Nivolumab Demonstrates Broad Efficacy in NSCLC

The latest FDA approval for nivolumab in non–small cell lung cancer means that the drug potentially can be administered to any patient in the second-line setting, regardless of tumor histology or PD-L1 expression level.

Renato G. Martins, MD, MPH

The latest FDA approval for nivolumab (Opdivo) in non—small cell lung cancer (NSCLC) means that the drug potentially can be administered to any patient in the second-line setting, regardless of tumor histology or PD-L1 expression level, according to Renato G. Martins, MD, MPH.

Martins, the medical director for thoracic/head and neck oncology at Seattle Cancer Care Alliance, discussed nivolumab in a presentation and interview at the 10th Annual New York Lung Cancer Symposium. He also is a professor of medicine at the University of Washington.

The concept of targeting the PD-1 immune checkpoint pathway was introduced in 2012 in research findings that included data for nivolumab in NSCLC, and marked one of most important milestones in the treatment of the disease, noted Martins. “The big breakthrough really was the recognition that non—small cell lung cancer could be a disease treated by immune therapy,” he said.

Since then, the PD-1 inhibitors nivolumab and pembrolizumab (Keytruda) have gained FDA approvals in NSCLC while other agents targeting checkpoint’s ligand PD-L1, notably atezolizumab (MPDL3280A) and durvalumab (MEDI4736), are advancing in clinical development.

“These agents have had a tremendous impact in lung cancer,” said Martins. “The combination of the positive side-effect profile and the quality of the responses is what has made us so enthusiastic about these agents.”

Overall, the PD-1 inhibitors have proved more effective in patients with higher levels of PD-L1 protein expression, but patients with <1% levels also have responded, Martins noted.

“As of now, I don’t think that any patient is clearly not a candidate for these drugs,” he said in an interview. “We have seen responses in patients who are ‘negative’ for PD-L1 and the response rate was still 8.9%, which compares with what chemotherapy would do in this setting —with the difference that even for those patients that are ‘negative,’ it seems that the quality of their response is as good as the quality of responses that we see in those who are PD-L1 positive.”

Nivolumab’s Journey

Pembrolizumab was approved as a treatment for patients with metastatic NSCLC with progressive disease whose tumors express PD-L1 as measured by a companion diagnostic, which thus far is the PD-L1 IHC 22C3 pharmDx test. For nivolumab, there is a complementary test, the PD-L1 IHC 28-8 PharmDx assay, that is not required to use the drug.Nivolumab was initially approved in March or the treatment of patients with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy. In October, the FDA expanded the indication to include patients with progression on or after platinum-based chemotherapy with nonsquamous histologies.

In squamous NSCLC, nivolumab’s efficacy was established in the CheckMate 063 trial, a single-arm phase II study in which patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects.1

The overall response rate (ORR) among 117 patients was 14.5%, with 77% of those responses ongoing at the time of analysis, said Martins. Grade 3/4 toxicities were observed in 17% of patients, with fatigue (4%), diarrhea (3%), pneumonitis (3%), and rash (1%) as the most common. Two deaths were attributable to the therapy, Martins said.

In the CheckMate-017 trial, 272 patients with advanced squamous NSCLC who had received one prior line of platinum-containing therapy were randomized to receive either nivolumab at 3 mg/kg every 2 weeks versus docetaxel at 75 mg/m2 every 3 weeks.2

In that trial, the median overall survival (OS) was 9.2 months with nivolumab versus 6.0 months with docetaxel, which translated into a 41% lower risk of death for those patients who received the immunotherapy agent. The ORR was 20% with nivolumab compared with 9% for docetaxel, with the median duration of response with nivolumab not yet reached after a follow-up of 11 months, Martins noted.

In nonsquamous NSCLC, the pivotal clinical evidence stems from the CheckMate-057 trial, in which 582 patients who had already received a platinum-based doublet were given either nivolumab or docetaxel at dosages similar to the CheckMate-017 trial.3

Nivolumab demonstrated a median OS of 12.2 months compared with 9.4 months for docetaxel (P = .0015). The immunotherapy also resulted in a 19% ORR with a 17.2-month median duration of response, while docetaxel demonstrated a 12% ORR that lasted a median of 5.6 months.

The rate of treatment-related serious adverse events (AEs) was 7% with nivolumab and 20% with docetaxel. Immune-related AEs of any grade associated with nivolumab therapy included rash (9%), hypothyroidism (7%), elevated AST (3%), increase in transaminases (3%), and pneumonitis/interstitial lung disease (4%). However, few of these toxicities were grade 3/4 events.

Martins also noted that nivolumab is under study in combination with ipilimumab (Yervoy), which targets the CTLA-4 immune checkpoint.

In the CheckMate-012 trial, the two drugs were administered as frontline treatment for patients with advanced disease.4 Multiple different dosing regimens of the combination were tested, with response rates ranging from 13% to 31%. Treatment-emergent grade 3/4 occurred in 28% to 35% of patients in each group.4

Martins noted that the efficacy of such a combination would have to be weighed against the toxicities generated by combining two checkpoint blockade agents. In October, the FDA approved a nivolumab plus immunotherapy regimen for patients with unresectable BRAF V600 wild-type metastatic melanoma.

“At least in terms of response rate, the benefit of the combination doesn’t seem as dramatic as they saw in melanoma, and I think the jury is still very much out if combinations will prove to be superior in non—small cell lung cancer,” said Martins.


  1. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257-265.
  2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135.
  3. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J. Med. 2015;373(17):1627-1639.
  4. Rizvi NA, Gettinger SN, Goldman MD, et al. Safety and efficacy of first-line nivolumab and ipilimumab in non-small cell lung cancer. Presented at 16th World Conference on Lung Cancer; September 6-9, 2015; Denver, CO. Abstract 786.


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