% in CHECKMATE-026), slightly different choice of platinum doublets in the control arms of each trial (65% received Alimta-based in KEYNOTE-024 and 76% received Alimta-based in CHECKMATE-026), and subtle differences in the definition of the primary PFS endpoint (RECIST criteria for KEYNOTE-024, IRRC for CHEKMATE-026). However, there was no clear factor(s) that was cited as the reason for the trial failure.
Opdivo Showed Consistent Efficacy Over Long Term in Pre-Treated NSCLC
The 2 year follow up results from CHECKMATE-057 (≥2L Non-Sq.) and ChECKMATE-017 (≥2L SqCC) were presented. Opdivo continued to demonstrate OS benefit and high rates of durable response versus docetaxel in patients with advanced NSCLC. 8% and 9% of patients remained on nivo treatment in CM-017 and CM-057, respectively, versus 0 patients in docetaxel group of either trial. The 2-year OS, PFS rates and ORRs were also higher with Opdivo (2 year OS: 23% vs. 8% (CM-017) and 29% vs. 16% (CM-057)) in both studies.