Use of multiple immune pathway inhibitors appears to be superior to checkpoint inhibitor therapy alone as neoadjuvant therapy for resectable non–small cell lung cancer (NSCLC), according to the results of the phase II NeoCOAST trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.¹

Neoadjuvant therapy with the PD-L1 inhibitor durvalumab combined with one of three novel agents—the anti-CD73 monoclonal antibody oleclumab, the anti-NKG2A monoclonal antibody monalizumab, or the anti-STAT3 antisense oligonucleotide danvatirsen, numerically improved major pathologic response rates, compared with durvalumab alone, in patients with resectable, early-stage NSCLC.¹

The primary endpoint of major pathologic response rate was associated with baseline tumor PD-L1 expression in the durvalu­mab-plus-oleclumab and durvalumab-plus-monalizumab arms. The safety profile of the durvalumab monotherapy arm in this trial was consistent with previously published data; no new safety signals were identified with any of the combination regimens.

The NeoCOAST study was designed before the results from the phase III CheckMate 816 trial and the phase II COAST trial were available.^2,3 “Neoadjuvant therapy with PD-1 and PD-L1 inhibitors leads to pathologic responses in patients with resectable NSCLC, both as monotherapy and in combination with CTLA-4 blockade. In the phase III CheckMate 816 trial, the PD-l inhibitor nivolumab combined with platinum-based chemotherapy improved pathologic complete response rate and event-free survival, compared with chemotherapy alone in patients with resectable NSCLC,” explained lead author Tina ­Cascone, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.

Tina ­Cascone, MD, PhD

“In the phase II COAST trial, durvalumab plus oleclumab or monalizumab provided additional clinical benefit compared with durvalu­mab alone for patients with unresectable, stage III NSCLC without disease progression following chemoradiotherapy,” she added.

Dr. Cascone commented on the value of this type of study. “The use of a neoadjuvant platform trial design with surrogate endpoints facilitates the rapid generation of clinical and translational data that can inform next-generation trials evaluating novel immunotherapy-based combination regimens for our patients with resectable NSCLC.”

Study Details

Between March 2019 and September 2020, the global, phase II open-label, multicenter, multidrug platform NeoCOAST trial randomly assigned 84 patients with resectable, stage I to IIIA NSCLC to one of four treatment arms: durvalumab monotherapy every 4 weeks; durvalumab every 4 weeks plus oleclumab every 2 weeks; durvalumab every 4 weeks plus monalizumab every 2 weeks; or durvalumab every 4 weeks plus danvatirsen every week. Treatment was administered for one 28-day cycle.

Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and bone marrow function, and no prior systemic therapy. Patients were stratified by lymph node involvement.

Patients could undergo surgical resection on days 29 through 42 after completing neoadjuvant therapy. Follow-up in the study continued until day 105.

The primary endpoint was major pathologic response rate. Secondary endpoints included pathologic complete response rate, safety/tolerability, feasibility of planned surgery, pharmacokinetics, and immunogenicity. Investigators also performed exploratory analyses of tumor, blood, and stool microbiome biomarkers, as well as best overall response and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1.

At baseline, demographic factors were well balanced across all treatment arms. Patient ages ranged from 51 to 87 years, and more than 50% of patients in each treatment arm were male. More than 80% of patients in each treatment arm were White. The proportion of current or former smokers was slightly higher in the combination arms than in the durvalumab monotherapy arm. Lymph node involvement was similar across all treatment arms.

Key Findings

In the intention-to-treat population, Dr. Cascone said that major pathologic response and pathologic complete response rates with durvalumab monotherapy were similar to previously published findings with anti–PD-1/PD-L1 antibodies. No major difference in pathologic complete response or objective response rates was observed between the treatment arms.

The rates of major pathologic response and pathologic complete response in the four treatment arms follow:

• Durvalumab monotherapy: 11.1% and 3.7%
• Durvalumab plus oleclumab: 19% and 9.5%
• Durvalumab plus monalizumab: 30% and 10%
• Durvalumab plus danvatirsen: 31.3% and 12.5%.

Objective response rates were 7.4% with durvalumab monotherapy, 4.8% with durvalumab plus oleclumab, 15% with durvalumab plus monalizumab, and 6.3% with durvalumab plus danvatirsen.

Pathologic regression at the time of surgery was assessed in all four treatment arms. “The number of resected patients with a major pathologic response was numerically higher in the combination arms, compared with a single dose of durvalumab in the monotherapy arm,” Dr. Cascone said.

Safety Profile

No new safety signals were reported with any of the durvalumab-containing combinations. Any-grade treatment-­emergent adverse events were observed in 69.2% of patients in the durvalumab arm, 90.5% of patients in the durvalumab plus oleclu­mab arm, 75.0% of patients in the durvalumab plus monalizumab arm, and 81.3% of patients in the durvalumab plus danvatirsen arm; treatment-emergent adverse events of grade 3 severity or higher were reported in 19.2%, 14.3%, 10%, and 31.3% of patients, respectively. Serious treatment-related adverse events occurred in 3.8% of patients in the durvalumab arm, 4.8% of patients in the durvalumab plus oleclumab arm, 0% of patients in the durvalumab plus monalizumab arm, and 6.3% of patients in the durvalumab plus danvatirsen arm.

In the as-treated population, more than 90% of patients completed surgery with no significant delay. Seven treated patients were unable to complete surgery—five due to disease progression, one due to a serious adverse event (non–treatment-
related), and one was lost to follow-up.

Exploratory analysis of tumor-based and blood-based biomarkers yielded some preliminary observations, including that patients with a major pathologic response who received neoadjuvant durvalumab plus oleclumab or durvalumab plus monalizumab had peripheral transcriptomic signatures related to immune cell function, suggesting that combined, multiple immune pathway inhibition may be superior to immune checkpoint inhibitor monotherapy. However, these numbers of patients were small, tissue samples were limited, and further translational analyses are ongoing.

Next Step

Based on the promising results of NeoCOAST and the findings from the CheckMate 816 study, the phase II NeoCOAST-2 trial (NCT05061550) has been launched and is actively recruiting patients with resectable, early-stage NSCLC. Patients will be randomly assigned to receive neoadjuvant durvalumab plus chemotherapy plus oleclumab followed by adjuvant durvalumab plus oleclumab after surgery (arm 1) or neoadjuvant durvalu­mab plus chemotherapy plus monalizumab followed by adjuvant durvalumab plus monalizumab after surgery (arm 2). Surgical resection will be performed within approximately 40 days from the last dose of neoadjuvant treatment. The primary endpoints will be pathologic complete response rate and safety/tolerability.

DISCLOSURE: The study was sponsored by AstraZeneca. Dr. Cascone reported relationships with the Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche, Medscape, PeerView, AstraZeneca, Merck, Genentech, Arrowhead Pharmaceuticals, and EMD Serono.

REFERENCES

1. Cascone T, Garcia-Campelo R, Spicer J, et al: NeoCOAST: Open-label, randomized, phase 2, multidrug platform study of neoadjuvant durvalumab alone or combined with novel agents in patients with resectable, early-stage non-small-cell lung cancer. AACR Annual Meeting 2022. Abstract CT011. Presented April 11, 2022.

2. Forde PM, Spicer J, Lu S, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. April 11, 2022 (early release online).

3. Herbst RS, Majem M, Barlesi F, et al: COAST: An open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non-small-cell lung cancer. J Clin Oncol. April 22, 2022 (early release online).