Boosting Responses to Neoadjuvant Therapy in Resectable NSCLC

NEW ORLEANS — Neoadjuvant combinations involving durvalumab (Imfinzi) plus novel agents led to major pathological responses (MPRs) in nearly a third of patients with early-stage non-small cell lung cancer (NSCLC), a phase II multi-drug platform study showed.

In the randomized NeoCOAST trial of operable NSCLC, those on the PD-L1 inhibitor durvalumab alone had an MPR rate of 11.1% and a pathological complete response (pCR) rate of 3.7%, reported Tina Cascone, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the American Association for Cancer Research annual meeting.

And while the study was not powered to compare arms, durvalumab-based combinations involving oleclumab, monalizumab, and danvatirsen resulted in numerically higher MPR and pCR rates:

• Durvalumab/oleclumab: MPR 19.0%, pCR 9.5%

• Durvalumab/monalizumab: MPR 30.0%, pCR 10.0%

• Durvalumab/danvatirsen: MPR 31.3%, pCR 12.5%

“The use of a neoadjuvant platform trial design and surrogate endpoints facilitates the rapid generation of data to inform next-generation trials evaluating novel, immunotherapy-based combination regimens in patients with early-stage resectable non-small cell lung cancer,” Cascone said during a plenary session here.

From March 2019 to September 2020, NeoCOAST enrolled 84 patients (median age 67.5) with untreated, resectable, stages I-IIIA NSCLC. These patients received a 28-day cycle of neoadjuvant durvalumab alone (n=27) or in combination with either the anti-CD73 monoclonal antibody oleclumab (n=21), the anti-NKG2A monoclonal antibody monalizumab (n=20), or the anti-STAT3 antisense oligonucleotide danvatirsen (n=16).

The primary endpoint of the trial was MPR, which was defined as ≤10% residual viable tumor cells in the resected tumor tissue and sampled nodes at surgery, and the primary intent was to seek preliminary signals of efficacy in order “to identify promising combinatorial strategies to be tested in subsequent studies,” Cascone explained.

Overall, 76 of 83 treated patients (91.6%) completed surgery with no significant delay, while 72 completed surgery within 42 days, which was the protocol-defined time not considered to be a delay.

The most common treatment-related adverse event (TRAE) across all treatment arms was fatigue. Grade 3 or higher TRAEs occurred in 19.2%, 14.3%, 10.0%, and 31.3% of patients in the durvalumab-alone, oleclumab, monalizumab, and danvatirsen arms, respectively, Cascone reported.

MPR was associated with baseline tumor PD-L1 expression of ≥1% in the oleclumab and monalizumab combination arms, she said. Additionally, patients with MPR who received neoadjuvant durvalumab plus oleclumab or monalizumab had peripheral transcriptomic signatures, which “suggests that combined, multiple immune pathway inhibition may be superior to immune checkpoint inhibitor monotherapy,” Cascone noted.

AACR-designated discussant Edward B. Garon, MD, of the University of California Los Angeles, called the study “impressive” and said it showed the benefit of three different drugs, with different mechanisms of action, when added to durvalumab. Still, he added, the results are limited by the availability of presurgical tissue, “making the findings from the correlative analysis mainly exploratory.”

Garon noted that most of the patients in each of the four study arms had PD-L1 results that were not evaluable. “PD-L1 is assessed by immunohistochemistry — it is one of the easiest correlative analyses to perform that we have — and it indicates that for most of these patients we just did not have sufficient baseline tumor to make a real assessment here. Patients were eligible for the study based on a biopsy, but in many cases we now know that the biopsy was not sufficient for correlative analysis for what was being evaluated as part of this study,” he said.

Cascone noted that she and her colleagues have launched the follow-up randomized NeoCOAST-2 trial, a larger study that is now enrolling patients with resectable, stages IIA-IIIA NSCLC to receive neoadjuvant durvalumab combined with chemotherapy and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab.

Commenting on that new trial, Garon said: “In terms of the tissue availability, PD-L1 expression is going to be a stratification factor, so that will increase the likelihood of having sufficient biopsies for correlative analyses.”