KEYNOTE: Most patients with advanced NSCLC can start treatment without chemo
“The era when chemotherapy was the only option for patients with NSCLC is drawing to a close. This study represents a true milestone. The majority of patients with NSCLC can start treatment without chemotherapy,” commented Dr John Heymach of the University of Texas MD Anderson Cancer Center, Houston, Texas, US, at an ASCO press briefing.
Pembrolizumab is approved for the first-line treatment of patients with metastatic NSCLC who have high PD-L1 expression (Tumour Proportion Score [TPS] ≥50 percent) with no EGFR or ALK genomic tumour aberrations. KEYNOTE-042 was conducted in patients (n=1,274) with locally advanced or metastatic NSCLC and a much lower PD-L1 expression level of ≥1 percent. The patients were randomized 1:1 to receive first-line treatment with pembrolizumab or chemotherapy (carboplatin plus paclitaxel or carboplatin plus pemetrexed). [Lopes G, et al, ASCO 2018, abstract LBA4]
In KEYNOTE-042, more than 70 percent of patients were male, 29 percent were enrolled in East Asia, and nearly 70 percent had an ECOG performance status of 1. Patients with sensitizing EGFR mutations or ALK translocations were excluded. TPS was 1–19 percent in 35–36 percent of patients, 20–49 percent in 16–18 percent of patients, and ≥50 percent in less than half of the patients.
“After a median follow-up of 12.8 months, significant improvements in OS were seen with pembrolizumab vs chemotherapy at all levels of PD-L1 expression,” reported investigator Dr Gilberto Lopes of the University of Miami Health System, Florida, US.
In the full cohort of patients with TPS ≥1 percent, a 19 percent improvement in OS was seen with pembrolizumab vs chemotherapy (median, 16.7 vs 12.1 months; hazard ratio [HR], 0.81; p=0.0018). In patients with TPS ≥20 percent, the OS improvement was 23 percent (median, 17.7 vs 13 months; HR, 0.77; p=0.0020). In those with TPS ≥50 percent, the OS improvement was 31 percent (median, 20 vs 12.2 months; HR, 0.69; p=0.0003).
The duration of response (DoR) was also longer with pembrolizumab vs chemotherapy at all levels of PD-L1 expression (median, 20.2 vs 8.3 months). Response rates were 27.3 percent vs 26.5 percent in the full cohort, 33.4 percent vs 28.9 percent in patients with TPS ≥20 percent, and 39.5 percent vs 32 percent in patients with TPS ≥50 percent.
“More patients reported grade 3–5 treatment-related adverse events [AEs] with chemotherapy than pembrolizumab [41 percent vs 17.8 percent],” said Lopes. “As expected, immune-related AEs were more frequent with pembrolizumab vs chemotherapy [27.8 percent vs 7.2 percent].”
“Based on these findings, we can conclude that pembrolizumab becomes an option for patients with advanced NSCLC without EGFR mutations or ALK translocations who have at least 1 percent PD-L1 expression,” he suggested.
Pembrolizumab + chemo beneficial in squamous NSCLC
Pembrolizumab also demonstrated significant improvements in OS when used in combination with chemotherapy in patients with metastatic nonsquamous NSCLC in the phase III KEYNOTE-407 trial (n=559). After a median follow-up of 7.8 months, patients randomized to receive pembrolizumab in combination with carboplatin and paclitaxel/nab-paclitaxel had a 36 percent improvement in OS vs those receiving chemotherapy plus placebo (median, 15.9 vs 11.3 months; HR, 0.64; p=0.0008). [Paz-Ares LG, et al, ASCO 2018, abstract 105]
“The OS benefit with pembrolizumab plus chemotherapy was observed across patients with TPS <1 percent [HR, 0.61], 1–49 percent [HR, 0.57], and ≥50 percent [HR, 0.64],” reported investigator Dr Luis Paz-Ares of the University Hospital 12 de October, Madrid, Spain.
Progression-free survival was also significantly improved with pembrolizumab vs placebo (median, 6.4 vs 4.8 months; HR, 0.56; p<0.0001), with benefit seen across all PD-L1 expression subgroups. Response rate was also significantly improved with pembrolizumab (58.4 percent vs 35 percent; p=0.0004), as was DoR (median, 7.7 vs 4.8 months).
“The rates of grade 3–5 AEs were similar between the two groups [69.8 percent vs 68.2 percent]. The observed AEs matched the known safety profiles of pembrolizumab and chemotherapy,” said Paz-Ares.
“This trial is a clear win. The pembrolizumab/chemotherapy combination will become a new frontline standard of care [for patients with metastatic nonsquamous NSCLC],” said discussant Dr Charles Drake of the Columbia University Herbert Irving Comprehensive Cancer Center, New York, US.