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Experimental immunotherapy

AACR 2019: Immunotherapy with bintrafusp alfa shows efficacy for HPV-associated tumors

Each year 630.000 human papillomavirus associated tumors are diagnosed world-wide1, for which standard chemotherapy regimens show only limited efficacy. An ongoing phase I trial evaluating immunotherapy M7824 delivered encouraging data at the AACR 2019 Annual Meeting.2

M7824 (bintrafusp alfa) is a novel cancer immunotherapy that is currently tested for multiple hard-to-treat cancer types. Bintrafusp alfa is a bifunctional fusion protein targeting two immune suppressive signaling pathways that are frequently used by cancer cells to evade the immune system, the transforming growth factor-beta (TGF-β), and programmed death ligand-1 (PD-L1) pathway. Also for HPV-associated tumors, an increased expression of PD-L1 and TGF-β was reported, explains lead author Julie Strauss, MD from the National Cancer Institute, Bethesda, Maryland, USA. In an open-lapel phase I trial (NCT02517398), bintrafusp alfa showed acceptable tolerability and durable responses in multiple advanced solid tumors, including head and neck cancer and cervical carcinoma.3–5

Results for HPV-associated tumors

Now Strauss presented a post-hoc analysis of 43 patients in the phase I trial, who had refractory, advanced HPV-associated tumors, including 25 cervical carcinomas, 14 head and neck tumors, and 4 anal carcinomas. 17 patients were in the dose escalation phase, receiving dosages of 0.3–30 mg/kg bintrafusp alfa every two weeks. 26 patients were in the expansion phase and were treated with the dosage of 1200 mg every two weeks as recommended in the phase II trial. The patients were not selected according to PD-L1 or HPV status, previous checkpoint inhibitor therapy was not allowed. 37.2 percent of patients had received three or more systemic therapy lines prior to the study. Safety and efficacy of bintrafusp alfa was analyzed separately for the general study population (n=43) and for patients with a positive HPV status (n=36)

Safety profile similar to other PD-(L)1 inhibitors

Therapy with bintrafusp alfa was generally well tolerated. The toxicity profile was in line with findings from other PD-1/PD-L1 inhibitors.6,7 Treatment-related adverse events occurred in 81.34 percent of patients (25.6 percent had grade 3 adverse events). 16.3 percent of patients had to permanently discontinue bintrafusp alfa due to treatment-related adverse events. Only one patient developed a grade 4 adverse event (gastroparesis-related hypokalemia). The most common side effects were rash (25.6 percent), pruritus (23.3 percent), skin lesions (hyperkeratosis, keratoacanthoma; 20.9 percent), acneiform dermatitis (16.3 percent), and hypothyroidism (16.3 percent). No treatment-related grade 5 adverse events occurred. Immune-related adverse events could be managed with therapy interruptions with or without corticosteroids in most cases. In line with what was described for other TGF-β inhibitors8, three patients had mucosal bleedings of grade 1 or 2 (2 had epistaxis, 1 had gingivitis).

Antitumor activity independent of PD-L1 status

An objective response according to RECIST v1.1 was confirmed in 27.9 percent of patients (n=12/43) in the general study population, and in 30.6 percent of patients (n=11/36) in the HPV-positive subgroup, including patients with visceral metastases. Two patients had a complete remission (both HPV-positive cervical carcinoma), and 10 patients had a partial remission, of whom 9 were HPV positive (4 head and neck tumors, 4 cervical carcinomas, 2 anal carcinomas). Three other patients (2 head and neck tumors, 1 cervical carcinoma) had a delayed response (partial remission) after initial pseudo-progression, and thus did not meet RECIST criteria for response. When these patients were included into analysis, a clinical response of 34.9 percent was calculated for the general study population, and 38.9 percent for the HPV-positive subgroup. Most remissions were durable; in four patients over 18 months, the longest remission lasted over two years. 75 percent of responders were still progression-free at database lock on January 9, 2019, and median duration of response was not reached. Response was independent of PD-L1 status. After 12 months, only 22 patients were still alive in the general study population (56.2 percent, median overall survival [mOS] 16.2 months), and 15 patients in the HPV-positive group (61.8 percent, mOS not reached).

References
  1. de Martel C et al., Int J Cancer 2017; 141: 664–70
  2. Strauss J et al., AACR 2019; oral presentation & Abstract # CT075
  3. Viens LJ et al., MMWR Morb Mortal Wkly Rep 2016; 65: 661–6
  4. Strauss J et al., Clin Cancer Res 2018; 24: 1287–95
  5. Paz-Ares L et al., J Clin Oncol 2018; 36(Suppl): Abstract 9017
  6. Cho BC et al., Ann Oncol 2018; 29(Suppl): Abstract 104BO
  7. Bauml J et al., J Clin Oncol 2017; 35: 1542–49
  8. Trachtman H et al., Kidney Int 2011; 79: 1236–43
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