Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial

Abstract

Neoadjuvant chemoimmunotherapy improves pathologic complete response rate and event-free survival in patients with resectable non-small cell lung cancer (NSCLC) versus chemotherapy alone. NeoCOAST was the first randomized, multidrug platform trial to examine novel neoadjuvant immuno-oncology combinations for patients with resectable NSCLC, using major pathologic response (MPR) rate as the primary endpoint. Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). MPR rates were higher for patients in the combination arms versus durvalumab alone. Safety profiles for the combinations were similar to those of durvalumab alone. Multiplatform immune profiling suggested that improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune cell activation.

Significance: A neoadjuvant platform trial can rapidly generate clinical and translational data using candidate surrogate endpoints like MPR. In NeoCOAST, patients with resectable NSCLC had improved MPR rates after durvalumab plus oleclumab or monalizumab versus durvalumab alone and tumoral transcriptomic signatures indicative of augmented immune cell activation and function. See related commentary by Cooper and Yu, p. 2306. This article is featured in Selected Articles from This Issue, p. 2293.

Trial registration: ClinicalTrials.gov NCT03794544.

Figure 1.

Study design and patient disposition. A, Eligible patients with resectable, early-stage [stage IA3 (>2 cm) to IIIA per AJCC staging, 8th edition) NSCLC were randomized to receive one 28-day cycle of durvalumab monotherapy or durvalumab in combination with oleclumab, monalizumab, or danvatirsen. Patients were stratified by lymph node involvement. Surgical resection was planned to occur between days 29 and 42 after the first dose of neoadjuvant therapy. After surgery, patients were followed for AEs up to day 105. The primary endpoint was the MPR rate, defined as the proportion of patients with ≤10% residual viable tumor cells in the surgical specimen (primary tumor and sampled lymph nodes at surgery). Tumor samples were collected, where possible, at screening (day −1 to day −21) and at surgery. Blood samples were collected, where possible, at screening (pretherapy), at baseline (day 1), at the end of neoadjuvant treatment (day 28), and at the end of study (day 105 ± 21 days). Stool samples were collected, where possible, at screening (within 21 days of the start of treatment) and on treatment (day 15 to day 28). B, Flow diagram depicts the disposition of patients through the phases of the study, from screening, neoadjuvant treatment, surgical resection, and study completion. The total numbers of patients in the ITT and as-treated populations, as well as reasons for discontinuations of treatment, are shown. Danva, danvatirsen; Durva, durvalumab; ECOG PS, Eastern Cooperative Oncology Group performance status; Mona, monalizumab; Ole, oleclumab; Q4W, once every 4 weeks; Q2W, once every 2 weeks; QW, every week. *The danvatirsen arm was stopped early, as the program was discontinued. ^†Patients who completed treatment with novel agent. ^‡One patient did not receive all planned doses of danvatirsen but had surgery. ^¶Death due to perioperative complications not considered related to treatment.

Figure 2.

Pathologic regressions at surgery; genomic profiles of ITT population and correlates with pathologic responses. A, The magnitude of pathologic response is shown by percent residual viable tumor cells in resected tumor and nodal samples for all patients with available data (total N = 75; durvalumab monotherapy arm: n = 24; durvalumab + oleclumab arm: n = 18; durvalumab + monalizumab arm: n = 18; durvalumab + danvatirsen arm: n = 15), and annotated with histologic subtype, tumor mutational burden (TMB; mutations/megabase), and history of smoking. PD-L1 status (≥1% positive; <1% negative) from baseline tumor biopsies was determined by IHC (SP263) for all evaluable patients (n = 33). Presence of activating EGFR mutations or ALK fusions was determined by whole-exome sequencing (n = 34). B, Residual viable tumor cells (RVT) from resected tumor and nodal samples are reported as 0% to 100%, and MPR (RVT ≤10%) for n = 60 patients (durvalumab monotherapy: n = 24, durvalumab + oleclumab: n = 18; durvalumab + monalizumab: n = 18). Best response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) is reported for n = 58 patients. Somatic tumor alterations identified in EGFR, KRAS, STK11, KEAP1, TP53, ALK, and RET genes are reported from tumor tissue for n = 35 patients. For patients with evaluable circulating tumor DNA (ctDNA) samples at baseline, each patient is identified as having detected or no detected ctDNA at baseline. For patients with detectable ctDNA at baseline (total N = 20; durvalumab monotherapy: n = 6; durvalumab + oleclumab: n = 7; durvalumab + monalizumab: n = 7), molecular response is depicted at end-of-treatment (day 28, n = 14) and follow-up (day 105, n = 15) time points for all patients with evaluable ctDNA at those time points and represented as complete molecular response [100% reduction in variant allele frequency (VAF) from baseline, also referred to as complete clearance], partial molecular response (≥50% reduction in VAF from baseline), or no molecular response (<50% reduction in VAF from baseline). BESTRESP, best response; FU, follow-up; MR, molecular response; WT, wild-type.

Figure 3.

Treatment-related transcriptomic changes in tumor and peripheral blood. A, Left: differential gene expression between tumors collected at pretherapy and at surgery was assessed in all patients with evaluable paired tumor samples (total, n = 13 patients). Paired samples in each arm had the following MPR rates: durvalumab monotherapy: 0/4; durvalumab + oleclumab: 1/5; durvalumab + monalizumab: 2/4. Right: gene set enrichment analysis (GSEA) was used to identify gene sets and signatures significantly down- or upregulated from pretherapy to surgery on each treatment arm. The durvalumab monotherapy arm is not pictured, as no significant gene enrichment was observed. B, Patients with MPR are indicated in closed teal circle; patients without MPR are indicated in open gray circle. Top and top middle: mRNA from select genes associated with T cells, NK cells, and cytotoxicity is shown from pretreatment and surgery tumor tissue (n = 69 samples; n = 35 pretherapy, n = 34 surgery). Patients with paired samples (an evaluable sample from both pretreatment and surgery) are connected by a line. Bottom and bottom middle: mRNA from select genes associated with tumor and blood lymphocyte recruitment is shown from pretherapy to end-of-treatment peripheral blood collections (n = 120 samples; n = 65 pretherapy, n = 55 end-of-treatment). Y-axes units are all [Log₂ (TPM + 0.01)], where TPM is transcripts per million. DN, down; Durva, durvalumab; IPA, Ingenuity Pathway Analysis; Mona, monalizumab; Ole, oleclumab.

Figure 4.

Treatment-related changes in the tumor microenvironment by IHC; relationship of IHC and peripheral blood RNA biomarkers and MPR. A, IHC biomarkers are shown in all patients with evaluable tumor samples at pretherapy and surgery. Patients with MPR are indicated in closed teal circle; patients without MPR are indicated in open gray circle. Patients with paired samples (an evaluable sample from both pretreatment and surgery) are connected by a line. Top: CD8⁺ (SP239) T-cell density as number of positive cells/mm² tumor area in all evaluable patients (n = 54 samples). Bottom left: Percentage of tumor cells positive for CD73 (D7F9A) at any intensity in paired cases only (n = 20 samples from 10 paired cases). Bottom right: NKG2A⁺ (AR9352) cell density as number of positive cells/mm² tumor area (n = 49 samples). B, Heat map of selected genes that were significantly differentially expressed between patients with and without an MPR in analyses of patients with paired pretherapy and end-of-treatment samples (n = 54). These analyses identified numerous genes associated with T-cell coactivation, B-cell signaling, and Ig complex upregulated in the peripheral blood of patients with an MPR in the durvalumab + oleclumab arm (n = 16 paired cases). In the durvalumab + monalizumab arm, genes associated with regulatory T cells (Treg) are upregulated in patients with an MPR (n = 14 paired cases). Durva, durvalumab; Mona, monalizumab; Ole, oleclumab.

Figure 5.

ctDNA dynamics as surrogate for response. Patients with MPR are indicated in closed teal circle; patients without MPR are indicated in open gray circle. Top left: mean VAF at baseline is compared between patients with an MPR and with no MPR across all arms. Top right: mean VAF at baseline associated across stage I, II, or III disease. Bottom left: mean VAF at baseline correlated with the sum of diameters among target lesions at baseline (mm) (total patients with ctDNA evaluable at baseline N = 33; durvalumab monotherapy arm: n = 13; durvalumab + oleclumab arm: n = 11; durvalumab + monalizumab arm: n = 9). Bottom right: for patients with detectable ctDNA at baseline (total N = 20; durvalumab monotherapy arm: n = 6; durvalumab + oleclumab arm: n = 7, durvalumab + monalizumab arm: n = 7), molecular response (≥50% reduction in VAF from baseline) is depicted at end of treatment (EOT; day 28) and follow-up (FU; day 105) time points for all patients with evaluable ctDNA at those time points (N are depicted above). W1D1, week 1, day 1.