Novel Perioperative Combinations Show Efficacy in Resectable NSCLC

Tina Cascone, MD, PhD

Numerically high pathologic complete response (pCR) rates and/or major pathologic response (mPR) rates were observed when patients with resectable non–small cell lung cancer (NSCLC) received 3 different novel combinations, according to data from the phase 2 NeoCOAST-2 trial (NCT05061550). Data presented at the 2024 IASLC World Conference on Lung Cancer also revealed that NeoCOAST-2 was the first global, phase 2 trial to show a manageable safety profile and efficacy of an antibody-drug conjugate (ADC) in the neoadjuvant setting for this patient population.¹

In the intention-to-treat population, patients in arm 1 of the trial who received oleclumab plus durvalumab (Imfinzi) and platinum-doublet chemotherapy (n = 60) experienced a pCR rate of 20.0% and a mPR rate of 45.0% per local or central pathological assessment. Those in arm 2 who received monalizumab plus durvalumab and platinum-doublet chemotherapy (n = 60) achieved a pCR rate of 26.7% and a mPR rate of 53.3%. Finally, in arm 4 patients who were treated with Dato-DXd plus durvalumab and single-agent platinum chemotherapy (n = 44) achieved a pCR rate of 34.1% and a mPR rate of 65.9%.

“The highest pCR and mPR rates were seen with Dato-DXd plus durvalumab and single-agent platinum chemotherapy. Treatments in all arms demonstrated manageable safety profiles and surgical rates that were comparable to currently approved regimens,” Tina Cascone, MD, PhD, said in a presentation of the data. Cascone is an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

Additionally, pCR rates were higher in each arm when patients had a PD-L1 tumor proportion score (TPS) of 50% or greater vs 1% to 49% or less than 1%. Rates were as follows for patients in: arm 1 with a PD-L1 TPS of less than 1% (n = 17; 17.6%), 1% to 49% (n = 18; 5.6%), and 50% or greater (n = 25; 32.0%), arm 2 with a PD-L1 TPS less than 1% (n = 20; 15.0%), 1% to 49% (n = 20; 30.0%), and 50% or greater (n = 20; 35.0%), and arm 4 with a PD-L1 TPS less than 1% (n = 12; 25.0%), 1% to 49% (n = 15; 33.3%), and 50% or greater (n = 17; 41.2%).

“Of note, in the Dato-DXd arm, pCR rates were comparable across histologic subtypes,” Cascone said. “Looking at PD-L1 subgroups, higher pCR rates were seen with increasing PD-L1 expression cutoff across the 3 arms. [However], caution should be applied in interpreting these results given the overall small sample size in each subgroup.”

The 4 Arms Enrolled in NeoCOAST-2

The open-label platform NeoCOAST-2 study enrolled patients with stage IIA to IIIB resectable NSCLC who had EGFR/ALK wild-type disease. Patients had a ECOG performance score of 0 or 1 and were stratified by PD-L1 TPS (less than 1% vs 1% or more). The primary end points of the study were pCR rate and safety/tolerability. Key secondary end points included feasibility of surgery, mPR rate, and event-free survival. Cascone noted that the primary goal of NeoCOAST-2 was to examine efficacy signals with the calculation of pCR rates and the study was not powered to make direct statistical comparisons between arms.

Patients were randomly assigned to receive neoadjuvant therapy for 4 cycles every 3 weeks; regimens included the anti-CD73 agent oleclumab plus durvalumab and platinum-doublet chemotherapy (arm 1), the anti-NKG2A agent monalizumab plus durvalumab and platinum-doublet chemotherapy (arm 2), volrustomig plus chemotherapy (arm 3), or the TROP2-directed ADC Dato-DXd plus durvalumab and single-agent platinum chemotherapy (arm 4). All patients then proceeded to surgery and received corresponding adjuvant therapy regimens excluding chemotherapy for up to 1 year. Data from arm 3 were not reported at IASLC.

Baseline patient characteristics were well balanced across arms 1 (n = 76), 2 (n = 72), and 4 (n = 54); most patients were White (63.2% vs 59.7% vs 68.5%), had an ECOG performance score of 0 (61.6% vs 69.0% vs 66.7%), had a histology of adenocarcinoma (65.8% vs 63.9% vs 61.1%), and had a PD-L1 TPS of greater than 1% (68.4% vs 66.7% vs 75.9%). The median age of patients was 66.5 years (range, 30-79) in arm 1, 66.0 years (range, 48-83) in arm 2, and 65.0 years (range, 38-81) in arm 4.

Further, patients in arms 1, 2, and 4, had stage IIA (9.2% vs 9.7% vs 3.8%), IIB (21.1% vs 26.4% vs 24.5%), IIIA (52.6% vs 45.8% vs 50.9%), and IIIB (17.1% vs 18.1% vs 20.8%) disease, respectively. Of the 202 patients randomly assigned to arms 1, 2, and 4, 74.3% vs 76.1% vs 72.1% of patients completed neoadjuvant therapy. Almost all patients underwent surgery (92.2% vs 92.1% vs 95.8%), and most patients started adjuvant therapy (83.6% vs 74.1% vs 83.3%), respectively.

Diving Into Safety Data

When examining adverse effects (AEs) by phase of therapy, patients in arm 1, the oleclumab plus durvalumab and chemotherapy arm, experienced grade 3 or higher treatment-related AEs (TRAEs) in the neoadjuvant (n = 74), post-surgery (n = 59), and adjuvant (n = 46) settings at rates of 31.1%, 0.0%, and 4.3%. AEs leading to treatment discontinuation by period occurred in 8.1%, 1.7%, and 6.5% of patients, respectively.

Additionally, in arm 1 grade 3 or higher treatment-emergent AEs (TEAEs) in the neoadjuvant setting included anemia, asthenia, neutropenia, arthralgia, and decreased appetite. Further, 3 patients died due to serious AEs; 2 patients died during the post-surgery period due to respiratory failure related to surgery and investigators noted both patients had a lobectomy. One patient died during the neoadjuvant phase of the trial due to intestinal ischemia related to chemotherapy.

When examining arm 2 of patients who received monalizumab plus durvalumab and chemotherapy, grade 3 or higher TEAEs in the neoadjuvant setting included anemia, neutropenia, alopecia, diarrhea, and thrombocytopenia. Grade 3 or greater TRAEs occurred in 29.6% of patients in the neoadjuvant period (n = 71), 1.7% in the post-surgery period (n = 58), and 12.5% in the adjuvant period (n = 40) of the study. AEs led to discontinuation in 12.7%, 0.0%, and 7.5% of patients, respectively. Further, 4 patients died due to serious AEs; 3 died during the post-surgery period due to sepsis related to pneumonectomy, septic shock related to lobectomy, and renal failure related to bilobectomy. One patient died in the adjuvant period due to cardiorespiratory arrest related to durvalumab and monalizumab.

In arm 4, the Dato-DXd plus durvalumab and chemotherapy arm, grade 3 or higher TRAEs only occurred in the neoadjuvant period of therapy (n = 54) and were seen in 18.5% of patients. Additionally, AEs only led to discontinuation of therapy in the neoadjuvant period; 7.4% of patients discontinued. Grade 3 or higher TEAEs occurring in the neoadjuvant setting included anemia, asthenia, neutropenia, alopecia, thrombocytopenia, nausea, vomiting, mucosal inflammation, and fatigue. One patient died due to a serious AE in the post-surgery period (n = 46).

“One patient in the post-surgical phase died due to idiopathic lung fibrosis, which was deemed unrelated to treatment per investigator, with independent adjudication still pending. This patient had a past medical history of idiopathic lung fibrosis, which represents an exclusion criterion for this study,” Cascone noted.

Disclosures: Dr Cascone did not cite any disclosures.

Reference

Cascone T, Guisier F, Bonanno L, et al. Neocoast-2: efficacy and safety of neoadjuvant durvalumab (d) + novel anticancer agents + CT and adjuvant d ± novel agents in resectable NSCLC.Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract PL02.07.