More Than 40% Pathological Complete Response with Nivolumab Before Lung Cancer Surgery!

Over the past 1 year, treatment of early-stage, that is, operable non-small cell lung cancer has been transformed by the success of immunotherapy. Very strong evidence for adding immunotherapy to preoperative treatment in these patients came from the NADIM II study presented at the ASCO 2022 meeting.

• The NADIM II study showed that neoadjuvant (preoperative tumor-shrinking) nivolumab plus carboplatin-based chemotherapy in stage IIIA non-small cell lung cancer (NSCLC) patients significantly improved pathological complete response compared with chemotherapy alone.
• This study corroborates the results of the CheckMate-816 trial, which previously led to FDA (US Food and Drug Administration) approval of this treatment.
• Adding neoadjuvant nivolumab to chemotherapy did not increase the rate of high-grade adverse events compared with chemotherapy alone and increased the surgery rate.

On March 4, 2022, the FDA approved neoadjuvant nivolumab plus chemotherapy for 358 patients with operable stage IB, II, and IIIA NSCLC (tumor ≥ 4 cm or node-positive), based on results of the randomized, open-label, phase III CheckMate-816 trial. The trial reported improvements in pathological complete response (pCR) and event-free survival among participants receiving combination therapy compared with chemotherapy alone. Median overall survival has not yet been reached.

Preoperative Immunotherapy in Lung Cancer Generates Great Excitement

One strength of the NADIM II study is its focus on stage IIIA disease. These patients do not have very good disease outcomes, and we do not have a standard approach for this group. These data reveal the best results to date for operable stage III NSCLC.

NADIM II included 86 patients at clinics in Spain randomly assigned in a 2:1 ratio to receive nivolumab plus carboplatin-based chemotherapy (57 patients) or chemotherapy alone (29 patients). Patients were required to have an ECOG performance status of 0 or 1 and no known EGFR  or  ALK  mutations.

The primary endpoint for the study was pCR assessed by blinded independent pathological review.

Figure. Pathological Complete Response Rates with Neoadjuvant Nivolumab Plus Chemotherapy Versus Chemotherapy in the Entire Patient Group

• pCR was defined as 0% residual viable tumor cells in both the primary tumor (lung) and sampled lymph nodes.
• Patients who did not undergo surgery were considered nonresponders.
• Patients receiving nivolumab plus chemotherapy also had significantly higher major pathological response (≤10% residual viable tumor in the primary tumor) and objective response rates, which were secondary endpoints.

Adding nivolumab to chemotherapy did not significantly increase adverse events in NADIM II. Grade 3/4 adverse events occurred in 25% of patients in the combination therapy arm and 10.3% in the chemotherapy-alone group. No treatment-related grade 5 adverse events occurred in either group.

In the combination therapy arm, 93% of patients underwent surgery after treatment, compared with 69% in the control group (OR 5.96, 95% CI [1.65, 21.56]; P = 0.00807).

It is clear that more patients receiving immunotherapy underwent surgery, because adding nivolumab appears more effective at shrinking the tumor without adding many adverse effects.

The earlier NADIM I study involved neoadjuvant nivolumab and carboplatin-based chemotherapy followed by adjuvant nivolumab monotherapy in 46 patients with operable stage IIIA NSCLC. This study recently reported overall survival of 81.9% at a median follow-up of 38 months.

From Puerta de Hierro Hospital in Madrid, Spain, and president of the Spanish Lung Cancer Group, Dr. Mariano Provencio led the NADIM I and II studies and presented the NADIM II findings at ASCO 2022.

“The first part of the story was a proof of concept, NADIM I, then CheckMate-816 confirmed the results. Now NADIM II confirms the results of CheckMate-816. I think we have completed the circle,” said Dr. Provencio.

CheckMate-816 and NADIM II continue to follow patients to determine median overall survival.

Carboplatin or Cisplatin?

The new NADIM II findings raised the question of whether carboplatin -based chemotherapy might be more effective than cisplatin-based chemotherapy in combination with nivolumab. CheckMate-816 found higher pCR rates among patients receiving nivolumab plus carboplatin-based chemotherapy than among those receiving nivolumab plus cisplatin-based chemotherapy (30.8% versus 21.8%). The pCR rate in NADIM II, which used carboplatin-based chemotherapy, was even higher at 36.8%.

Pathological Complete Response Reached 60% in PD-L1-Positive Subgroups

Similar to CheckMate-816, the NADIM II study found that a PD-L1 tumor proportion score (TPS) ≥ 1% identified patients with high PD-L1 expression who were more likely to achieve pCR after nivolumab plus chemotherapy.

In patients with PD-L1 positivity by TPS of 1–49% and ≥ 50%, pCR rates were 41.7% and 61.1%, respectively.

Among patients with PD-L1 expression by TPS < 1%, the pCR rate was 15%. This remains a higher rate than with chemotherapy alone, and patients with low PD-L1 expression are also likely to be eligible for this treatment.