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Adding novel agents to perioperative durvalumab (Imfinzi) for non-small cell lung cancer (NSCLC) led to higher rates of pathologic complete response (pCR) and major pathologic response (mPR) compared with historical rates with durvalumab and chemotherapy, a prospective study showed.

The highest response rates (pCR 34.1%, mPR 65.9%) occurred when the antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) was added to the PD-1 inhibitor and chemotherapy. Adding the anti-NKG2A antibody monalizumab led to a pCR rate of 26.7% and mPR of 53.3%, whereas the anti-CD73 antibody oleclumab resulted in a pCR rate of 20% and mPR of 45.0%.

Responses with all of the combinations exceeded historical benchmarks for perioperative treatment with durvalumab plus chemotherapy, reported Tina Cascone, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the World Conference on Lung Cancer.

"Treatments in all arms demonstrated manageable safety profiles and surgical rates that were comparable to currently approved regimens," she said. "This is the first global phase II study showing encouraging efficacy and manageable safety profile of an antibody-drug conjugate in the neoadjuvant setting for patients with resectable non-small cell lung cancer."

The historical comparator for the study was the phase III AEGEAN trial, which showed a pCR rate of 17.2% and mPR rate of 33.0% with perioperative durvalumab plus chemotherapy. All three regimens evaluated in the current study numerically exceeded those values, and results with Dato-DXd showed a doubling of the rates, noted invited discussant Nan Wu, MD, of Peking University Cancer Hospital in China.

For additional historical context, Wu pointed to two recent studies evaluating nivolumab (Opdivo) plus chemotherapy in resectable NSCLC. A neoadjuvant study showed a 24% pCR rate with nivolumab plus chemotherapy, whereas perioperative nivolumab plus chemotherapy produced a pCR rate of 25%.

"Novel immuno-oncology combinations, with or without chemotherapy, showed promising efficacy and safety data in the perioperative setting," said Wu. "A using patient-level data from [the two nivolumab trials] supported perioperative nivolumab as a treatment option for eligible patients with resectable non-small cell lung cancer. Phase III randomized controlled trials are needed for further evaluation."

Cascone reported findings from the phase II trial evaluating durvalumab-based perioperative therapy for resectable NSCLC. The study represented a rational progression of clinical evaluation, following phase II studies that evaluated durvalumab plus oleclumab or monalizumab in unresectable stage III NSCLC and as neoadjuvant therapy for resectable NSCLC.

The study also followed the path of perioperative combinations of anti-PD-(L)1 agents and chemotherapy. NeoCOAST-2 was designed to investigate PD-1 inhibition plus novel agents as a strategy to improve on results with perioperative combinations of PD-(L)1 inhibition and chemotherapy. Dato-DXd was included in the investigation to build on results of a phase III trial that showed improved progression-free survival in advanced NSCLC when the TROP2-directed ADC was added to chemotherapy.

Cascone reported findings for 202 patients with stage IIA-IIIB resectable NSCLC, randomized to oleclumab and durvalumab before and after surgery, monalizumab and durvalumab before and after surgery, or Dato-DXd and durvalumab before surgery followed by durvalumab after surgery. All patients received neoadjuvant chemotherapy.

The primary endpoints were pCR and safety/tolerability. Key secondary endpoints were mPR (no viable tumor cells in tumor specimen and ≤10% residual viable tumor cells in lymph nodes) and feasibility of surgery.

Across the three treatment arms, 72.1% to 76.1% of patients completed neoadjuvant therapy, 92.1% to 95.8% underwent surgery, 89.7% to 96.2% had R0 surgical outcomes, and 74.1% to 83.6% started adjuvant therapy.

The data showed that 65% of 60 evaluable patients achieved pCR/mPR with oleclumab-durvalumab, 80% of 60 evaluable patients with monalizumab-durvalumab, and 100% of 44 evaluable patients with Dato-DXd-durvalumab. Analysis of pCR by PD-L1 expression showed modest improvement with oleclumab-durvalumab in patients with PD-L1 total positive score (TPS) ≥1% versus <1% (20.9% vs 17.6%). The pCR rate more than doubled with monalizumab-durvalumab in patients with TPS ≥1 (32.5% vs 15.0%) and improved meaningfully with Dato-DXd-durvalumab (37.5% vs 25.0%).

A comparison of TPS 1-49% vs ≥50% showed a big improvement with the higher TPS for oleclumab-durvalumab (5.6% vs 32.0%) and smaller increases with monalizumab-durvalumab (30.0% vs 35.0%) and Dato-DXd-durvalumab (33.3% vs 41.2%).

Grade ≥3 treatment-related adverse events (TRAEs) occurred during the neoadjuvant phase in about 30% of patients treated with oleclumab or monalizumab versus less than 20% with Dato-DXd. Grade ≥3 TRAEs were uncommon during adjuvant therapy in all three arms. Rates of discontinuation because of AEs during neoadjuvant therapy were 8.1% with oleclumab, 12.7% with monalizumab, and 7.4% with Dato-DXd. Respective discontinuation rates during adjuvant therapy were 6.5%, 7.5%, and 0%.

There was one patient death in the oleclumab arm during neoadjuvant therapy (chemotherapy-related intestinal ischemia) and two during surgery. There were none in the monalizumab arm during neoadjuvant therapy, three during surgery, and one during adjuvant therapy. In the Dato-DXd arm, there was one during surgery.

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