Hsiang-Fong Kao

Background: Prognosis is poor for patients with recurrent/metastatic (R/M) head and neck squamous cell cancer (HNSCC), warranting novel treatments. Epidermal growth factor receptor (EGFR) and MET are overexpressed in HNSCC and contribute to cancer progression and metastasis. Amivantamab, an EGFR-MET bispecific antibody, has demonstrated single-agent efficacy in R/M HNSCC after immune checkpoint inhibitor and platinum-based chemotherapy. Here, we report the efficacy and safety of first-line amivantamab plus pembrolizumab in participants with R/M HNSCC. Methods: Cohort 2 of the phase 1b/2 OrigAMI-4 (NCT06385080) study enrolled participants with previously untreated R/M HNSCC and PD-L1 combined positive score ≥1. Patients with p16-positive oropharyngeal cancer and prior anti-EGFR or anti-PD-(L)1 therapy were excluded. Subcutaneous amivantamab and intravenous pembrolizumab were administered every 3 weeks. Primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: Overall, 39 participants received ≥1 dose of subcutaneous amivantamab plus intravenous pembrolizumab in Cohort 2. At a median follow-up of 13.6 months, confirmed ORR was 59% (95% CI, 42-74), with 7 (18%) complete responses. Median DoR was not reached (NR). CBR was 74% (95% CI, 58-87). Shrinkage of target lesions occurred in 82% of participants. Median PFS was 7.7 months (95% CI, 5.0-NR); median OS was NR. The safety profile was consistent with prior reports, with no new safety signals identified. Conclusion: Subcutaneous amivantamab plus intravenous pembrolizumab demonstrated meaningful antitumor activity and may be a promising new option for previously untreated R/M HNSCC.

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b–restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell–mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8+ cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell–mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted.

Table 2 sgRNA genes and sequences