Merck KGaA has announced new and updated results from expansion cohorts of two ongoing Phase I clinical trials (NCT02517398 and NCT02699515) for its immunotherapy M7824.

M7824 is an investigational bifunctional immunotherapy that brings together a TGF‑β trap and 'fuses' it with the anti-PD-L1 mechanism. Designed to simultaneously block the two immunosuppressive pathways, M7824 is thought to control tumor growth by potentially restoring and enhancing anti-tumor responses. M7824 is an important part of a novel combination approach that seeks to harness the power of the immune system and address the tremendously complex nature of difficult-to-treat tumors.

New data presented include the first presentation of results for M7824 in advanced squamous cell carcinoma of the head and neck (SCCHN), biliary tract cancer (BTC) and esophageal cancers (esophageal squamous cell carcinoma [ESCC] and esophageal adenocarcinoma [EAC]). In addition, updated data for M7824 in non-small cell lung cancer (NSCLC) and gastric cancer add to the growing evidence for M7824's clinical anti-tumor activity in a number of challenging cancers.

New data from an ongoing Phase I expansion cohort (32 patients, NCT02517398) showed signs of promising early clinical activity in patients with refractory metastatic second-line SCCHN, especially in HPV-positive SCCHN patients. The overall response rate (ORR) was 15.6%, with a numerically higher ORR in HPV-positive patients (36.4%, 4/11 patients experienced a partial response), with two additional delayed responses resulting in a 54.5% clinical response rate for the HPV-positive population.

At ASCO 2018, data from the dose escalation cohort of a Phase I, open-label study in advanced HPV-associated cancers (including SCCHN) were presented in collaboration with the National Cancer Institute, which showed that M7824 delivered an ORR of 41.7% in HPV-positive tumors. These new data from the SCCHN expansion cohort add to the evidence of encouraging activity in HPV-positive tumors. A total of 11 patients (34.4%) experienced Grade 3 treatment-related adverse events (TRAEs) and no Grade 4 or 5 TRAEs were seen. The most common TRAEs were rash (18.8%), asthenia (15.6%), pruritus (15.6%), hypothyroidism (15.6%), increased alanine aminotransferase (12.5%), increased aspartate aminotransferase (12.5%) and skin neoplasm (12.5%).

Updated results (now with longer follow-up and independent review committee [IRC] assessed data) from an ongoing Phase I trial (NCT02517398) in patients with previously treated, advanced NSCLC, demonstrated an ORR of 37.0% (10/27 patients) and progression free survival of 9.5 months in patients with PD-L1+ tumors (≥1%). In patients with high PD-L1+ expressing tumors (cut-off of ≥80% using the 73-10 assay; ≥80% cut-off with 73-10 assay is most comparable to ≥50% cut-off with the 22C3 test based on internal comparability studies), ORR was 85.7% (6/7 patients). Grade 3 TRAEs occurred in 23 patients (28.8%) and Grade 4 TRAEs occurred in 2 patients (2.5%): hypokalemia and decreased blood magnesium and increased amylase and lipase levels. The most common TRAEs were pruritus (21.3%), maculopapular rash (18.8%), decreased appetite (12.5%), asthenia (11.3%) and rash (10.0%).

New data from an ongoing expansion cohort (NCT02699515) in Asian patients with BTC who had progressed after platinum-based first-line treatment, demonstrated clinical activity with M7824 treatment. The ORR among the total of 30 patients was 20%, as assessed by IRC. Responses were observed across all PD-L1 levels and duration of response ranged from 8.3 months to 13.9+ months. Grade 3 or higher TRAEs were experienced by 10 patients (33.3%). The most common TRAEs were rash (10%) and lipase increase (10%). Three deaths due to adverse events were reported: one due to septic shock (bacteremia, etiology unknown) and two due to interstitial lung disease (ILD; reported term: interstitial pneumonitis). Both patients with ILD were Japanese, which is consistent with the higher incidence of drug-induced ILD observed among Japanese patients compared with the non-Japanese population.

Three additional posters featuring new data from two cohorts of ongoing Phase I studies in patients with ESCC and advanced EAC (studies NCT02699515 and NCT02517398 respectively) and updated data in gastric cancer (NCT02699515) were also presented. These data provide further indications of the potential of M7824 in cancers with significant unmet needs.

To date more than 650 patients with various types of solid tumors have been treated across the program with M7824. The safety profile is consistent with that observed with other PD-1/PD-L1 inhibitors. Previously described rash/skin lesions (keratoacanthomas, SCC, hyperkeratosis) associated with transforming growth factor-β (TGF-β) inhibiting therapies have also been observed.

Merck has recently initiated a trial to investigate M7824 compared with pembrolizumab as a first-line treatment in patients with PD-L1 expressing advanced NSCLC. The multicenter, randomised, open-label, controlled study is evaluating the safety and efficacy of M7824 versus pembrolizumab as monotherapy treatment.