Multiple Immune Pathway Inhibition Bests ICI Therapy in Resectable, Early-Stage NSCLC


Targeting multiple immune cell pathways may elicit better major pathologic and pathologic complete responses in patient with resectable, early-stage non–small cell lung cancer versus immune checkpoint inhibition alone.

Patients with resectable, early-stage non–small cell lung cancer (NSCLC) treated with neoadjuvant the PD-L1 inhibitor durvalumab (Imfinzi) combined with either the anti-CD73 monoclonal antibody (mAb) oleclumab, anti-NKG2A mAb monalizumab, or anti-STAT3 antisense oligonucleotide danvatirsen displayed improvement in major pathologic response (MPR) compared with those who received durvalumab alone in the phase 2 NeoCOAST clinical trial.

In the arms containing durvalumab plus oleclumab and durvalumab plus monalizumab, MPR correlated with baseline tumor PD-L1 expression, according to findings presented during the American Association for Cancer Research (AACR) Annual Meeting 2022. Also, the safety profiles of durvalumab alone were similar to previous reports.

Prior research in support of NeoCOAST include the phase 3 CheckMate-816 study and the phase 2 COAST study. Presenter of the NeoCOAST data at AACR, Tina Cascone, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX explained their relevance.

“Neoadjuvant therapy with PD-1 and PD-L1 inhibitors leads to pathological responses in patients with resectable non–small cell lung cancer both as a monotherapy and in combination with CTLA-4 blockade. In the phase 3 Checkmate 816 trial, nivolumab combined with chemotherapy, improved pathological complete responses and event-free survival compared with chemotherapy alone in patients with resectable non–small cell lung cancer,” she said.

“In the phase 2 COAST trial durvalumab plus the anti-CD73 monoclonal antibody oleclumab and the anti-NKG2Q monoclonal antibody monalizumab provided additional clinical benefit over durvalumab alone for patients with unresectable stage III non–small cell lung cancer without disease progression following chemoradiotherapy," Cascone continued.

In NeoCOAST (NCT03794544), a global, phase 2 open-label, multicenter, randomized study, 84 patients with stage I to IIIA resectable NSCLC who had an ECOG performance status of 0 or 1, adequate organ and bone marrow function and who has not received prior systemic therapy were included. Stratified by whether or not they had lymph node involvement, patients were randomized to 1 of 4 treatment arms: durvalumab monotherapy every 4 weeks (Q4W), durvalumab Q4W with oleclumab Q2W, durvalumab Q4W with monalizumab Q2W or durvalumab Q4W with danvatirsen QW. Treatment in the study was 1 28-day cycle.

According to the study protocol, following systemic therapy, patients would undergo surgical resection on days 19 through 42. Follow-up in the study continued until day 105.

The primary end points explored in the study was MPR rate per investigator assessment, and the secondary end points included pathological complete response (pCR) rate, safety and tolerability, and the feasibility of planned surgery. Investigators also assessed tumor, blood, and stool microbiome biomarkers as well as overall response rate (ORR) per RECIST v1.1 as exploratory end points.

Of the 84 patients randomized between March 2019 and September 2020, 83 were treated. Twenty-seven patients received durvalumab alone, and of those patients 26 completed treatment, and 24 went on to surgery. In the durvalumab plus oleclumab arm, 21 patients were included, 20 of those patients who completed treatment, and 18 had surgery. In the durvalumab plus monalizumab arm, 20 patients were randomized, 19 of whom completed treatment, and 18 of whom went on to surgery. Finally, of the 16 patients in the durvalumab/danvatirsen arm, 15 completed treatment, and 16 had surgery.

In terms of baseline characteristics and demographics, the study population was between the ages of 51 and 87 years old, and more than 50% of patients in each treatment arm were male. More than 80% of patients in each treatment arm identified as White, with the second majority race being Black or African American.

“Overall demographic characteristics were well balanced across arms, noted Cascone. “There was a slightly higher proportion of patients with adenocarcinoma histology in the durvalumab arm and the durvalumab plus oleclumab arm. The proportion of current or former smokers were slightly higher in the combination regimens as compared to the durvalumab monotherapy arm. There were some differences in the distribution of patients with various stages across arms, given the overall small sample size of each arm. In the durvalumab plus monalizumab arm, there was a slightly higher number of patients with stage I and III disease as compared to the durvalumab plus oleclumab and durvalumab plus damvatirsen arms. In the durvalumab monotherapy arm. There were also fewer than 10% of patients with stage III disease. And despite this difference in stage, the proportion of patients with lymph node involvement was overall well balanced across arms.”

In the intention-to-treat population, it appeared that MPR and pCR rates with durvalumab were similar to published findings from other anti-PD-1/PD-L1 antibodies, which range between 6.7% to 45% for MPR and 0% to 16.2% for pCR. There was no difference in pCR between the investigational treatment arms, nor was there a difference in ORR rates.

Durvalumab monotherapy had a MPR of 11.1% and a pCR of 3.7%. the ORR with the single-agent was 7.4% which consisted of partial response (PR) in 7.4%, stable disease in 81.5%, and progressive disease (PD) in 3.7%, with the other 3.7% not evaluable (NE) for response.

Among patients treated with durvalumab in combination with oleclumab, the MPR was 19.0% and the pCR was 9.5%. The durvalumab/oleclumab arm had an ORR of 4.8%, which included PRs in 4.8%, SD in 81.0%, and PD in 14.3%.

Patients treated with durvalumab combined with monalizumab had a 30.0% MPR and a pCR of 10.0%, The ORR with the addition of monalizumab to durvalumab was 15.0%, consisting of PRs in 15.0%, SD in 75.0%, and PD in 5.0%, with the remaining 5.0% NE.

In the durvalumab/danvatirsen arm, the MPR was 31.3%, and the pCR was 12.5%. Objective response to the combination were observed in 6.3%, which included PRs in 6.3%, SD in 87.5%, and PD in 6.3%.

Pathological regression at the time of surgery was assessed in all 4 treatment arms. “The proportion of resected patients achieving MPR was numerically higher with the combination regimens as compared to the bottom number monotherapy with an MPR of 22.2% in the drama plus oleclumab and 33.3% in the durvalumab plus monalizumab and durvalumab plus damvatirsen arms as compared to 12.5% in the durvalumab monotherapy arm,” Cascone explained.

There were no new safety signals identified with any of the durvalumab-containing combinations. Any-grade treatment-emergent adverse events (TEAEs) were observed in 69.2% of the monotherapy arm, 90.5% of the durvalumab/oleclumab arm, 75.0% of the durvalumab/monalizumab, and 81.3% of the durvalumab/danvatirsen arm. TEAEs were grade 3 or higher in 19.2%, 14.3%, 10.0%, and 31.3%, respectively. Although treatment-related AEs (TRAEs) were rare in the study, serious TRAEs did occur in 3.8% of the monotherapy arm, compared with 4.8% of the durvalumab/oleclumab arm, 0% of the durvalumab/monalizumab arm, and 6.3% of the durvalumab/danvatirsen arm.

More than 90% of patients in the as-treated population complete surgery with no significant delay. Moreover, 72 patients completed surgery within 42 days. Of the 7 patients who were unable to complete surgery, PD was observed in 5, 1 patient was lost to follow-up, and 1 had a serious AE of pneumonia, making them ineligible for surgery.

Transcriptomic assessments in the NeoCOAST study are ongoing, however, tumor-, and blood-based biomarker data were presented. The data showed high CD73 with fewer viable tumor cells at the time of surgery in the durvalumab plus oleclumab arm as well as a decreased in CD73 observed in treatment in the durvalumab plus oleclumab arm, but not on other treatment arms.

Further, there was an increase in NKG2A-positive cell density in the tumor center in the durvalumab plus oleclumab arm, which suggests increased infiltration of effector cells in the tumor microenvironment on treatment, according to Cascone. In the durvalumab plus monalizumab arm, the investigators noticed an upregulation of CXCL9 and CXCL11 chemokines on treatment. Both chemokines were notably upregulated in the peripheral blood.

The study findings suggest that combined, multiple immune pathway inhibition may be superior to using immune checkpoint inhibitor alone, according to Cascone. “The use of a neoadjuvant platform trial design with surrogate end points facilitates the rapid generation of clinical and translational data that can inform next-generation trials, evaluating novel immunotherapy-based strategies for our patients with resectable non­–small cell lung cancer.”


Cascone T, Garcia-Campelo R, Spicer J, et al. CT011 - NeoCOAST: open-label, randomized, phase 2, multidrug platform study of neoadjuvant durvalumab alone or combined with novel agents in patients (pts) with resectable, early-stage non-small-cell lung cancer (NSCLC). Presented at: AACR Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Abstract CT011.

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