Cabozantinib in combination with atezolizumab in non-small cell lung cancer (NSCLC) patients previously treated with an immune checkpoint inhibitor: Results from cohort 7 of the COSMIC-021 study.

Abstract

9610 Background: First-line immunotherapy with/without chemotherapy is standard of care for patients (pts) with advanced NSCLC; however, there is a need for effective treatment options after progression on a prior immune checkpoint inhibitor (ICI). Cabozantinib (C) may augment response to ICI by inhibiting kinases implicated in suppressing immune cell responses and has shown encouraging clinical activity in combination with ICI in other tumor types including RCC and HCC. COSMIC-021, a multicenter phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from cohort 7 in NSCLC pts after prior ICI therapy. Methods: Eligible pts had ECOG performance status (PS) 0-1 and radiographic progression after one prior anti-PD-1/PD-L1 ICI given alone or in combination with chemotherapy for metastatic non-squamous NSCLC. Up to 2 lines of prior systemic anticancer therapies were permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Primary endpoint is ORR per RECIST 1.1 by investigator. Other endpoints include safety, duration of response (DOR), progression-free survival, and overall survival. Results: Thirty pts with advanced NSCLC were enrolled. Median age was 67 yrs (range 41, 81), 43% were male, 57% had ECOG PS 1, and 23% had liver metastases. Median duration of prior ICI therapy was 4.8 months (mo; range 0.8, 29), and 15 (50%) pts were refractory to prior ICI (progressive disease as best response). As of December 20, 2019, the median follow-up was 8.9 mo (range 5, 20) with 9 (30%) pts continuing study treatment. The most common treatment related adverse events (TRAEs) of any grade were diarrhea (53%), fatigue (37%), nausea (23%), decreased appetite (20%), palmar-plantar erythrodysesthesia (20%) and vomiting (20%). Grade 3/4 TRAEs occurred in 14 (47%) pts, and 1 (3.3%) had grade 5 TRAEs of myocarditis and pneumonitis. Confirmed ORR per RECIST 1.1 was 23% (7 of 30 pts; all partial responses including 3 pts refractory to prior ICI). Time to response was 1.4 mo (range 1, 3), and median DOR was 5.6 mo (range 2.6, 6.9). DCR (CR+PR+SD) was 83%. Conclusions: The combination of C and A had an acceptable safety profile and showed encouraging clinical activity in pts with advanced NSCLC who had progressed after prior ICI therapy. The response rate was greater than previously observed with C monotherapy. Due to the promising data, enrollment in this cohort has been expanded and is ongoing. Clinical trial information: NCT03170960 .

Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer

“…The dose-escalation phase of this study determined the optimal dose of cabozantinib to be 40 mg daily in combination with atezolizumab. 89 In ASCO 2020, Neal et al 90 reported the results from cohort 7 of NSCLC with unknown MET status patients after prior immune checkpoint inhibitor (ICI) therapy. In the 30-patient cohort, confirmed ORR was 27%; time to response was 1.4 months; median DOR was 5.7 months; DCR was 83%; median PFS was 4.2 (95% CI: 2.7-7) months.…”

Comparison of Efficacy of Systemic Therapies in Advanced Hepatocellular Carcinoma: Updated Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials

“…The success of this anti-VEGF and ICI combination is in keeping with the move towards combination therapy evaluations in clinical trials where this specific combination is currently the most frequently evaluated regimen. 8 For instance, the COSMIC-021 trials have demonstrated promising efficacy data for atezolizumab and cabozantinib in prostate cancer, nonsmall cell lung cancer, renal cell carcinoma, and urothelial carcinoma, [9][10][11][12] and the CAMILLA study has demonstrated the potential efficacy of durvalumab with cabozantinib in advanced GI cancers. 13 Furthermore, a recent, multi-center, Phase II trial tested the safety and efficacy of a camrelizumab (anti-PD-1 antibody) plus apatinib (anti-VEGFR-2) in aHCC patients who were either treatment-naïve or refractory to first line therapy.…”

Cabozantinib: An evolving therapy for hepatocellular carcinoma

“…As discussed earlier, preclinical studies have demonstrated the immunomodulatory potential of cabozantinib in a variety of tumor models [38,40,41]. Preliminary results from clinical studies of cabozantinib/ICI combinations in solid tumors have reported promising activity [45,[84][85][86][87][88][89], and the recent phase 3 CheckMate 9ER in advanced RCC demonstrated improved PFS, OS, and ORR with the combination of cabozantinib/nivolumab versus sunitinib in the first-line setting [90].…”

“…Preliminary results from the clear cell RCC cohort reported outcomes in 70 patients with advanced disease treated with 40 or 60 mg of cabozantinib/atezolizumab, with clinically meaningful activity in both dose cohorts and manageable safety profiles. Data for the HCC cohort have not yet been reported, but response outcomes in RCC [85][86][87] and other tumor cohorts, including CRPC [45] and NSCLC [88], have supported the development of a phase 3 program for this combination.…”