Perioperative durvalumab plus chemotherapy plus new agents for resectable non-small-cell lung cancer: the platform phase 2 NeoCOAST-2 trial

Abstract

In the phase II NeoCOAST-2 platform study, 202 patients with untreated, resectable stage IIA-IIIB non-small-cell lung cancer (NSCLC) were randomized to receive neoadjuvant durvalumab plus platinum-doublet chemotherapy with oleclumab, a CD73 inhibitor (Arm 1), or with monalizumab, a NKG2A inhibitor (Arm 2), or neoadjuvant durvalumab plus single-agent platinum chemotherapy with the TROP-2 antibody-drug conjugate (ADC) datopotamab deruxtecan (Arm 4), followed by surgical resection and adjuvant durvalumab with oleclumab or monalizumab (Arms 1 and 2) or durvalumab alone (Arm 4). Primary endpoints were pathological complete response (pCR) rate and safety; secondary endpoints included feasibility of surgery and major pathological response (mPR) rate. In the modified intention-to-treat population (n = 198; Arm 1, n = 74; Arm 2, n = 70; Arm 4, n = 54), pCR rates were 20.3% (15/74; 95% CI, 11.8-31.2), 25.7% (18/70; 95% CI, 16.0-37.6) and 35.2% (19/54; 95% CI, 22.7-49.4), and mPR rates were 41.9% (31/74; 95% CI, 30.5-53.9), 50.0% (35/70; 95% CI, 37.8-62.2) and 63.0% (34/54; 95% CI, 48.7-75.7) in arms 1, 2, and 4, respectively. In the safety population, 69/74 (93.2%), 66/71 (93.0%), and 51/54 (94.4%) patients underwent surgery, respectively. Overall, grade ≥3 treatment-related adverse events occurred in 27/74 (36.5%), 29/71 (40.8%) and 11/54 (20.4%) patients, respectively. In NeoCOAST-2, the first neoadjuvant trial examining an ADC plus chemo-immunotherapy in resectable NSCLC, pCR rates were highest in the datopotamab-deruxtecan-containing arm, warranting further investigation in larger trials of ADCs and checkpoint inhibition in the neoadjuvant setting. ClinicalTrials.gov identifier: NCT05061550 .

Fig. 1. CONSORT diagram and summary of patient disposition.

The median (and range) numbers of adjuvant cycles completed in Arms 1, 2 and 4 were 9 (1–12), 10 (1–12) and 7 (1–12), respectively. ^aThe denominator includes patients from the safety population. ^bThe reasons for not having surgery (and the number of patients for each reason) were as follows: AE, 1 (grade 3 renal infarct); PD, 2; study discontinuation, 1; death, 1 (intestinal ischemia and septic shock). ^cThe reasons for not having surgery (and the number of patients for each reason) were as follows: AE, 2 (1 patient experienced grade 4 mediastinal abscess; 1 patient experienced grade 3 syncope); investigator or patient decision, 3. ^dThe reasons for not having surgery (and the number of patients for each reason) were as follows: investigator or patient decision, 3. ^eSurgical margins are calculated for patients who completed surgery. ^fThe reasons for discontinuation of study treatment (and the number of patients for each reason) were as follows: AE, 3; PD, 6; other, 3. ^gThe reasons for discontinuation of study treatment (and the number of patients for each reason) were as follows: AE, 5; PD, 4; other, 2. ^hThe reasons for discontinuation of study treatment (and the number of patients for each reason) were as follows: AE, 2; PD, 3; other, 3. ⁱThe reasons for not starting adjuvant therapy after receiving surgery (and the number of patients for each reason) were as follows. In Arm 1: AE, 3 (1 patient each owing to grade 3 empyema, grade 3 pneumonia and grade 2 asthenia); PD, 3; investigator or patient decision, 4; death, 2 (1 due to pneumonia and 1 due to atrial fibrillation). In Arm 2: AE, 5 (1 each owing to grade 3 psoriasis, grade 3 anaphylaxis and grade 3 eczema; 1 owing to grade 2 arthralgia and grade 2 asthenia; 1 owing to grade 2 renal disorder, grade 2 rash, grade 2 alanine aminotransferase (ALT) increase, grade 4 neutrophil count decrease and grade 2 C-reactive protein increase); PD, 1; patient decision, 2; death, 3 (1 due to sepsis, 1 due to septic shock and 1 due to postoperative renal failure); other, 2. In Arm 4: AE, 1 (grade 2 colitis); death, 1 (Idiopathic pulmonary fibrosis); other, 2. n = 202 randomized patients, n = 199 patients in the safety population and n = 198 in mITT population. PD, progressive disease.

Fig. 2. pCR and mPR rates across treatment arms in the mITT population.

The proportion of patients with pCR or mPR for Arm 1 (n = 74), Arm 2 (n = 70) and Arm 4 (n = 54) in the mITT population. Data are presented as percentages, with error bars showing the 95% CI around the observed proportion of patients in the treatment arm. The CIs for each treatment arm were calculated using the Clopper–Pearson method. The number of patients with pCR or mPR and the total number of patients in the mITT population in each treatment arm are shown above each bar. The mITT population includes all randomized patients with confirmed NSCLC histology who received at least one dose of study treatment.

Fig. 3. pCR rates across baseline PD-L1 tumor proportion scores and in the mITT population.

a, pCR rates in patients in the mITT population with a baseline PD-L1 tumor proportion score of <1% (Arm 1, n = 25; Arm 2, n = 28; Arm 4, n = 16) or ≥1% (Arm 1, n = 49; Arm 2, n = 42; Arm 4, n = 38). b, pCR rates in patients in the mITT population with a baseline tumor proportion score of <1% (Arm 1, n = 25; Arm 2, n = 28; Arm 4, n = 16), 1-49% (Arm 1, n = 20; Arm 2, n = 18; Arm 4, n = 21) and ≥50% (Arm 1, n = 29; Arm 2, n = 24; Arm 4, n = 17). Data are presented as percentages with error bars showing the 95% CI around the observed proportion of patients in the subgroup. The CIs for each subgroup were calculated using the Clopper–Pearson method. The number of patients with pCR and the total number of patients in each subgroup are shown above each bar. The mITT population includes all randomized patients with confirmed NSCLC histology who received at least one dose of study treatment. Baseline PD-L1 status was assessed using central (VENTANA SP263) or local testing (VENTANA SP263, pharmDx 28-8, or pharmDx 22C3). Central results in the mITT population were reported for 70.3%, 75.7% and 63.0% of patients in Arms 1, 2 and 4, respectively.

Fig. 4. Any-grade treatment-emergent adverse events in ≥10% of patients in Arms 1, 2 and 4, and rates of adverse events of special interest in Arm 4 in the neoadjuvant period (safety population).

a–c, Any-grade TEAEs in ≥10% of patients in the neoadjuvant period in Arm 1 (a), Arm 2 (b) and Arm 4 (c). d, Rates of adverse events of special interest (AESIs) in the neoadjuvant period in Arm 4. Data are shown for the safety population, which consisted of all patients who received at least one dose of any study intervention. Only the neoadjuvant period is shown owing to the maturity of the data. Patients with multiple occurrences in the same category were counted once per category regardless of the number of occurrences. ^aThis grouped term includes mouth ulceration, odynophagia, oral pain, oropharyngeal pain, pharyngeal inflammation and stomatitis. ^bThis grouped term includes conjunctivitis, dry eye, keratitis, lacrimation increased and ocular toxicity.

Extended Data Fig. 1. Study design.

Arms shown in gray are ongoing and will be reported at a later date. *Carboplatin + paclitaxel for squamous tumor histology, pemetrexed + cisplatin or carboplatin for non-squamous tumor histology. ^†Physician’s choice of carboplatin or cisplatin. ^‡Within 40 days of the last dose of neoadjuvant treatment. ^§Proportion of patients with no viable tumor cells (pCR) or ≤10% residual viable tumor cells (mPR) in resected tumor specimen and sampled nodes at surgery (primary tumor only for mPR). ALK, anaplastic lymphoma kinase; Dato-DXd, datopotamab deruxtecan; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; IASLC, International Association for the Study of Lung Cancer; PD-L1, programmed cell death ligand-1; Q3W, every 3 weeks; TPS, tumor proportion score.

Extended Data Fig. 2. Pathological regression in primary tumor.

(a,b,c) Pathological regression in primary tumor assessed by central blinded independent pathology review in patients in the mITT population with evaluable %RVT in (a) Arm 1, (b) Arm 2, and (c) Arm 4. Data cutoff: December 19, 2024. Pathological regression in primary tumor is defined as %RVT -100%. CT, platinum-doublet chemotherapy; Dato-DXd, datopotamab deruxtecan; LN, lymph node; mITT, modified intention-to-treat population; mPR, major pathological response; pCR, pathological complete response; PD-L1, programmed cell death ligand-1; Plt, single agent platinum chemotherapy; RVT, residual viable tumor.