Nivolumab-platinum chemo combo improves response in early NSCLC

The combination of nivolumab and platinum chemotherapy in the neoadjuvant setting improved pathological complete response (pCR) in patients with resectable non-small cell lung cancer (NSCLC), according to results of the phase III CheckMate-816 trial.

“For the first time in a phase III trial, we see the potential for an anti-PD-1 immunotherapy to improve outcomes in earlier-stage NSCLC,” remarked Associate Professor Patrick Forde from the Sidney Kimmel Comprehensive Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, Baltimore, Maryland, US, who presented the findings at AACR 2021.

“We are highly encouraged by the marked improvement in pCR, the overall good tolerability, and the absence of impact on surgery feasibility when nivolumab is added to neoadjuvant chemotherapy,” he said.

Participants were 358 patients with newly diagnosed, resectable (stage IB–IIIA) NSCLC, ECOG performance score 0–1, and no EGFR or ALK alterations. They were randomized 1:1 to receive nivolumab (360 mg) + platinum-doublet chemotherapy or chemotherapy only Q3W for three cycles, followed by surgery within 6 weeks of the last treatment dose. Patients who did not undergo subsequent surgery were considered non-responders. Adjuvant chemotherapy with or without radiotherapy could be offered based on investigator discretion. The patients were followed up for a minimum 7.6 months.

Baseline characteristics were generally well balanced between groups. Forty-eight and 51 percent of patients in the nivolumab + chemotherapy and chemotherapy-only groups, respectively, were from Asian countries, and 63 and 64 percent had stage IIIA disease. Squamous and non-squamous histologies were evenly split and 50 percent of patients had PD-L1 ≥1 percent.  

The combination of nivolumab and chemotherapy significantly increased pCR rates, defined as 0 percent residual viable tumour cells in both primary lung tumour and lymph nodes, compared with chemotherapy alone (24.0 percent vs 2.2 percent; odds ratio [OR], 13.94, 99 percent confidence interval [CI], 3.49–55.75; p<0.0001). [AACR 2021, abstract CT003]

The results were consistent across multiple subgroups including disease stage (IB/II: 26.2 percent vs 4.8 percent; ≥IIIA: 23.0 percent 0.9 percent), PD-L1 expression (<1 percent: 16.7 percent vs 2.6 percent; ≥1 percent: 32.6 percent vs 2.2 percent), tumour mutational burden level (low: 22.4 percent vs 1.9 percent; high: 30.8 percent vs 2.7 percent), and histology (squamous: 25 percent vs 4 percent; non-squamous: 23 percent vs 0 percent).

Nivolumab + chemotherapy also improved major pathological response (MPR; ≤10 percent residual viable tumour in both lung and lymph nodes) vs chemotherapy alone (36.9 percent vs 8.9 percent; OR, 5.70, 95 percent CI, 3.16–10.26), objective response rate (53.6 percent vs 37.4 percent), and radiographic downstaging rate (30.7 percent vs 23.5 percent).

Median residual viable tumour cells were 10 and 74 percent in the nivolumab + chemotherapy and chemotherapy-only groups, respectively.

In a subset of patients, circulating tumour (ct)DNA clearance was more frequent in the combination therapy group, and those who achieved clearance were more likely to achieve pCR.

About 83 percent of patients in the nivolumab + chemotherapy group underwent definitive surgery compared with 75.4 percent of the chemotherapy-only group. Surgery was cancelled due to disease progression in 12 and 17 patients, respectively, and due to adverse events (AEs) in two patients in each group. Lobectomy was the most common surgery performed (77 and 61 percent of the nivolumab + chemotherapy and chemotherapy-only groups, respectively), and 17 and 25 percent underwent pneumonectomy.

Grade 3–4 treatment-related AEs (TRAEs) occurred in 33.5 and 36.9 percent of the nivolumab + chemotherapy and chemotherapy-only groups, respectively, and grade 3–4 surgery-related AEs in 11.4 and 14.8 percent, respectively. Grade 3–4 TRAEs led to discontinuation in 6 and 3 percent, respectively. The three treatment-related deaths occurred in the chemotherapy-only group. The two grade 5 surgery-related AEs in the nivolumab + chemotherapy group were considered unrelated to treatment.

“Immune-mediated AEs were generally infrequent and similar to what has been previously reported,” noted Forde. “Remarkably, despite the addition of nivolumab to neoadjuvant chemotherapy, there was no associated increase in TRAEs, and rates of AEs leading to surgery delay or cancellation were low. This provides reassurance that side effects from the combination will not adversely impact patients’ ability to have curative surgery,” he said.

A place in the treatment algorithm?

“The standard treatment for resectable lung cancer is surgery to remove the tumour. Despite this, many patients experience recurrence of their lung cancer and when this happens, it is usually incurable,” said Forde.

“Platinum-based chemotherapy given either before (neoadjuvant) or after (adjuvant) surgery improves survival of patients by only 5 percent at 5 years. Data accumulated to date from several retrospective studies show a clear trend that patients who achieve a pCR with neoadjuvant chemotherapy live longer than those who do not.”

“The significant improvement in pCR and absence of any meaningful increase in toxicity or decrease in the feasibility for surgery suggest that neoadjuvant nivolumab + chemotherapy is a viable option for patients with resectable NSCLC at high risk of recurrence. While neoadjuvant therapy has historically been less commonly used than adjuvant therapy for this patient population, I believe that CheckMate-816 has the potential to change that treatment paradigm,” he said.

According to Forde, pCR assessment based on blinded pathology central review was an added advantage. “[T]his provides a unique and more stringent assessment of pCR, as compared to other early trials evaluating immunotherapy in the neoadjuvant setting,” said Forde.

The study continues to mature for the event-free survival outcome, he added.