Meeting NewsPerspective

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

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.

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.

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.

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.

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.

    Perspective
    Igor Puzanov

    Igor Puzanov

    Meric-Bernstam and colleagues reported results from their phase 1b combination trial of intratumoral MIW815, a novel synthetic cyclic dinucleotide that activates the STING pathway, and spartalizumab, a humanized IgG4 monoclonal antibody that blocks the binding of PD-1 to PD-L1/2.

    Researchers observed partial responses in patients with PD-1-naive triple-negative breast cancer and PD-1-relapsed/refractory melanoma. Among eight evaluable patients with triple-negative breast cancer, one who was anti-PD-1-naive achieved a complete response and two anti-PD-1-naive patients achieved partial responses.

    Fewer patients with melanoma responded to this combination — the team saw partial responses in two patients out of 25 in the melanoma cohort — but, importantly, these were patients whose melanoma progressed after previous immunotherapy. With a 12.5% complete response rate and 25% partial response rate, the overall response rate was 37.5%.

    These findings are early but promising. The combination was well-tolerated, with no dose-limiting toxicities reported to date. Taken together with recently presented data from the MK-1454 STING agonist in combination with pembrolizumab (Keytruda, Merck) showing minimal single-agent and 25% combination activity in PD-1-naive patients, we are left with yet another immuno-oncology combination looking for its appropriate patients.

    At this time, my suggestion would be to spend more time in preclinical studies trying to tease out the biology of patient selection and enrichment criteria instead of starting another anti PD-1/PD-L1-plus “drug of choice” trial.

    • Igor Puzanov, MD
    • Roswell Park Comprehensive Cancer Center

    Disclosures: Puzanov reports no relevant disclosures.

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