COM701 Plus Nivolumab Confers Modest Efficacy in Metastatic MSS-CRC

COM701 plus nivolumab demonstrated modest antitumor activity but a favorable safety profile in patients with metastatic microsatellite stable colorectal cancer.

COM701 plus nivolumab (Opdivo) demonstrated modest antitumor activity but a favorable safety profile in patients with metastatic microsatellite stable colorectal cancer (MSS-CRC), according to findings from a phase 1 trial (NCT03667716) presented at the 2022 SITC Annual Meeting.1

The results showed that the objective response rate (ORR), which comprised all partial responses and was sustained for at least 6 months, was 9% (n = 2). Four patients (18%) experienced stable disease and 13 (59%) had progressive disease, translating to a disease control rate of 27% (n = 6). Three patients (13%) had clinical progressive disease or lack of clinical benefit.

Among patients with liver metastases (n = 17; 77%), 2 (12%) experienced partial response and 3 (18%) achieved stable disease, translating to a DCR of 29% (n = 5).

“MSS-CRC is a cold tumor that is typically not responsive to immunotherapy, especially in [those with] MSS-CRC with liver metastases representing about 70% of all patients [with CRC],” presenting author Michael Overman, MD, of The University of Texas MD Anderson Cancer Center in Houston, said in a press release.2

“Adding COM701 to nivolumab resulted in a response rate of 9% in 22 [patients with] MSS-CRC with 2 partial responses occurring in 17 patients with liver metastases. This stands in contrast to other novel immunotherapy combinations where responses in [those with] MSS-CRC with liver metastases have been extremely rare to non-existent. While the numbers of patients were small, the data are encouraging and warrant further evaluation.”

MSS-CRC represents 95% of mCRC cases, but standard-of-care treatments such as regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf) have modest activity. Most patients who reach third-line treatment have liver metastases, which confers lack of efficacy to PD-(L)1 inhibition.

COM701 is a novel, first-in-class, humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG, inhibiting its interaction with its natural ligand PVRL2, which is expressed in tumor cells and antigen-presenting cells.

Previously, COM701 has shown antitumor and pharmacokinetic activity alone and in combination in several tumor types.

To be eligible for enrollment in the phase 1 trial, patients had to have histologically confirmed adenocarcinoma of the colon/rectum; measurable stage IV disease; documented MSS status; disease progression on at least 2 systemic therapies for metastatic disease including fluoropyrimidines, irinotecan, and oxaliplatin; and be eligible for PD-(L)1 therapy.

Patients would be excluded if they had active autoimmune disease requiring systemic therapy or a history of immune-related toxicities on prior immunotherapy treatment leading to discontinuation. 

The study consisted of dose-escalation and dose-expansion phases. In the dose-escalation phase, patients received 1 of 5 regimens: 0.3 mg/kg COM701 plus 360 mg nivolumab; 1 mg/kg COM701 plus 360 mg nivolumab; 3 mg/kg COM701 plus 360 mg nivolumab every 3 weeks; or 10 mg/kg COM701 plus 480 mg nivolumab; or 20 mg/kg COM701 plus 480 mg nivolumab every 4 weeks, the latter of which was selected for dose-expansion.

Safety and tolerability of the combination served as the primary end point. Immunogenicity and antitumor activity of the combination were also evaluated as secondary end points.

Most patients were male (n = 16; 73%), white (n = 18; 82%), and below the age of 65 years (n = 17; 77%). Additionally, most patients had KRAS mutations (n = 13; 59%) and liver metastases (n = 17; 77%). Patients received a median of 3 prior therapies (range, 2-10). Few patients had received prior PD-(L)1 inhibitors (n = 2; 9%) or regorafenib or TAS-102 (n = 7; 32%).

The median number of treatment cycles was 2 (range, 1-16), and all patients discontinued treatment because of progressive disease (n = 17; 77%), physician decision or loss of clinical benefit (n = 3; 14%), or an adverse effect (AE; n = 2; 9%).

Regarding safety, treatment-emergent AEs included anemia (grade 1/2, n = 7; grade 3, n = 1), hypoalbuminemia (grade 1/2, n = 5), fatigue (grade 1/2, n = 5), ascites (grade 1/2, n = 3; grade 3, n = 1), vomiting (grade 1/2, n = 3; grade 3, n = 1), aspartate aminotransferase increase (grade 1/2, n = 4), and peripheral edema (grade 1/2, n = 4).

Serious AEs included abdominal distension (grade 3, n = 1), abdominal pain (grade 3, n = 1), small intestinal obstruction (grade 3, n = 1), blood bilirubin increase (grade 3, n = 2), troponin increase (grade 1/2, n = 1), device-related infection (grade 3, n = 1), sepsis (grade 3, n = 1), hyperbilirubinemia (grade 3, n = 1), hypokalemia (grade 3, n = 1), back pain (grade 1/2, n = 1), cancer pain (grade 3, n = 1), device dislocation (grade 3, n = 1), and dyspnea (grade 1/2, n = 1).

Notably, the combination was also shown to modulate the immune tumor microenvironment (TME), showing increased levels of PD-L1 combined positive score (n = 9/13), CD8 percentage (n = 7/11), and IFNγ signature (n = 5/8).

Additionally, the combination modulated the TME in responders, eliciting an inflamed TME in a patient with an excluded TME pretreatment and significant T-cell infiltration following treatment in a patient with an immune desert TME.

“These data increase our confidence that what we are seeing is a COM701 driven effect. We have shown that adding COM701 to nivolumab in patients with MSS-CRC, results in both antitumor activity and potent tumor microenvironment immune activation in a tumor type that typically does not respond to immunotherapy. Our data suggest that blocking PVRIG with COM701 is making the tumors more sensitive to anti–PD-1 alone,” Anat Cohen-Dayag, PhD, president and chief executive officer of Compugen, said.

“We are excited to be pursuing the further clinical evaluation of [patients with] MSS-CRC blocking the full DNAM-1 axis with our fully owned COM701 and COM902 in combination with an anti–PD-1. Based on the suggested COM701 mechanism of action and the totality of our preclinical and clinical findings showing more potent immune activation with triple blockade of the DNAM-1 axis, we are hoping to further enhance the ORR already achieved with dual blockade,” Cohen-Dayag concluded.

References

  • Rasco DW, Dumbrava EE, Sharma M, et al. COM701 plus nivolumab demonstrates preliminary antitumor activity and immunemodulation of tumor microenvironment in patients with metastatic MSS-CRC and liver metastases. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 659
  • Compugen’s COM701 (anti-PVRIG) in combination with nivolumab demonstrates preliminary anti-tumor activity and potent immune activation in metastatic MSS-CRC patients. News release. Compugen. November 7, 2022. Accessed November 30, 2022. https://yhoo.it/3gORN37
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