Background: The tyrosine kinase inhibitor cabozantinib showed clinical activity in 1L RCC as well as RCC and HCC in 2L after treatment with anti-angiogenic therapy where it prolonged survival. Immune checkpoint inhibition (ICI) is rapidly becoming a 1L standard of care across tumor types. We evaluated the effectiveness of cabozantinib in a 2L post-ICI setting. Experiments focused on anti-tumor efficacy of cabozantinib ± ICI after ICI in one of several syngeneic mouse tumor models partly refractory to ICI. Cabozantinib monotherapy was also tested.
Methods: Colon38 tumors were established in C57Bl6 mice and dosed with anti-PDL1 (5 mg/kg ip q2d 3x/wk) as 1L ICI treatment for 2 weeks. Animals were defined as initial responders (R) or non-responders (NR) based on, respectively, a >10% decrease or increase in tumor volume (TV) during week 2 of ICI therapy. 2L treatment was initiated in week 3 with cabozantinib (10 mg/kg po qd) or ICI for 3 weeks alone or combined in R and NR arms (n=10/cohort). Cabozantinib was also dosed as monotherapy from week 1 (cohort Cwk1) or week 3 (cohort Cwk3). Time (days) to reach a TV of 1000mm³ (TTRV1000) was used as efficacy measure.
Results: Cabozantinib monotherapy was effective with 1-3 complete regressions (CR) seen for cohorts Cwk3 with a TTRV1000 of 38.5d (21.5-98) and Cwk1 with a TTV1000 of 47.5d (36.5-98). Vehicle-dosed tumors had a median TTRV1000 of 18.5d (range 14-34.5) after randomization. R tumors reacted well to 1L ICI with a TTRV1000 of 45.5d (29-98) and 4-6 CR seen in 2L R cohorts regardless of 2L treatment. The remaining non-CR tumors had for 2L ICI treatment a TTRV1000 of 36.5d (30.5-43; n=4) as compared to 40d (29-47; n=6) for 2L vehicle-dosed controls, suggesting they had become refractory to ICI. 2L treatment with cabozantinib had a TTRV1000 of 58d (45.5-80.5; n=6), while cabozantinib+ICI had a TTRV1000 of 56d (42-98; n=5). 2L cabozantinib ± ICI thus led to longest TTRV1000 values for refractory non-CR tumors after 1L ICI across R cohorts. NR tumors receiving ICI had a TTRV1000 of 27d (13.5-32) and thus behaved similar to vehicle alone. 2L cabozantinib ± ICI effects were comparable in magnitude to the efficacy of cabozantinib monotherapy in cohort Cwk3; 2L cabozantinib after 1L ICI in NR tumors had a TTRV1000 of 40.5d (26-47.5), while 2L cabozantinib+ICI after 1L ICI yielded a TTRV1000 of 43.5d (20-59.5).
Conclusion: Cabozantinib showed robust anti-tumor efficacy in refractory post-ICI settings. Further investigation of the mechanisms of action of sequential combination is warranted.
Citation Format: Sylvie Rolland, Stephan Klinz, Sophie Chaumeron, Florence Meyer-Losic, Marc Hillairet de Boisferon. Efficacy of cabozantinib after immune checkpoint inhibition in a syngeneic tumor model [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO053.