Issue At Hand

With the ongoing paradigm shift in the standard of care treatment for several advanced solid tumors, first-line treatment of advanced colorectal cancer (CRC) has been the same for a few decades; chemotherapy regimens that include fluorouracil in combination with platinum, irinotecan, or both. In the second line, options only get narrower, including tyrosine kinase inhibitors (TKI), monoclonal antibodies, or target-specific regimens that offer suboptimal efficacy. Yet a few percentages (~3-5%) of advanced CRC patients harboring an increased tumor mutational burden or high microsatellite instability have the option of immune checkpoint inhibitors (ICI) based on FDA approvals of anti-PD-1 regimens with or without anti-CTLA-4. However, the remaining majority (~95%) of patients with microsatellite stable (MSS) CRCs still have limited options upon progression on two or more lines of systemic therapy and consequently have poor overall survival.

Harnessing the Synergy of Immunotherapy & TKIs

Cabozantinib, a multi-target TKI, has emerged as a potential candidate that harbors immunomodulatory effects that actively impede the immune suppressive nature of the tumor microenvironment by stimulating both local and systemic anti-tumor immune cascades in several solid tumors. This was evident in pre-clinical studies in patient-derived xenograft models of immune cold MSS CRC treated with cabozantinib (1). Furthermore, early-phase clinical trials further highlighted the synergistic effect of combining cabozantinib with ICIs in patients with advanced solid tumors such as hepatocellular carcinoma (HCC) and genitourinary cancers (2–3). This evidence has triggered our efforts to develop the CAMILLA phase I/II trial in which we investigate the efficacy and safety of combining cabozantinib and durvalumab (an anti-PD-L1) in previously treated MSS advanced gastrointestinal (GI) cancer patients. We previously reported on our phase 1 results across GI cancers which included 20 CRC patients, 10 gastroesophageal cancer patients, and 5 HCC patients (4). We demonstrated a tolerable safety profile (treatment-related grade ≥ 3 adverse events: 34%) and promising efficacy (objective response rate (ORR): 30%, a disease-control rate: 83.3%, and a median overall survival (OS) of 8.7 months). In our currently published study, we further expand on our metastatic MSS CRC cohort by providing transcriptomic and genomic correlative insights (5). Among 29 CRC evaluable patients, we report an ORR of 27.6% and a median OS of 9.1 months, and notably among RAS wildtype patients the ORR reached 50% and median OS of 21.5 months which demonstrates the potential influence of RAS mutational status possibly contributing to deeper and more durable responses to cabozantinib plus durvalumab (5). Notably, our exploratory spatial transcriptomic analysis showed upregulation of VEGF and MET signaling pathways, cell adhesion signatures, and pre-existing anti-tumor immune responses co-existing with T cell migration barriers in responders compared to non-responders (Figure 1). These findings provide insights into the synergistic interaction between cabozantinib and durvalumab as modulation of angiogenesis by VEGF receptor inhibition and extracellular matrix modulation possibly through interrupting joint integrin c-MET signaling seem to be involved in improving T cell migration into the tumor core further facilitating anti-tumor immune response. In contrast to other VEGFR2 TKIs previously explored with PD-1/PD-L1 inhibitors in advanced MSS CRC such as regorafenib and lenvatinib, cabozantinib is the only multi-TKI that targets the MET pathway. This alongside the reported higher response rates in the RAS wildtype subgroup could explain the more favorable outcome seen in the CAMILLA and COSMIC-021 trials. Broader Implications: Our promising results of the phase I/II CAMILLA trial have led to the activation of the phase III STELLAR 303 trial (6) investigating the combination of zanzalintinib (a next generation VEGFR & MET multi-kinase inhibitor, with similar major targets to cabozantinib) and atezolizumab versus regorafenib in previously treated metastatic MSS CRC patients (6). Our work alongside the efforts of previous groups focusing on advancing ICI in MSS CRC will help illuminate and guide further innovative strategies for combinational ICI-based regimens that are warranted to challenge the status quo of MSS CRC being an irreversible immune desert.

References

1.    Lang J, Leal AD, Marín-Jiménez JA, Hartman SJ, Shulman J, Navarro NM, et al. Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint blockade by immune modulation in human immune system mouse models. Front Oncol [Internet]. 2022 Nov 7 [cited 2024 Feb 21];12. Available from: https://pubmed.ncbi.nlm.nih.gov/36419897/
2.    Yau T, Zagonel V, Santoro A, Acosta-Rivera M, Choo SP, Matilla A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. https://doi.org/101200/JCO2020384_suppl478 [Internet]. 2020 Feb 4 [cited 2024 Feb 21];38(4_suppl):478–478. Available from: https://ascopubs.org/doi/10.1200/JCO.2020.38.4_suppl.478
3.    Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. J Clin Oncol [Internet]. 2020 Nov 1 [cited 2024 Feb 21];38(31):3672–84. Available from: https://pubmed.ncbi.nlm.nih.gov/32915679/
4.    Saeed A, Park R, Dai J, Al-Rajabi R, Kasi A, Baranda J, et al. Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results. Cell Rep Med [Internet]. 2023 Feb 21 [cited 2024 Feb 21];4(2). Available from: https://pubmed.ncbi.nlm.nih.gov/36702123/
5.    Saeed A, Park R, Pathak H, Al-Bzour AN, Dai J, Phadnis M, et al. Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort. Nature Communications 2024 15:1 [Internet]. 2024 Feb 20 [cited 2024 Feb 21];15(1):1–13. Available from: https://www.nature.com/articles/s41467-024-45960-2
6.    Saeed A, Tabernero J, Wang G, Ma X, Smith R, Hecht JR. Zanzalintinib (XL092) plus atezolizumab versus regorafenib in previously treated MSS/MSI-low metastatic colorectal cancer (mCRC): The randomized phase 3 STELLAR-303 study. https://doi.org/101200/JCO2024423_supplTPS229 [Internet]. 2024 Jan 22 [cited 2024 Feb 22];42(3_suppl):TPS229–TPS229. Available from: https://ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.TPS229