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First-line nivolumab fails to extend PFS in non–small cell lung cancer

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June 21, 2017

Nivolumab did not result in longer PFS than platinum-based chemotherapy as first-line treatment for stage IV or recurrent non–small cell lung cancer in patients with a PD-L1 expression level of 5% or more, according to an open-label phase 3 study published in The New England Journal of Medicine.

However, nivolumab (Opdivo, Bristol-Myers Squibb) — a PD-1 inhibitor — conferred higher response rates in patients with PD-L1 expression level of 50% or more and high tumor mutational burden. The agent also demonstrated a favorable safety profile, researchers reported.

David P. Carbone

“The good news is that we discovered that a subset of patients who had both high tumor mutation burden and high PDL-1 positive status did experience a significant benefit from immunotherapy,” David P. Carbone, MD, PhD, professor of medicine at The Ohio State University Comprehensive Cancer Center, said in a press release. “This study is an important step toward understanding the impact of tumor mutation burden and PD-L1 in immunotherapy response. These data show we should evaluate these two factors independently to most accurately define who will benefit from immunotherapy.”

In previous phase 3 clinical trials, platinum-based chemotherapy conferred a median PFS of 4 months to 6 months and a median OS of 10 months to 13 months in patients with advanced NSCLC. In patients with metastatic NSCLC who experienced disease progression during or after chemotherapy, nivolumab conferred significantly longer OS than docetaxel, regardless of PD-L1 expression level.

In this study, researchers randomly assigned 541 patients (median age, 64 years; 61% men; 92% stage IV; 88% current or former smokers) with untreated stage IV or recurrent NSCLC and a PD-L1 tumor expression level of 1% or more to receive IV nivolumab (3 mg/kg once every 2 weeks) or platinum-based chemotherapy (once every 3 weeks for up to six cycles).

A total of 418 patients (77%) had PD-L1 expression levels of 5% or more and 214 patients (40%) had PD-L1 expression levels of at least 50%.

Researchers allowed cross over to nivolumab at the time of disease progression on chemotherapy.

PFS among patients with a PD-L1 expression level of 5% or more served as the primary endpoint.

Median follow-up was 13.5 months.

In total, 128 of 212 participants (60%) in the chemotherapy group received nivolumab as subsequent therapy.

In the primary efficacy analysis population, researchers reported median PFS of 4.2 months with nivolumab compared with 5.9 months with chemotherapy (HR = 1.15; 95% CI, 0.91-1.45). Nivolumab also did not significantly extend median OS (14.4 months vs. 13.2 months; HR = 1.02; 95% CI, 0.8-1.3).


Twenty-six percent of patients in the nivolumab arm and 33% in the chemotherapy arm responded to treatment, but median duration of response appeared longer with nivolumab (12.1 months vs. 5.7 months).

In the exploratory subgroup of patients with PD-L1 levels of 50% or greater, researchers reported an HR for PFS of 1.07 (95% CI, 0.77-1.49) and HR for OS of 0.9 (95% CI, 0.63-1.29). Nivolumab conferred a response rate of 34% (95% CI, 24-45) compared with 39% (95% CI, 30-48) for chemotherapy. However, researchers noted fewer patients randomly assigned to the nivolumab arm had PD-L1 levels of 50% or more (32% vs. 47%), which may limit conclusions drawn from this subgroup.

Nivolumab conferred higher response rates (47% vs. 28%) and longer median PFS (9.7 months vs. 5.8 months; HR = 0.62; 95% CI, 0.38-1) in patients with high tumor mutation burden.

Seventy-five percent of patients with both high tumor mutation burden and PD-L1 levels of at least 50% responded to nivolumab, compared with 16% of patients with none of these factors. However, researchers noted this comparison was not powered for statistical analysis.

“Given that nivolumab therapy prolongs survival among previously treated patients with advanced NSCLC, the high frequency of subsequent nivolumab treatment may have contributed to the favorable OS in the chemotherapy group,” Carbone and colleagues wrote.

A smaller proportion of patients assigned nivolumab experienced treatment-related adverse events of any grade (71% vs. 92%) or grade 3 and grade 4 (18% vs. 51%). The most common toxicities included skin-related events in the nivolumab group, and gastrointestinal events in the chemotherapy group.

Researchers attributed five deaths to study treatment — two from the nivolumab group (multi-organ failure, pneumonitis) and three from the chemotherapy group (febrile neutropenia, n = 2; sepsis, n = 1).

Edward B. Garon

The correlation between tumor PD-L1 expression and efficacy of this class of drugs appears imperfect and has differed among trials, Edward B. Garon, MD, associate professor of medicine at Geffen School of Medicine at UCLA, wrote in an accompanying editorial.

“Outcomes in all studies of single-agent nivolumab were assessed with the use of an anti–PD-L1 antibody that differed from that used in the assay in the pembrolizumab [Keytruda, Merck] studies,” Garon wrote.

Previously published studies of nivolumab assessed three prespecified PD-L1 cutoff points — 1%, 5% and 10% — which identified a population enriched for better clinical outcomes in one of two phase 3 trials comparing nivolumab with chemotherapy in previously treated patients, Garon added.


“The primary analysis in the trial conducted by Carbone [and colleagues] evaluated patients with a PD-L1 expression level of at least 5%, a level seen in approximately half the screened patients,” Garon wrote. “The use of a cutoff point that leads to the inclusion of more patients expands the studied population at the risk of including patients who are less likely to benefit from PD-1 inhibition. Could the lower cutoff point explain the conflicting results? Not entirely, because nivolumab was not superior to chemotherapy, even in patients with a PD-L1 expression level of at least 50%.” – by Chuck Gormley

Disclosure: Bristol-Myers Squibb and ONO Pharmaceutical funded this study. Carbone reports personal fees from Ariad, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Genentech, Janssen, Merck, Novartis and Teva outside the study. Please see the full study for a list of all other researchers’ relevant financial disclosures.

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Martin J. Edelman

This is an important trial that demonstrates many current issues with immunotherapy. Recent trials have demonstrated that several immune checkpoint inhibitors are very active in lung cancer and, in many instances, superior to older chemotherapy agents. These drugs allow the immune system to recognize and kill cancer cells.

The current report involves a trial very similar in design to one with pembrolizumab (Keytruda, Merck), another anti–PD-1 antibody. That study was positive, demonstrating the superiority of pembrolizumab over chemotherapy as the initial treatment for advanced non–small cell lung cancer.

The current trial is negative, for reasons that are very unclear given the similarities of the two antibodies. However, the study with nivolumab (Opdivo, Bristol-Myers Squibb) does indicate substantial activity of immunotherapy in advanced lung cancer. Further, an analysis of tissues obtained from the study indicates that tumor mutational burden — an indication of the degree of DNA damage in the cancer cells — may be a marker for activity.

The message from this and other studies is that immunotherapy is active in a significant fraction of patients with advanced lung cancer. However, despite this, the majority of patients — even those identified with various biomarkers — do not benefit or benefit for only a short period of time.

New agents and strategies are being evaluated to further extend the benefits of immunotherapy. Some of these approaches combine the new drugs with older drugs (ie, chemotherapy) and radiation. In addition, other drugs that target the immune system may potentially enhance the activity of the currently available immunotherapy agents.

Martin J. Edelman, MD
Fox Chase Cancer Center

Disclosure: Edelman reports no relevant financial disclosures.