Gene- and immune-targeted therapy combinations using dual-matched biomarkers for patient selection

Abstract

Combinations of gene-targeted therapy and immune checkpoint inhibitors (ICIs) have been conducted, though generally without biomarker-based patient selection for both therapy types. We evaluated outcomes of 17 patients with advanced cancers treated with both targeted agents and ICIs, matched to distinct genomic and immune biomarkers, from a cohort of 715 cases discussed at our Molecular Tumor Board. Despite 29% of patients having undergone ≥3 prior therapies, the disease control rate (includes SD ≥ 6 months or objective response) was 53%, with a median progression-free survival (PFS) of 6.1 months (95% CI, 2.9-not estimable) and median overall survival (OS) of 9.7 months (95% CI, 6.7-not estimable). Three patients (~18%) achieved prolonged PFS and OS (PFS: 23.4+, 33.0, 59.7 months; OS: 23.4+, 43.6, 62.1+ months) in B-cell lymphoma unclassifiable, ovarian, and gastroesophageal cancers. Median dosages were 100% for ICIs and 50% for gene-targeted agents, with Grade 3-4 serious adverse events occurring in 24%. We additionally conducted a database search to evaluate the prevalence of biomarker-based dual therapy trials, which revealed only 1.3% (4/314) of such clinical trials included biomarkers for both targeted therapies and ICIs. These findings highlight the potential of dual biomarker-matched combination therapy even after multiple therapy lines and support further investigation of dual-matched therapy.

Fig. 1. The rationale for the dual-matched therapy with ICI and targeted agent.

This heatmap illustrates gene aberrations and the corresponding targeted agents utilized for treatment. Each column within the heatmap represents an individual patient. For instance, patient #1 was treated with vismodegib for PTCH1 mutation. Additionally, patient #1 exhibited positive immune markers, including TMB ≥ 10 (muts/Mb), an ARID1A alteration, and MSI-high, and thus, received immunotherapy. ICI immune checkpoint inhibitor, IHC immunohistochemistry, Mb megabase, MSI microsatellite instability, muts mutations, TMB tumor mutation burden.

Fig. 2. Utilization of genomically targeted drugs and immune checkpoint inhibitors in the context of dual-matched therapy.

The upper segment of the figure depicts the types of the immune checkpoint inhibitors implemented in the dual-matched therapy. Nivolumab and pembrolizumab are anti-PD-1 agents; atezolizumab is an anti-PD-L1 agent. The lower portion of the figure depicts individualized boxes representing the targeted agent(s) used in dual-matched therapy. The background colors of molecular targeted agent(s) denote the simultaneously administered immune checkpoint inhibitor with the same background color (blue, nivolumab; yellow, pembrolizumab; orange, atezolizumab). This tailored combination approach was customized for each patient’s unique and complex molecular profile. Patients could receive a single drug that targeted more than one biomarker (since small molecule inhibitors often have multiple targets) or more than one drug that targeted the same biomarker.

Fig. 3. Clinical outcomes of the dual-matched therapy.

A Clinical benefit rate (SD ≥ 6 months/CR/PR) of the 17 patients who underwent dual-matched therapy was 53% (9/17). B The swimmer’s plot provides information on the duration of survival and the timing of progression for each patient. The arrow indicates that the patients were progression-free at the date of their last follow-up. Two patients did not show apparent progression, but their therapy was suspended due to an adverse event (ID 8) or lost to follow-up (ID 17). C, D Kaplan–Meier curves for progression-free survival (PFS, Panel C) and overall survival (OS, Panel D) of 17 patients who received dual-matched therapy for treatment-refractory diverse cancers. Median follow-up period was 8.1 months (range 2.1–62.1). The pale red area indicates the 95% confidence interval (CI). Median PFS was 6.1 months (95% CI, 2.9–not estimable), and median OS was 9.7 months (95% CI, 6.7–not estimable). CNS central nervous system, CR complete response, PD progressive disease, PR partial response, SD stable disease.

Fig. 4. Dose percentage of each administered agent.

This heatmap describes the initial dose percentage of each drug given. Each cell contains dose percentage with its corresponding color. Each row indicates each patient, and each column indicates each administered agent. Dose percentage of immune checkpoint inhibitors (N = 17) was 100% in all patients, and that of targeted agents (N = 22) was 50% (median) and ranged from 25% to 100%. Patients whose ID are with an asterisk had serious adverse events (Grade ≥3) during their treatment course.

Fig. 5. Trial search results.

A PRISMA flow chart of the trial search (See Methods). Search was conducted on Mar 24, 2023, for ClinicalTrials.gov, using the search terms “(PD-1 OR PD-L1 OR CTLA4 OR LAG3) AND (targeted OR combination)” with a start date of Jan 1, 2018. After the screening, 1389 records did not meet the inclusion criteria and were therefore excluded from the further assessment. B Proportion of trials that utilized biomarkers for both the immune checkpoint inhibitor and the gene-targeting agent. Of the 314-trials assessed, 235 trials (75% [235/314]) did not assess biomarkers for patient inclusion. Forty-six trials checked gene alterations or immunohistochemistry for the targeted gene. The details of the four trials that assessed biomarkers for both the immune- and the gene-targeted therapy are presented in Supplementary Table 4. ICI immune checkpoint inhibitor.