Robert L. Ferris, MD, PhD, co-physician editor-in-chief of <em>Targeted Therapies in Oncology</em>, highlights a series of exciting results presented across various topics, which affect cancer research and treatment, during the 2019 AACR Annual Meeting.
Robert L. Ferris, MD, PhD
In the afterglow of the annual American Association for Cancer Research (AACR) in Atlanta, Georgia, it seems worthwhile to highlight a series of exciting results presented across various topics, which affect cancer research and treatment. The annual meeting again focused heavily on advances in cancer immunotherapy in several cancers.
Although clinical trials involving rare tumors such as neuroendocrine carcinomas have been historically poorly represented, a study involving the immunotherapy combination of ipilimumab (Yervoy) and nivolumab (Opdivo) in this tumor type demonstrated a 40% response rate and good tolerability in the DART trial. Lead author Sandip Patel, MD, an associate professor of medicine at the University of California, San Diego, School of Medicine, reported on the phase II DART trial, the first NCI [National Cancer Institute]funded rare tumor immunotherapy basket study.1As the current therapeutic options available for those with high-grade disease are generally limited to aggressive chemotherapy regimens, Patel emphasized that these findings are particularly exciting for this patient population.
Two studies suggested that CAR T cells may be on the horizon for solid tumors. In those cancers expressing the tumor antigen mesothelin, CAR T cells targeting this antigen demonstrated safety and efficacy in a preliminary clinical evaluation in patients with malignant pleural disease. Objective responses occurred in eight of 11 patients who received a combination of cyclophosphamide conditioning therapy, the CAR T cells, and at least 3 doses of an antiPD-1 agent with no on-target/off-tumor toxicity, no evidence of immunogenicity, and no severe toxicity, reported by Prasad S. Adusumilli, MD, of Memorial Sloan Kettering Cancer Center.2Secondly, Shoba A. Navai, MD of Baylor College of Medicine presented data from the phase I, dose-escalation clinical study HEROS 2.0 (NCT00902044), showing that lymphodepletion prior to HER2-CAR T cells safely augments T cell expansion and induces clinical responses in patients with advanced sarcomas, which was tolerated and associated with objective clinical benefit in some patients with advanced HER2+ sarcoma.3
Innovative findings that focused on biomarkers of PD-1-based immunotherapy response were also reported. In one presentation, Mien-Chie Hung, PhD from the University of Texas, MD Anderson Cancer Center described the modulation of PD-L1 expression level by N-glycosylation, which prevents proteasome-dependent degradation of PD-L1, leading to immunosuppression activity. PD-L1 is glycosylated at multiple sites by the epidermal growth factor receptor (EGFR) pathway, which protects PD-L1 from its degradation. In turn, this suppresses T cell effector activity and causes immunosuppression. PD-L1 expression detected by a deglycosylation method accompanied with immunohistochemistry analysis predicted clinical response better than the conventional method in a study of 82 patients. In addition, deglycosylation of patient samples is beneficial to therapeutic selection to prevent false-negative detection of PD-L1 in a cohort of patients with lung cancer (44 out of 95).4
In a novel therapeutic strategy, Rom Leidner, MD, of Providence Cancer Center presented on neoadjuvant immuno-radiotherapy in head and neck cancer (HNSCC; NCT03247712). This is the first study to evaluate the safety and efficacy of neoadjuvant nivolumab plus stereotactic body radiation therapy for treatment of patients with HNSCC. A high response rate and lower toxicity profile favors the 8 Gy x 3 cohort for future development. Analyses of blood and tumor tissues is ongoing.5
Targeting multiple checkpoint receptors, Giuseppe Curigliano, MD, PhD, from the Istituto Europeo di Oncologia IRCCS reported on a trial of MBG453 and spartalizumab. The agents block binding of immune checkpoint receptors TIM-3 to phosphatidylserine and PD-1 to PD-L1 and PD-L2, respectively. Preclinical studies show synergistic antitumor activity of TIM-3 + PD-1 co-blockade. Based on promising early data the dose expansion phase II study is ongoing in patients with melanoma or NSCLC resistant to anti-PD-1/PD-L1.6
F. Stephen Hodi, MD, of the Dana-Farber Cancer Institute presented data from 2 randomized phase III trials, CheckMate 066 (NCT01721772) and CheckMate 067 (NCT01844505). The studies evaluated nivolumab versus dacarbazine (CheckMate 066) and nivolumab plus ipilimumab combination therapy or nivolumab versus ipilimumab, respectively, in advanced melanoma (CheckMate 067).7Genomic correlates of response were evaluated for association of tumor mutational burden and an inflammatory gene signature with clinical outcomes in melanoma patients. Tumor mutation burden (TMB)-high and a high inflammatory signature scores were not correlated and independently associated with clinical outcomes. Higher inflammatory status increased clinical response and longer survival for nivolumab plus ipilimumab and nivolumab, suggesting further evaluation of these biomarkers to better characterize the response to immuno-oncology regimens in melanoma.
Ryan J. Sullivan, MD, from Massachusetts General Hospital presented data from the multicohort study ENCORE-601 (NCT02437136), which evaluated entinostat plus pembrolizumab in patients with advanced melanoma. The combination therapy with entinostat plus pembrolizumab demonstrated significant clinical activity and acceptable safety in patients with melanoma who have progressed on prior PD-1 or PD-L1 blockade. Preliminary biomarker analysis supported the hypothesis that the addition of entinostat decreases myeloid derived suppressor cell and restores inflammation in the tumor microenvironment necessary for successful re-treatment with an anti-PD-(L)1.8
Robert L. Ferris, MD, PhD, is the co-physician editor-in-chief ofTargeted Therapies in Oncology,and director of the University of Pittsburgh Medical Center’s Hillman Cancer Center, the Hillman professor of oncology, associate vice chancellor for cancer research and co-director of the Tumor Microenvironment Center.