Combination of monalizumab and cetuximab in recurrent or metastatic head and neck cancer patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.

Abstract

6516 Background: Monalizumab is a first-in-class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed on subsets of Natural Killer (NK), gd T and tumor-infiltrating CD8+T cells. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8+T cells and enhances NK cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab. In a Phase I study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort 1 of 40 patients (pts) who had progressed after platinum-based therapy, we reported an overall response rate (ORR) of 27.5%, a 4.5 month median PFS and an 8.5 month median OS. In a subset of patients (n=18) previously treated with PD-(L)1 inhibitors (IO), corresponding results were 17%, 5.1, and 14.1 months, respectively (ESMO 2019). Here we present data from a second expansion cohort 2 (n=40) conducted specifically in the post-IO setting to independently confirm the cohort 1 results. Methods: Eligible patients had R/M SCCHN previously treated with platinum and a PD-(L)1 inhibitor. Pts received monalizumab 750 mg q2weeks and cetuximab according to the label until progression or toxicity. Cohort 2 was designed as a confirmatory multicenter single arm phase II study, with a pre-planned total of 40 patients. The primary endpoint was ORR assessed per RECIST 1.1. Results: As of January 31, 2020, 40 pts have been treated in cohort 2. Median follow-up is 7.3 months (range, 1.9-13.6+). Eight (8) pts have a confirmed partial response (PR); ORR is 20% [95% confidence interval: 11-35]. Median time to response is 1.6 months [1.6-5.3]. At the time of data analysis, 3 pts were still in PR and 3 pts had stable disease continue on treatment. PFS and OS are still immature. Conclusions: In pts previously treated with platinum and PD-(L)1 inhibitors, the combination of monalizumab and cetuximab demonstrated promising activity. The second extension cohort confirmed prospectively the ORR reported in cohort 1. A randomized phase III trial of monalizumab and cetuximab is planned in this platinum and IO-pretreated SCCHN population. Clinical trial information: NCT02643550 .

Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

“…The combination of monalizumab and cetuximab has been studied in a multi-centric phase Ib-II trial (NCT02643550), the results of the phase II cohort concerning platinum resistant patients 45% of which had received an anti-PD-(L)1 are particularly interesting [55]: over 40 patients, a rate of 27.5% of objective response is achieved with a median PFS of 4.5 months and a median survival of 8.5 months. Results of an expansion cohort concerning patients who had all been treated with platinum and immunotherapy confirm a 20% ORR with a median duration of 5.2 months [50]. These results have led to planned a phase III (INTERLINK-1) for HNSCC patients in the R/M setting pretreated with platinum and anti-PD-(L)1 randomizing cetuximab + monalizumab vs. cetuximab + placebo.…”

Arrested development: suppression of NK cell function in the tumor microenvironment

“…The phase II clinical trial results of the combination of monalizumab and cetuximab, demonstrated a 30% objective response rate in immunotherapy-refractory in patients with head and neck squamous cell carcinoma compared to 12.6% in previous studies using cetuximab alone. 106 Although these results are promising, it may prove to be even more useful to generate NKG2A deficient NK cells for use in adoptive transfer since NK cells are often found in very low numbers in the TME 18 and may not effectively respond to anti-NKG2A therapy.…”

Natural killer cells in cancer biology and therapy

“…Moreover, soluble MULT1, a high affinity mouse NKG2D ligand stimulates NKG2D in distant NK cells and enhances NK cell tumor immunity [ 106 ]. Hence, a clinically used antibody, monalizumab, has been developed targeting NKG2A, an inhibitory checkpoint of NK cells, which not only promotes NK cell function in various preclinical models, as previously characrerized, but also potentiates anti-PD-1 [ 226 ] and anti-EGFR (cetuximab) therapy [ 227 ]. In addition to antibody, NKG2A null NK cells, constructed through retroviral transduction of NKG2A blocker which inhibits de novo NKG2A expression, present increased anti-tumor activity in pre-clinical model [ 228 ].…”