INTerpath-002 与 INTerpath-009 研究设计：辅助治疗中 Intismeran Autogene（个体化新抗原疗法）联合帕博利珠单抗治疗非小细胞肺癌

Background: Neoantigens are immunogenic molecules arising from patient-specific tumor mutations. Intismeran autogene (intismeran; formerly V940, mRNA-4157), an mRNA-based individualized neoantigen therapy (INT) encoding ≤34 neoantigens unique to each patient’s tumor, is designed to promote an antitumor immune response. In early-phase studies, adjuvant intismeran plus pembrolizumab showed antitumor activity with solid tumors. Standard-of-care therapy for non-small cell lung cancer (NSCLC) tumors ≥4 cm includes platinum-based chemotherapy and pembrolizumab given after (adjuvant) or both before and after (perioperative) surgical resection. We describe study designs for the INTerpath-002 and INTerpath-009 studies evaluating the addition of intismeran to adjuvant pembrolizumab-based therapy in stage II-IIIB (N2) NSCLC.

Methods: INTerpath-002 and INTerpath-009 are randomized, double-blind, phase 3 trials. Eligible participants for INTerpath-002 have completely resected, margin-negative, stage II-IIIB (N2) NSCLC (American Joint Committee on Cancer staging manual, eighth edition) and have received 1 to 4 cycles of adjuvant platinum-based chemotherapy. Eligible participants for INTerpath-009 have resectable stage II-IIIB (N2) NSCLC and have received ≤4 cycles of neoadjuvant pembrolizumab plus chemotherapy every 3 weeks. Participants with tumors that do not achieve a pathologic complete response, per pathologic examination of the resected tumor specimen, and have R0-R1 resection are eligible for randomized treatment. In both studies, participants are randomized 1:1 to receive pembrolizumab intravenously every 6 weeks plus either intismeran intramuscularly every 3 weeks or placebo. The primary endpoint in both studies is disease-free survival per investigator.

Results: Recruitment is ongoing for both studies.

Conclusions: Results from these studies will provide insight into the potential role of INT in NSCLC.

Intismeran autogene, an individualized neoantigen therapy, promotes an antitumor immune response.

INTerpath-002 is a phase 3 study evaluating adjuvant intismeran autogene plus pembrolizumab for completely resected, margin-negative, stage II-IIIB (N2) non-small cell lung cancer (American Joint Committee on Cancer staging manual, eighth edition) after adjuvant platinum-based chemotherapy.

INTerpath-009 is a phase 3 study evaluating adjuvant intismeran autogene plus pembrolizumab in participants with R0-R1 resected stage II-IIIB (N2) non-small cell lung cancer (American Joint Committee on Cancer staging manual, eighth edition) who did not achieve pathologic complete response after neoadjuvant pembrolizumab plus chemotherapy.

Incorporation of checkpoint inhibitors into the standard of care for operable non-small cell lung cancer (NSCLC) has dramatically improved outcomes. Adjuvant pembrolizumab (anti‒programmed cell death protein 1) is approved by multiple regulatory agencies for patients with stage IB (T2a ≥4 cm) to IIIA NSCLC following resection and platinum-based chemotherapy, based on results from KEYNOTE-091 in participants with stage IB (tumors ≥4 cm) to IIIA NSCLC (American Joint Committee on Cancer [AJCC] staging manual, seventh edition). Neoadjuvant pembrolizumab plus chemotherapy is also approved for patients with resectable (tumor ≥4 cm or node-positive) NSCLC, with pembrolizumab continued after surgery, based on results from KEYNOTE-671 in participants with stage II-IIIB (N2) NSCLC (AJCC staging manual, eighth edition). However, despite advances in neoadjuvant, adjuvant, and perioperative treatments with the incorporation of immune checkpoint inhibitors, approximately 27% to approximately 50% of patients experience disease progression or recurrence, and more effective options are needed.

Neoantigens are cancer-specific immunogenic molecules that arise from patient-specific tumor mutations and are a potential target for cancer immunotherapies. Intismeran autogene (intismeran; formerly V940, mRNA-4157) is a novel mRNA-based individualized neoantigen therapy (INT) encoding ≤34 neoantigens specific to each patient’s tumor, which promotes a T cell‒mediated response against the neoantigens. Intismeran design uses next-generation sequencing of patient blood and tissue samples (described in the Supplemental Material). In the phase 1 KEYNOTE-603 study, which included 16 participants with resected solid tumors (11 with NSCLC) treated with intismeran monotherapy, 14 of 16 participants remained disease free on study at 114 weeks.

Intismeran may also provide improved antitumor activity when it is paired with pembrolizumab. In participants treated with this combination in KEYNOTE-603 (which included 10 participants with checkpoint inhibitor‒refractory NSCLC), preliminary antitumor activity was observed. Subsequently, in the phase 2 KEYNOTE-942 study, participants with resected cutaneous melanoma treated with adjuvant intismeran plus pembrolizumab showed clinically meaningful improvement in recurrence-free and distant metastasis–free survival vs pembrolizumab alone, which was maintained after approximately 3 years of follow-up. Intismeran plus pembrolizumab demonstrated manageable safety with infrequent additional grade ≥3 adverse events compared with the well-established safety profile of pembrolizumab.

We hypothesized that combination adjuvant therapy with intismeran and pembrolizumab may improve clinical outcomes in patients with stage II-IIIB (N2) NSCLC (AJCC staging manual, eighth edition). Herein, we describe the study designs for the phase 3 INTerpath-002 and INTerpath-009 trials.

Both studies are being conducted in accordance with Good Clinical Practice guidelines. The study protocols and amendments are approved by the appropriate institutional review board or independent ethics committee at each study site. All participants will provide written informed consent before entering the trial.

INTerpath-002 study design. aMay be provided before full screening period. (ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death ligand 1.)

INTerpath-002 (NCT06077760) is a phase 3, randomized, double-blind study of adjuvant intismeran plus pembrolizumab vs placebo plus pembrolizumab in adults with completely resected, margin-negative (no microscopic or macroscopic tumor at the cut line), stage II-IIIB (N2) NSCLC who have received 1 to 4 doses of adjuvant platinum-doublet therapy. As participants have margin-negative resection, they are not candidates for adjuvant radiotherapy. Participants must have a surgical tumor sample available for programmed cell death ligand 1 (PD-L1) testing and next-generation sequencing. The study design and key eligibility criteria are presented in Figure 1 and Supplemental Table 1.

INTerpath-009 (NCT06623422) is a phase 3, randomized, double-blind study of adjuvant intismeran plus pembrolizumab vs placebo plus pembrolizumab in adults with resected (R0-R1) stage II-IIIB (N2) NSCLC who did not have pathologic complete response following neoadjuvant pembrolizumab and platinum-doublet chemotherapy.

INTerpath-009 study design. aSurgery will be performed ≤20 weeks from start of neoadjuvant treatment and ≤8 weeks from last dose of neoadjuvant treatment. (ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death ligand 1.)

The study design and key eligibility criteria are presented in Figure 2 and Supplemental Table 2. Participants with no prior treatment of resectable NSCLC may enter the study at the neoadjuvant phase; those who have received the specified neoadjuvant treatment and surgery may enter at the adjuvant phase. Participants in the neoadjuvant phase receive pembrolizumab plus chemotherapy every 3 weeks for up to 4 cycles, followed by surgical resection. Chemotherapy is the investigator’s choice of cisplatin or carboplatin plus pemetrexed (nonsquamous only), gemcitabine (squamous only), or paclitaxel (any histology). Those with R1 resection receive postoperative radiotherapy as indicated. Participants with tumors that do not have a pathologic complete response, per local pathologist assessment of the tumor and resected lymph nodes, and have R0 or R1 resection, including uncertain status, are eligible for randomization. Participants must have a surgical tumor sample that is suitable for PD-L1 testing and next-generation sequencing. Participants who have previously received ≤4 cycles of pembrolizumab and standard-of-care platinum-doublet chemotherapy and had an R0 or R1 lobectomy or pneumonectomy may enter the study at the adjuvant phase if all eligibility criteria are met.

In both studies, randomization (1:1) is performed after next-generation sequencing of blood and tumor samples and eligibility criteria are met. Stratification factors are shown in Figures 1 and 2. Participants receive pembrolizumab 400 mg intravenously every 6 weeks plus intismeran 1 mg intramuscularly every 3 weeks or placebo.

In INTerpath-002, participants receive 9 cycles of pembrolizumab and 9 doses of intismeran or placebo. In INTerpath-009, participants receive 7 cycles of adjuvant pembrolizumab and 9 doses of intismeran or placebo. The maximum exposure to pembrolizumab in INTerpath-009 is 11 doses (4 neoadjuvant [200 mg every 3 weeks] and 7 adjuvant [400 mg every 6 weeks]). In both studies, combination treatment begins after the first dose of adjuvant pembrolizumab when the participant’s intismeran or placebo is available at the site. Placebo initiation is randomly adjusted to maintain study blinding but will not exceed the last allowable date of intismeran initiation. Treatment continues until disease recurrence, participant withdrawal, unacceptable toxicity, or additional malignant disease requiring active treatment. Treatment beyond local or locoregional recurrence is permitted.

In both studies, tumor imaging (inclusive of computed tomography and magnetic resonance imaging) is performed at baseline and every 12 weeks from randomization through week 48. Thereafter, imaging is performed every 24 weeks through week 144 and then every 48 weeks until distant metastasis, pregnancy, withdrawal of consent, or death. Baseline imaging occurs before neoadjuvant treatment (INTerpath-009) and before randomization (both studies). Baseline brain scans are required to rule out detectable brain metastasis.

Adverse events are assessed from randomization (INTerpath-002) or the first dose of study treatment (INTerpath-009; including neoadjuvant treatment if the participant entered the study at this phase) through 30 days after the last dose (90 days for serious adverse events). Adverse events are graded in severity according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

During the neoadjuvant phase of INTerpath-009, patient-reported outcome questionnaires are administered on day 1 of cycles 1 and 4 when there is a visit (3-week cycles). During adjuvant treatment in both studies, questionnaires are administered on days 1 and 22 of cycles 1 through 4 when there is a visit, on day 1 of cycles 5 through 7 (INTerpath-009) or 9 (INTerpath-002; 6-week cycles), and at the treatment discontinuation and follow-up visits.

PD-L1 expression in surgically resected tumor tissue is centrally assessed with PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA, USA).

The primary endpoint in both studies is disease-free survival (time from randomization to any recurrence or occurrence of new primary NSCLC per investigator, or death due to any cause, whichever occurs first).

Secondary endpoints include overall survival, distant metastasis–free survival, lung cancer‒specific survival, and safety. An additional secondary endpoint in INTerpath-009 is disease-free survival 2 (time from randomization to subsequent recurrence or disease progression after initiation of next-line anticancer therapy, or death due to any cause).

Patient-reported outcomes (secondary endpoints) in both studies include change from baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire‒Core 30 (QLQ-C30) global health status/quality of life, physical functioning, and role functioning scores. Additional secondary endpoints in INTerpath-002 include changes from baseline in the EORTC QLQ-C30 dyspnea score and EORTC Quality of Life Questionnaire‒Lung Cancer (QLQ-LC24) cough and chest pain scores.

In both trials, efficacy will be analyzed in all randomized participants and safety will be analyzed in all participants who receive ≥1 dose of study treatment. Patient-reported outcomes will be analyzed in all randomized participants who have baseline assessment and ≥1 assessment available for the specific endpoint and have received ≥1 dose of study treatment.

In both trials, treatment differences in disease-free survival and overall survival will be assessed by stratified log-rank test. Hazard ratios and their 95% CIs will be estimated by a stratified Cox regression model with the Efron method of tie handling. Event rates over time will be estimated with the Kaplan-Meier method. Safety endpoints will be analyzed descriptively. Treatment effects on patient-reported outcome score changes will be assessed with a mixed-effect model for repeated measures.

The first participant was enrolled in INTerpath-002 on December 6, 2023; recruitment is currently ongoing across 200 sites in 33 countries. Approximately 868 participants will be randomized. Estimated study completion date is December 2035.

The first participant was screened for INTerpath-009 on October 21, 2024; recruitment is currently ongoing across 240 sites in 31 countries. Approximately 680 participants will be randomized. Estimated study completion date is January 2038.

Results from these studies will provide insight into the potential role of INT in NSCLC.