Issue: July 25, 2019

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June 17, 2019
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MIW815 plus spartalizumab safe, active among certain patients with advanced breast cancer, melanoma

Issue: July 25, 2019
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CHICAGO — Patients with anti-PD-1-naive triple-negative breast cancer and PD-1-relapsed or refractory melanoma demonstrated antitumor benefit from MIW815 plus spartalizumab, according to results of a phase 1b study presented at ASCO Annual Meeting.

Perspective from Igor Puzanov, MD

The combination also appeared well-tolerated in the ongoing dose-escalation study.

"The stimulation of interferon genes, or STING, pathway, senses intracellular DNA, triggering an immediate production of type 1 interferon,” Funda Meric-Bernstam, MD, chair of the department of investigational cancer therapeutics, medical director of the Institute for Personalized Cancer Therapy, and professor in the divisions of cancer medicine and surgery at The University of Texas MD Anderson Cancer Center, said during her presentation. “MIW815 is a synthetic cyclic dinucleotide, a first-in-class STING agonist. In mouse models, intratumoral injection of single-agent MIW815 [ADU-S100, Aduro Biotech] resulted in tumor regression in both injected and noninjected lesions.”

Meric-Bernstam and colleagues evaluated data from 83 patients (median age, 61 years; range, 27-93; 50.6% men) with advanced/metastatic solid tumors or lymphoma. The most common primary diagnoses were melanoma (42.2%) and triple-negative breast cancer (13.3%). Most patients (72.3%) received prior immunotherapy.

Patients received 400 mg IV spartalizumab (PDR001, Novartis) monthly with intratumoral MIW815 injections (50-800 µg) on either a weekly (3 weeks on/1 week off; n = 53) or monthly (n = 30) basis. The researchers acquired injected and noninjected tumor biopsies at baseline and during treatment.

Safety and tolerability served as primary endpoints. The researchers also are evaluating preliminary antitumor activity, pharmacokinetics and pharmacodynamics in the ongoing study.

As of the April 5 data cutoff, 61 patients (73.5%) discontinued treatment, including 37 patients in the MIW815 weekly-dose cohort and 24 patients in the monthly-dose cohort. Reasons for discontinuation included progressive disease (43.4%), physician decision (19.3%), patient decision (7.2%), adverse events (2.4%) and death (1.2%).

The most common treatment-associated adverse events, occurring among five or more patients, included injection site pain (13.3%), pyrexia (12%), diarrhea (9.6%) and rash (6%).

Grade 3 to grade 4 treatment-related adverse events included increased lipase (3.6%), diarrhea (2.4%), increased alanine aminotransferase (2.4%) and increased aspartate aminotransferase (2.4%)

“In this study, there were no dose-limiting toxicities, and the adverse events we observed were no more frequent and no more severe than that which we observed with single-agent treatment with either agent,” Meric-Bernstam said.

The pharmacokinetic analysis showed rapid absorption of MIW815 to plasma with a short plasma half-life, ranging from 8 to 28 minutes. Concentrations of interferon-beta appeared to increase with greater exposure to MIW815.

Five patients in the MIW815 weekly-dose cohort achieved confirmed responses, including one complete response. Three of these responses, including the complete response, occurred among patients with immunotherapy-naive triple-negative breast cancer, two of whom had PD-L1 expression greater than 1% at baseline. The other two responders had previously received immunotherapy.

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Twelve patients in the weekly-dose cohort achieved stable disease, including patients with sarcoma, melanoma, squamous cell carcinoma, skin cancer, breast cancer, lymphoma and head and neck cancer.

No patients in the monthly-dose cohort achieved a response, although six patients attained stable disease. Tumor types among these patients included ovarian, breast, uveal melanoma, head and neck, and cutaneous melanoma. Four of these patients maintained stable disease for 6 months or longer.

“MIW815 and spartalizumab was generally well-tolerated in our patient population, with no dose limiting toxicities,” Meric-Bernstam said . “The maximum tolerated dose has not been reached and dose escalation continues.” – by Jennifer Byrne

Reference:

Meric-Bernstam F, et al. Abstract 2507 Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Meric-Bernstam reports honoraria from Dialectica and Sumitomo Group; consultant/advisory roles with Aduro Biotech, Clearlight Diagnostics, Darwin Health, Debiopharm Group, Genentech, Inflection Biosciences, Mersana, Origimed, Pieris Pharmaceuticals, Samsung Bioepis, Spectrum Pharmaceuticals and Xencor; and research funding from AbbVie, Aileron Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim (institutional), Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm Group, eFFECTOR Therapeutics, Genentech, GlaxoSmithKline, Guardant Health (institutional), Jounce Therapeutics, Novartis, Pfizer, PUMA Biotechnology, Taiho Pharmaceutical and Zymeworks. Please see the abstract for all other authors’ relevant financial disclosures.