COMMENTARY

At ESMO, New Data on Managing Long-term Immunotherapy Responders

H. Jack West, MD

Disclosures

November 13, 2018

With the European Society for Medical Oncology (ESMO) annual conference occurring in late October, just a few weeks after the World Conference on Lung Cancer, we might have suspected that there would be relatively few new data to help refine our management of patients receiving immunotherapy for advanced non–small cell lung cancer (NSCLC).

Nevertheless, a couple of important ESMO presentations provided valuable insight on how we can manage two populations for whom we have had very little evidence on optimal immunotherapy strategies: patients who have received years of immunotherapy without progression, and those with a performance status (PS) of 2.

KEYNOTE-010: Managing a Prolonged Response to Immunotherapy

Roy Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut, presented the long-term survival results of KEYNOTE-010, a randomized trial of pembrolizumab administered at either of two doses (2 mg/kg or 10 mg/kg IV every 3 weeks) for up to 2 years, compared with docetaxel (75 mg/m2 IV every 3 weeks) in chemotherapy-pretreated patients with advanced NSCLC and positive tumor PD-L1 expression (> 1%).[1] This trial was previously reported as demonstrating a statistically and clinically significant improvement in overall survival (OS) in recipients of pembrolizumab,[2] but at ESMO we saw updated OS results with an additional 30 months of follow-up. These results were notable for a hazard ratio (HR) for OS of 0.69 (P < .00001), a median OS of 11.8 vs 8.4 months, and a 3-year OS of 23% vs 11% in the broad population (tumor PD-L1 > 1%), all favoring pembrolizumab (results pooled for two dose levels). For patients with PD-L1 > 50%, the benefit favoring pembrolizumab was even more pronounced, with an HR for OS of 0.53 (P < .00001), a median OS of 16.9 vs 8.2 months, and a 3-year OS of 35% vs 13%.

It was especially valuable to learn the outcomes of those who had completed 2 years of pembrolizumab, a subgroup of 79 patients among the 690 assigned to pembrolizumab. In that population, 75 of 79 (95%) achieved either a complete response (CR) or partial response (PR) as their best response, as measured by RECIST criteria version 1.1, as per independent central review. Among these patients, 48 (64%) demonstrated an ongoing response well after discontinuing pembrolizumab, with the median duration of response not reached in this cohort. While the median OS had not been reached, the Kaplan-Meier estimate of their 3-year OS was 99%. Among those who completed 2 years of pembrolizumab, 25 (32%) demonstrated progressing disease subsequently. Of the 14 patients who were "re-challenged" with pembrolizumab upon progressing disease, 6 (43%) demonstrated a second response (a PR in all of these cases) by independent central review.

Despite the limited data available, the KEYNOTE-010 findings offer important additional insights into how we may approach patients with a prolonged response to immunotherapy. In this setting, our perspective has largely been shaped by CheckMate-153, a trial that evaluated patients unselected for tumor PD-L1 expression who received second-line nivolumab for up to a year for advanced NSCLC without progressing disease or prohibitive toxicity, randomly assigning them to ongoing nivolumab or discontinuation of immunotherapy.[3] This study demonstrated a highly significantly superior progression-free survival (PFS; HR, 0.42) along with a suggestion of improved OS (HR, 0.63) with continuous nivolumab. While these earlier results strongly suggest a value in continuing immunotherapy potentially indefinitely and at least beyond 1 year, the long-term results of KEYNOTE-010 illustrate that many patients still responding after 2 years, particularly those with a strong response to immunotherapy, may continue to enjoy a prolonged response long after discontinuing pembrolizumab. Moreover, many who subsequently demonstrate progressing disease after discontinuing immunotherapy can respond again after re-challenge with pembrolizumab.

PePS2 Trial: Immunotherapy in Performance Status 2 NSCLC

Turning to another understudied question in immunotherapy for advanced NSCLC, patients with a marginal PS of 2 represent a significant minority that has largely been excluded from the vast majority of trials of immunotherapy. Gary Middleton, MB, MD, presented the results of the UK-based PePS2 trial, which administered pembrolizumab at the fixed and US Food and Drug Administration–approved standard dose of 1200 mg/m2 IV every 3 weeks to 60 patients with advanced NSCLC and a PS of 2. All were immunotherapy-naive, but the majority (51, or 85%) had previously received another anticancer therapy.[4] There was no required threshold of tumor PD-L1 expression; 15 patients (25%) had high tumor PD-L1 expression (> 50%). The overall findings revealed a durable clinical benefit rate of 33% in the broad population, though the results were notably more favorable among the subgroup with high PD-L1 expression, among whom the response rate was 58.3%.

Similarly, the median PFS and OS results in the full trial population were 5.4 and 11.7 months, respectively, again with far superior results in patients with high tumor PD-L1 expression (median PFS, 8.5 months; median OS, 16.6 months).

Toxicity was not clearly greater than that seen in prior experience, and there were no grade 5 adverse events. Overall, these results support treating PS2 patients with pembrolizumab monotherapy, with those who have high tumor PD-L1 expression particularly likely to benefit, and without unexpected or prohibitive toxicities.

Though we still have several gaps in our knowledge base about best practices for treating our advanced NSCLC patients with immunotherapy, these trials help address several clinical questions in which we have had to rely primarily on our best judgment and inferences from other populations.

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