Following Merck & Co.’s announcement back in June 2016 that Keytruda improved PFS and OS in first-line NSCLC, all eyes were on Sunday’s Presidential Symposium at the ESMO 2016 Congress, where the company revealed data from its pivotal Phase III KEYNOTE-024 trial. The eagerly anticipated results certainly did not disappoint and are likely to have a major impact in the first-line management of NSCLC.
Dr. Martin Reck presented the results from KEYNOTE-024, which compared Keytruda with platinum-based doublet chemotherapy in previously untreated metastatic NSCLC patients whose tumors expressed PD-L1 at levels of 50% or greater. Keytruda led to a significant improvement in median PFS over chemotherapy—10.3 months versus 6.0 months (P<0.001)—corresponding to a 50% reduction in the risk of disease progression or death (HR = 0.50). In addition, Keytruda significantly improved median OS versus chemotherapy (not reached in either arm; HR = 0.60; P = 0.005), as well as tumor response (ORR 45% vs. 28%; P=0.0011). The safety and tolerability profile of Keytruda was consistent with previous studies and strongly favored the agent over chemotherapy, with approximately half as many reported treatment-related grade 3-4 adverse events (26% vs. 51%, respectively).
The first-line NSCLC setting is commercially lucrative and the results demonstrated by Keytruda place Merck & Co. in a very strong position in this market. However, the implications of KEYNOTE-024 are even greater when viewed in the context of Bristol Myers-Squibb (BMS) Opdivo’s failure to meet the primary endpoint of PFS in the first-line NSCLC CheckMate-026 trial. In the same Presidential Session at ESMO, BMS released data from its much-maligned CheckMate-026, which showed that Opdivo performed poorly compared with chemotherapy across all efficacy endpoints—including in high PD-L1 expressers. These results have smothered all hopes for Opdivo monotherapy in first-line NSCLC, although the agent’s development in combination with Yervoy or chemotherapy continues. Meanwhile, Keytruda looks set to capitalize on its competitor’s misfortunes by becoming the first immune checkpoint inhibitor to receive approval as a single-agent for first-line metastatic NSCLC. This will be a remarkable rebound for Keytruda in the NSCLC market, as the agent has struggled to gain traction in the second-line setting due to its requirement for PD-L1 testing. While prescribing of Keytruda in the first-line setting will likely be restricted by PD-L1 status, biomarker testing is standard procedure for first-line metastatic NSCLC patients and thus is unlikely to limit the agent’s uptake. Furthermore, it is possible to surmise that Keytruda’s strong efficacy in PD-L1 positive patients could drive increased PD-L1 testing in the second-line setting—an interesting hypothesis that we will continue to monitor.
In the clinical context, it is important to bear in mind that Keytruda’s success was achieved in a highly selected population. As highlighted by Dr. Jean-Charles Soria during his discussion of the KEYNOTE-024 data, the strict patient selection criteria applied for trial recruitment mean that the number of patients that can benefit from Keytruda may be greatly diminished. It is particularly noteworthy that 75% of the patients initially evaluated were excluded from the trial due to the requirement for tumor PD-L1 positivity of ≥50%. Therefore, alternative approaches such as combination therapy may help increase the number of patients that can benefit from immune checkpoint inhibitor therapy in first-line metastatic NSCLC. On this front, Merck & Co. revealed additional exciting results at the ESMO congress for Keytruda in combination with chemotherapy in first-line nonsquamous NSCLC. The data from the Phase II KEYNOTE-021 (Cohort G) study showed that Keytruda plus chemotherapy almost doubled the ORR (55% versus 29%) and significantly improved median PFS (13.0 versus 8.9 months; HR = 0.53) compared with chemotherapy alone. The trial recruited patients regardless of PD-L1 status and higher response rates could be observed with combination treatment in both PD-L1-negative and PD-L1-positive (≥50%) subgroups. Therefore, combining Keytruda with chemotherapy represents a promising approach to extend its use to a larger proportion of first-line metastatic NSCLC patients.
With an onslaught of positive data and high physician excitement at the ESMO congress, it is tempting to think that Keytruda will rapidly become the new standard of care for the first-line treatment of metastatic NSCLC. However, based on current evidence, it can only be concluded that Keytruda will achieve strong uptake in a select group of first-line metastatic NSCLC patients. In the future, Keytruda plus chemotherapy, as well as Opdivo in combination with Yervoy or chemotherapy, have the potential to offer treatment options for patients irrespective of PD-L1 status. The first-line metastatic NSCLC market is set to become increasingly fragmented with market entries of additional immune checkpoint inhibitors—alone or as part of combination regimens—resulting in increased treatment options for patients. Nevertheless, in the race for patient share in the highly lucrative first-line metastatic setting, Keytruda is first out of the starting blocks.
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- Reck M et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine.2016 Oct 8 [Epub ahead of print] DOI: 10.1056/NEJMoa1606774
- Reck M et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. ESMO 2016; LBA8_PR
- Langer C. et al. Randomized, phase 2 study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. ESMO 2016; LBA46_PR.
- Socinski M et al. CheckMate 026: A phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage iv/recurrent programmed death ligand 1 (PD-L1)−positive NSCLC. ESMO 2016; LBA7_PR.