BARCELONA, Spain — Immunotherapy in the form of programmed cell death (PD-1 and PD-L1) inhibitors is rapidly transforming the landscape in advanced non-small cell lung cancer (NSCLC), extending progression-free survival and even overall survival (OS) in some patients to unprecedented lengths without significantly compromising quality of life, say experts.

"Historically, overall survival in advanced NSCLC was less than 5% at 5 years," Federico Cappuzzo, MD, PhD, director of medical oncology at AUSL della Romagna in Ravenna, Italy, told a press briefing here at the IASCL 2019 World Conference on Lung Cancer.

"Today we have a growing proportion of patients of between 15% and 20% who are alive after 5 years, and this is an important message for our patients — that the possibility of extending life is increasing with immune therapies," he said.

First Report of 5-Year Overall Survival in Lung Cancer

The first report from any randomized trial to document 5-year OS rates in NSCLC, presented by Scott Gettinger, MD, Yale School of Medicine, New Haven, Connecticut, showed that 13.4% of patients treated with single agent nivolumab (Opdivo, Bristol-Myers Squibb) were still alive at 5 years compared with only 2.6% for those treated with docetaxel (Taxotere, sanofi-aventis) .

"This is really unprecedented — we would never have expected any patients to be alive out to 5 years in this scenario, and this was in both squamous and non-squamous cell lung cancer," Gettinger said.

The finding is based on pooled results from the similarly designed CheckMate 017 and 057 trials, he noted.

Furthermore, progression-free survival (PFS) again at 5 years was 8% in the nivolumab arm vs 0% in the docetaxel arm.

"More commonly, we see zero patients without progression at 5 years, and that is exactly what we saw with the docetaxel arm," Gettinger confirmed.

Median duration of response was 19.9 months for patients who received nivolumab vs 5.6 months for their docetaxel counterparts. At 5 years, almost one third of patients who responded to the immune checkpoint inhibitor were still without disease progression.

Indeed, "we found that 60% of patients across these two trials who did not have disease progression at 2 years still did not have progression at 5 years, with 82% of them still being alive at 5 years," Gettinger noted.

Similarly, if patients made it out to 3 years without disease progression, 78% were still without progression at 5 years and 93% of them were still alive at the same time point.

For those who made it out to 4 years without disease progression, 88% were still without progression at 5 years, all of whom were still alive at 5 years, he added.

Importantly, "we saw no new safety signals with long-term nivolumab," Gettinger observed, "and there was no evidence of late-onset grade 3 or 4 treatment-related adverse events (AEs)."

In fact, at 5 years, 10% of nivolumab survivors were off the study drug for varying degrees of time and still had not progressed, nor had they received any subsequent treatment.

"So we clearly see benefit for patients long after they receive a course of immunotherapy," and also see benefit in patients "who have stopped treatment for some reason," Gettinger emphasized.

"This represents the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC," he concluded.

The two CheckMate trials had a pooled total of 854 patients with stage III to IV NSCLC who had progressed during or after first-line, platinum-based chemotherapy. They received either nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks, until progression or unacceptable toxicity.

After investigators had completed their primary analysis, patients in the docetaxel group could cross over to receive nivolumab, and almost two thirds of patients in the docetaxel group did so.

More Long-Term Survival Data

Updated results from the KEYNOTE-024 trial in NSCLC confirm that there continues to be improvement in survival odds with over 3 years of follow-up in stark favor of the PD-1 inhibitor pembrolizumab (Keytruda, Merck).

Median OS was 26.3 months in patients treated with single-agent pembrolizumab compared with 14.2 months of chemotherapy in the form of a platinum doublet.

At 3 years, 43.7% of patients were still alive on the immune checkpoint inhibitor group compared with 24.9% on the chemotherapy group, noted Martin Reck, MD, PhD, head of the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf in Germany.

In this trial, 305 patients were randomized to pembrolizumab, 200 mg every 3 weeks for 2 years or a platinum doublet for 4 to 6 cycles; in the nonsquamouos NSCLC KEYNOTE cohort, this could be followed by optional maintenance therapy.

Reck noted that 38 patients in this particular KEYNOTE trial received 2 years of pembrolizumab (this consisted of up to 34 cycles of treatment).

While treatment duration was longer for patients receiving pembrolizumab, "tolerability was in favor of the monotherapy regimen, with a lower frequency of treatment-related AEs," Reck noted, "and this was particularly relevant to treatment-related grade 3 to 5 AEs," he added.

"Duration of response was very high," he noted, "in that 81% of patients who received 2 years of treatment with pembrolizumab had a duration of response of at least 2 years; and at data cutoff, 71% of these patients still had stable disease without the need for any additional treatment."

After 2 years of treatment with the anti-PD-1 agent, a handful of patients have also received a second course of pembrolizumab on disease progression.

Though this group is very small — only about 10 patients — "we do see clinical activity even after being re-exposed to pembrolizumab, so we see disease stabilization on re-exposure," Reck noted.

"And we continue to show benefit in OS despite the fact that 65% of patients on chemotherapy crossed over to pembrolizumab," Reck added.

As Reck explained to Medscape Medical News during the press briefing, immunotherapy essentially forces the immune system to control the tumor by "putting the brakes on" cell proliferation, although treatment does not necessarily eradicate the tumor, at least not in all stages of the disease.

"However, in some patients, we can achieve disease control, and this has been the case in this trial where we could show disease control for a substantial group of patients," he noted.

While researchers were unable to identify any features that might predict which patients will respond to anti-PD-1 therapy, "the trial was already done in a selected group of patients because we only took those patients with high PD-1 expression on tumor cells — so this was already a selection criteria for patients with NSCLC," Reck explained.

Immunotherapy Plus Chemotherapy

Another highlighted clinical trial had investigated adding immunotherapy, this time with the PD-L1 inhibitor atezolizumab (Tecentriq, Genentech), onto chemotherapy.

This was the IMpower131 trial, conducted in 1021 patients with stage IV squamous cell NSCLC who were randomly assigned to one of three groups: atezolizumab plus carboplatin and paclitaxel; atezolizumab and carboplatin with nab-paclitaxel; and carboplatin plus nab-paclitaxel.

At this meeting, final OS results for the latter two groups were presented by AUSL della Romagna's Cappuzzo.

There was no statistically significant difference in OS between patients treated with the carboplatin and nab-paclitaxel combination, or the same chemotherapy given together with atezolizumab, followed by maintenance atezolizumab.

However, as Cappuzzo emphasized, there was a significant 25% prolongation in PFS in the atezolizumab plus chemotherapy group at 6.5 months compared with 5.6 months in the carboplatin plus nab-paclitaxel group (hazard ratio [HR], 0.75).

More importantly, in the subset of patients whose tumors strongly expressed PD-1, "there was a clinically meaningful improvement in OS," Cappuzzo reported, at a median OS of 23 months for patients receiving atezolizumab plus chemotherapy compared with 10 months in patients receiving chemotherapy alone (HR, 0.48). He observed that "in this specific subgroup of patients, we had a reduction in the risk of death that was more than 50% with additional atezolizumab."

"These data clearly suggest that these patients in particular may benefit from the combination of atezolizumab plus chemotherapy," Cappuzzo concluded.

In answer to questions from journalists, a consensus from the speakers emerged: there appear to be no differences in clinical activity or side effects between the PD-1 inhibitors (such as nivolumab and pembrolizumab) and the PD-L1 inhibiting agents (such as atezolizumab).

All three clinical trials were sponsored by the manufacturers of the immunotherapy they were investigating: CheckMate was sponsored by Bristol-Myers Squibb, KEYNOTE was sponsored by Merck & Co, and IMpower was sponsored by Genentech.

Cappuzzo has disclosed no relevant financial relationships. Gettinger reports serving as a consultant for Bristol-Myers Squibb and Nektar. Reck reports serving on the advisory board and has received speaker's bureau fees from Roche, Bristol-Myers Squibb, AstraZeneca, MSD, Merck, Boehringer Ingelheim, Celgene, Lilly, Novartis, AbbVie and Pfizer.

IASLC World Conference on Lung Cancer (WCLC) 2019: Abstracts OA14.04, OA14.01, OA14.02. Presented September 10, 2019.

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