Presurgical Nivo/Chemo Boosts pCR Rates in NSCLC

Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.

However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.

Adding the immune checkpoint inhibitor nivolumab (Opdivo) to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.

Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.

This difference translated into an odds ratio (OR) for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.

This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.

“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.

Forde presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

The higher pCR rates were seen regardless of programmed cell death–ligand-1 (PD-L1) expression or tumor mutational burden, Forde said.

The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination, vs 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7%, vs 2.8%).

Change in Trial Design

Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, Florida, pointed out that the Checkmate 816 trial originally included an experimental arm with double immunotherapy ― ipilimumab (Yervoy) plus nivolumab ― added onto chemotherapy.

However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 Keynote-021 showed that adding pembrolizumab (Keytruda) to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).

“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.

Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”

She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.

“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Gray said.

CheckMate 816 Particulars

CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors ≥4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.

Patients were randomly assigned on an equal basis to receive either nivolumab 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.

Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.

In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.

Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% vs 8.9%, translating into an OR of 5.70 (95% CI, 3.16 – 10.26).

In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of cycle 1 to day 1 of cycle 3 using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.

Safety Similar

“Remarkably, safety was quite similar across the two treatment arms,” Forde said.

The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3–4 adverse events occurred in 41% of patients in the combination arm, vs 44% in the chemotherapy-alone arm.

Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.

Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.

The investigators are continuing to assess event-free survival and overall survival.

Checkmate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical Company. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.

American Association for Cancer Research (AACR) Annual Meeting 2021: Abstract CT003. Presented April 10, 2021.

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