T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study.

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021.

Strategies for successful dose optimization in oncology drug development: a practical guide.

Dose optimization is a critical challenge in drug development. Historically, dose determination in oncology has followed a divergent path from other non-oncology therapeutic areas due to the unique characteristics and requirements in Oncology. However, with the emergence of new drug modalities and mechanisms of drugs in oncology, such as immune therapies, radiopharmaceuticals, targeted therapies, cytostatic agents, and others, the dose-response relationship for efficacy and toxicity could be vastly varied compared to the cytotoxic chemotherapies. The doses below the MTD may demonstrate similar efficacy to the MTD with an improved tolerability profile, resembling what is commonly observed in non-oncology treatments. Hence, alternate strategies for dose optimization are required for new modalities in oncology drug development. This paper delves into the historical evolution of dose finding methods from non-oncology to oncology, highlighting examples and summarizing the underlying drivers of change. Subsequently, a practical framework and guidance are provided to illustrate how dose optimization can be incorporated into various stages of the development program. We provide the following general recommendations: 1) The objective for phase I is to identify a dose range rather than a single MTD dose for subsequent development to better characterize the safety and tolerability profile within the dose range. 2) At least two doses separable by PK are recommended for dose optimization in phase II. 3) Ideally, dose optimization should be performed before launching the confirmatory study. Nevertheless, innovative designs such as seamless II/III design can be implemented for dose selection and may accelerate the drug development program.

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. METHODS: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. FINDINGS: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). INTERPRETATION: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. FUNDING: Bristol Myers Squibb.

OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors.

PURPOSE: This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, ± nivolumab and/or ipilimumab in patients with advanced solid tumors. PATIENTS AND METHODS: Patients (with non-small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20-320 mg) ± nivolumab (240-480 mg) and/or ipilimumab (1-3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1. RESULTS: Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a follow-up of 1.1 to 103.6 weeks, the most common (≥5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3-4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts. CONCLUSIONS: In this study, BMS-986178 ± nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.

An Integrative Approach to Inform Optimal Administration of OX40 Agonist Antibodies in Patients with Advanced Solid Tumors.

PURPOSE: The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study. EXPERIMENTAL DESIGN: We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade. RESULTS: Administration of the ligand-blocking anti-mouse surrogate antibody OX40.23 or BMS-986178 as monotherapy or in combination with checkpoint blockade led to increased peripheral CD4+ and CD8+ T-cell activation in tumor-bearing mice and patients with solid tumors, respectively. OX40 receptor occupancy between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a receptor occupancy > 40% led to a profound loss in OX40 receptor expression, with clear implications for availability for repeat dosing. CONCLUSIONS: Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic.