Dr. Hecht on the Investigation of XL092/Atezolizumab in MSS/MSI-L mCRC

J. Randolph (Randy) Hecht, MD, a professor of Clinical Medicine at the David Geffen School of Medicine of University of California, Los Angeles (UCLA), and the director of the UCLA Gastrointestinal Oncology Program, discusses the investigation of XL092 plus atezolizumab (Tecentriq) in patients with microsatellite stable (MSS)/microsatellite instability–low (MSI-L) metastatic colorectal cancer (mCRC).

The actively accruing phase 3 STELLAR-303 trial (NCT05425940) is investigating the combination of XL092 plus atezolizumab in patients with MSS/MSI-low mCRC who have progressed on or are intolerant to standard-of-care therapy options. XL092 is a TKI targeting MET, VEGF2, and the TAM kinases AXL and MER.

Patients with mCRC typically respond well to first-line therapy and can benefit from second-line therapy; however, patients have historically not done well with salvage therapy, Hecht says. Regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf) represent salvage therapy options, but these therapies only produce modest benefit. This has created an unmet need that must be addressed within the mCRC patient population, Hecht explains. 

Immunotherapy has not been an effective treatment option for most patients with mCRC, and investigators are aiming to find ways to make immunotherapy work in patients who do not have a genetic marker that makes them sensitive to this treatment, Hecht explains. A small fraction of patients with mCRC have microsatellite instability (MSI) or mismatch repair deficiency (dMMR), and, initially, those patients are sensitive to standard checkpoint inhibitors. However, for the vast majority of other patients with mCRC, these drugs do not work, Hecht says. There has been an effort to explore other approaches and combinations that make patients sensitive to checkpoint inhibition.

Inhibiting PD-1 or PD-L1 alone may not be sufficient enough to elicit an immune response. Therefore, investigators are exploring ways to inhibit other immunosuppressive mechanisms to get a response, and using a TKI in combination with a checkpoint inhibitor could represent one way to improve responses to immunotherapy in patients with mCRC, Hecht concludes.