Targeting the MET Pathway in Urothelial Carcinoma

Division Of Basic Sciences - Nci

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Abstract

Effect of cabozantinib on peripheral blood immune subsets in urothelial carcinoma and other GU tumors We conducted a study to assess the impact of cabozantinib on systemic innate and adaptive immune cells. TKIs against VEGFR and other receptor tyrosine kinases may have antitumor immune mediated mechanisms. MET is expressed in tumor cells and in immunosuppressive myeloid cells including human monocytes and granulocytic, MDSCs. Signaling downstream of HGF MET interaction in monocytes may shift the Th1/Th2 balance and expand MDSCs and Tregs. We hypothesized that cabozantinib can modify the tumor microenvironment by modulating immunosuppressive Tregs and MDSCs. We assessed peripheral blood mononuclear cell (PBMC) immune subsets, including effector T cells, exhausted T cells, Tregs, MDSCs, and the functional markers PD 1 and TIM 3, using flow cytometry in metastatic urothelial carcinoma patients undergoing treatment with cabozantinib at baseline and after 2 cycles of continuous cabozantinib treatment, and correlated our findings with clinical response to therapy, PFS, and OS. In summary, our study showed that cabozantinib has innate and adaptive immunomodulatory properties that provide a rationale for combining cabozantinib with immunotherapeutic strategies. Cabozantinib modulated peripheral blood myeloid populations, including decreasing classical monocytes, increasing non classical monocytes, and decreasing MDSCs. Cabozantinib also favorably impacted CD4 polarization to decrease Tregs, increase the ratio of CD8 T cells to Tregs, and upregulate PD 1 expression on Tregs. We plan to validate these findings in 155 patients treated with CaboNivo or CaboNivoIpi with a larger immune subset panel and additional functional markers with the goal to further understand the immune response of innate mononuclear cells that may serve as a targetable nexus for therapeutic engagement of adaptive immunity. Combining cabozantinib with checkpoint inhibition with nivolumab and ipilimumab Based on the immunomodulation seen with cabozantinib, I initiated a multicenter phase 1 study where I combined CaboNivo or CaboNivoIpi. The study included a phase 1 study with 8 dose levels (n = 54) and 7 expansion cohorts, including urothelial carcinoma, renal cell carcinoma, urothelial carcinoma patients previously treated with checkpoint inhibitors, adenocarcinoma of the bladder/urachal, penile cancer, squamous cell carcinoma, and other rare tumors (n = 155). The phase 1 portion is complete, but we are still running the expansion cohorts. Safety of the combination of CaboNivo and CaboNivoIpi: In a phase 1 study, I assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) with or without ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma and other GU malignances. Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase 2 dose (RP2D). Overlapping toxicities with the use of TKIs and checkpoint inhibitors included thyroid dysfunction, diarrhea, and elevated liver enzymes. Cabozantinib 60 mg/day led to higher rates of clinical treatment related adverse events of all grades, including fatigue, diarrhea, anorexia, weight loss, nausea, vomiting, mucositis, and dehydration. Although the study did not have any dose limiting toxicities, the RP2D was cabozantinib 40 mg/day plus nivolumab 3 mg/kg for the doublet and cabozantinib 40 mg/day, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for the triplet, based on better clinical tolerability and similar efficacy of cabozantinib at 40 mg/day vs. 60 mg/day. These data established the safety of the combinations and the RP2D for larger trials. Activity of CaboNivo and CaboNivoIpi: In the phase 1 study of CaboNivo and CaboNivoIpi (n = 54), we reported an ORR of 30.6% for all patients and 38.5% for urothelial carcinoma patients.23 Median duration of response was 21.0 months for all patients and not reached for metastatic urothelial carcinoma patients. Median PFS was 5.1 months for all patients and 12.8 months for urothelial carcinoma patients. Median OS was 12.6 months for all patients and 25.4 months for metastatic urothelial carcinoma patients. Based on the initial efficacy seen in the phase 1 patients, additional expansion cohorts were added to the study. Expansion cohorts of CaboNivo and CaboNivoIpi in patients naive to checkpoint inhibition: The pooled data from the phase 1 and expansion cohorts in patients naive to immune checkpoint inhibition (n = 120) are currently being analyzed. For all currently evaluable patients (n = 109), the ORR = 37.6%, CR = 9.2%, PR = 28.4%, and SD = 43.1%. The urothelial carcinoma expansion cohort included 24 patients treated with CaboNivo (n = 12) and CaboNivoIpi (n = 12). Similar to the phase 1 study where the ORR was 38.5%, in the urothelial carcinoma expansion cohort the ORR = 42.9% for the 24 urothelial carcinoma patients and for the phase 1+ expansion cohort (n = 40) the ORR = 41.2%, CR = 20.6%, PR = 20.6%, SD = 38.2%, and progressive disease = 23.5%. The clear cell renal cell carcinoma (RCC) patients included patients with sarcomatoid features. In phase 1, all 3 RCC patients had a PR, the RCC expansion cohort included 12 patients treated with CaboNivo (n = 6) and CaboNivoIpi (n = 6), and an additional RCC sarcomatoid patient from the rare tumor cohort. The phase 1 + RCC expansion cohort (n = 16) had an ORR = 62.5%, CR = 12.5%, PR = 50%, SD = 37.5%, and progressive disease = 0%. The promising activity seen in this phase 1 study has led to additional expansion cohorts within this study, including cohorts for urothelial carcinoma, RCC, and other rare GU tumors with no standard treatment options, and has also led to larger trials in GU tumors including CheckMate 9ER, a randomized phase 3 trial of CaboNivo vs. sunitinib in the first line treatment of mRCC, PDIGREE, an adaptive phase 3 trial of CaboNivoIpi in untreated mRCC, COSMIC 313, a phase 3 trial of CaboNivoIpi vs. NivoIpi plus placebo in mRCC, and the Alliance ICONIC study of CaboNivoIpi for rare GU tumors. Several other trials are testing CaboNivo in non clear cell RCC, carcinoid tumors, metastatic triple negative breast cancer, locally advanced hepatocellular carcinoma, advanced endometrial cancer, recurrent uterine carcinosarcoma, poorly differentiated neuroendocrine tumors, and non small cell lung cancer. A study of CaboNivoIpi in unresectable advanced melanoma is also underway. I am on the steering committee for CheckMate 9ER. The first results from the randomized phase 3 study, n = 651 were presented in the presidential symposium at ESMO 2020 showing first line CaboNivo vs. sunitinib improves PFS, 16.6 vs. 8.3 months, OS, 40% decrease in risk of death and ORR, 55.7 vs. 27.1%, with benefit in all International Metastatic RCC Database Consortium risk groups. CaboNivo has potential as first line therapy for metastatic RCC patients. I am an author of the manuscript which was submitted to the New England Journal of Medicine. I am currently working on a subset analysis for patients with sarcomatoid RCC within the 9ER study. For bladder cancer patients, I am working on developing a phase 3 study for the second line treatment of patients post platinum based therapy.