Neoantigen-Directed GRANITE Immunotherapy Improves PFS as Maintenance in MSS mCRC

Botensilimab/Baltstilimab in MSS CRC |

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Maintenance therapy with the individualized neoantigen-targeting immunotherapy GRANITE plus atezolizumab (Tecentriq), fluoropyrimidine, bevacizumab (Avastin), and one dose of ipilimumab (Yervoy) demonstrated an improvement in progression-free survival (PFS) vs fluoropyrimidine plus bevacizumab alone in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), according to interim data from a phase 2/3 trial (NCT05141721).^1,2

At a data cutoff of August 19, 2024, the results pointed to a 21% reduction in the risk of disease progression or death with the investigational approach (HR, 0.79; 95% CI, 0.42-1.50), although the developer stated the study was not statistically powered to detect an improvement in PFS. Additional results indicated that the 50% of patients who had lower disease burden as confirmed by circulating tumor DNA (ctDNA) analysis at baseline derived the greatest benefit (HR, 0.62; 95% CI, 0.23-1.70). Moreover, of the 20 patients who have not experienced disease progression most in the investigational (n = 12/13) and control (n = 4/7) arms had stable ctDNA titers below the assay limit of quantitation.

“We are excited by the potential of GRANITE to extend both progression-free and overall survival [OS] in a disease where relentless progression is the rule with existing therapies,” Andrew Allen, MD, PhD, co-founder, president, and chief executive officer of Gritstone bio, stated in a news release. “The field of neoantigen-targeting immunotherapy is evolving rapidly, and the focus is shifting to patients with lower volume disease. Notably, patients with newly diagnosed metastatic disease who have low ctDNA at study entry and thereby relatively low disease burden, could benefit from this type of immunotherapy.”

The vaccine under study uses two vaccine vectors as a heterologous prime/boost approach: GRT-C901 first followed by GRT-R902 to stimulate an immune response. The phase 2 portion of the trial will determine the clinical activity of the regimen according to molecular response, and the phase 3 portion will measure its activity through PFS.

To be eligible for enrollment patients must have histologically confirmed mCRC who are planned for or have received no more than 30 days of frontline treatment in the metastatic setting with bevacizumab plus any of the following regimens: FOLFOX, CAPEOX, FOLFOXIRI, or CAPOXIRI. Measurable and unresectable metastatic disease according to RECIST v1.1, access to formalin-fixed paraffin-embedded tumor specimens, an ECOG performance status of 0 or 1, and adequate organ function are also required.

In the investigational arm patients will first receive 24 weeks of induction therapy with fluoropyrimidine, oxaliplatin, and bevacizumab with or without irinotecan per standard of care. Following vaccine production screening, patients will receive a total of 6 administrations of GRT-C901/GRT-R902 plus 30 mg of ipilimumab co-administered only with the first dose of GRT-C901 and GRT-R902. All patients will receive 1680 mg of atezolizumab once every 4 weeks plus a fluoropyrimidine and bevacizumab as part of maintenance therapy. GRT-C901 will be administered via intramuscular injection at a dose of 1 x 1012 viral particles 2 times over the course of the first year followed by GRT-R902, which will be administered at a dose of 30 ug 4 times within the first year.

A total of 104 patients were randomly assigned 1:1, 69 of which were included in the present analysis (investigational, n = 39; control, n = 30). Demographics and clinical characteristics including stage, sidedness, presence of liver metastases were balanced between arms, with 80% of patients having liver metastases in the treated analysis. Thirty-five patients (investigational, n = 12; control, n = 23) did not proceed to study treatment after induction chemotherapy, predominantly because of withdrawn consent (n = 15), disease progression (n = 8), and other reasons (n = 12).

“Success for immunotherapy typically manifests as an elevated plateau in PFS and OS Kaplan-Meier curves, and we may be seeing this in our low disease burden population. We need more time to let these data mature. The most recent ‘low and stable’ ctDNA measurements in most GRANITE patients are encouraging since that pattern is not typically seen in patients about to develop disease progression. The potential PFS benefit observed in MSS CRC, a notoriously ‘cold’ tumor, suggests the opportunity for even greater effects in tumors more typically amenable to immunotherapy,” Allen said.

In terms of safety no patients discontinued study treatment because of an adverse effect (AE).

Common AEs mimicked the mild systemic and local effects associated with potent vaccines, according to the press release. One treatment-related serious AE of fatigue was reported in the investigational arm, which did not affect the competition of study treatment.

Additionally, immune data were consistent with clinical activity. Functional neoantigen-specific T cells were observed in all 16 patients in the investigational arm who were tested by ELISPOT. Moreover, an association was seen between PFS and peak ex vivo ELISPOT responses, indicating that ex vivo ELISPOT may be a surrogate for PFS.

“These data support further exploration of GRANITE in frontline MSS CRC and in other low burden [neo]adjuvant settings. With this new dataset in hand, we continue to actively explore several strategic and funding alternatives to rapidly advance our innovative immunotherapy for the benefit of patients,” Allen added.

Gritstone intends to discuss these data with the FDA in the coming months to determine the next steps in GRANITE’s development, which may include a phase 2 or 3 trial using ctDNA levels to determine eligibility. OS data are expected in the second half of 2025.

References

1. Gritstone bio announces interim phase 2 data for GRANITE individualized neoantigen targeting immunotherapy in frontline metastatic microsatellite stable colorectal cancer. News release. September 30, 2024. Accessed October 1, 2024. https://ir.gritstonebio.com/news-releases/news-release-details/gritstone-bio-announces-interim-phase-2-data-granite
2. A study of a patient-specific neoantigen vaccine in combination with immune checkpoint blockade for patients with metastatic colorectal cancer. ClinicalTrials.gov. Updated December 22, 2023. Accessed October 1, 2024. https://clinicaltrials.gov/study/NCT05141721#study-plan