Personalized Vaccine Yields Early PFS Benefit in Metastatic MSS-CRC

“These preliminary results indicate that GRANITE is inducing a potentially significant immune response in a disease that has been felt to be immunologically cold,” according to J. Randolph Hecht, MD.

The use of the personalized neoantigen cancer vaccine GRANITE (GRT-C901/GRT-R902) in combination with immune checkpoint blockade and fluoropyrimidine/bevacizumab (Avastin) yielded an early progression-free survival (PFS) benefit among patients with microsatellite-stable colorectal cancer (MSS-CRC), according to a press release on phase 2 portion findings from a phase 2/3 study (NCT05141721).¹

An early trend in improved PFS with the vaccine-based combination vs fluoropyrimidine/bevacizumab alone occurred across the overall population (HR, 0.82; 95% CI, 0.34-1.67; 62% censored). Additionally, a trend in improved PFS with the vaccine combination was reported among those with high-risk disease, which included a median PFS of 12 months in the experimental arm vs 7 months in the control arm (HR, 0.52; 95% CI, 0.15-1.38; 44% censored). PFS outcomes in the GRANITE and control arms began to separate at 1 to 2 months after patients initiated study treatment, which investigators described as comparable with prior reports of the vaccine’s induced immune response kinetics.

Regarding circulating tumor DNA (ctDNA) biomarker results, short-term molecular responses were uninformative based on the unanticipated continuation of ctDNA drops following induction chemotherapy. Short-term molecular responses among evaluable patients occurred in 30% (n = 6/20) of the vaccine arm and 42% (n = 5/12) of the control arm.

Long-term ctDNA responses appeared to correlate with PFS trends, favoring the vaccine arm. Among patients with high-risk disease, ctDNA shifted from high to low variant allele frequencies in 56% (n = 9/16) of patients in the vaccine arm vs 22% (n = 2/9) of those in the control arm. Among those who had ctDNA negativity following induction chemotherapy, ctDNA-negative status was sustained in 67% (n = 6/9) of patients who received the vaccine compared with 38% (n = 3/8) of those in the control arm.

Findings highlighted that most adverse effects (AEs) in the vaccine arm were grade 1/2, and that common toxicities were mild, systemic events typically related to any potent vaccine such as transient flu-like illness. Additionally, there were no AEs leading to discontinuation of the vaccine. Overall, investigators concluded that the vaccine exhibited a favorable safety and toxicity profile.

“These preliminary results indicate that GRANITE is inducing a potentially significant immune response in a disease that has been felt to be immunologically cold,” study investigator J. Randolph Hecht, MD, a professor of Clinical Medicine and director of the University of California, Los Angeles (UCLA) Gastrointestinal Oncology Program, said in the press release.

“The PFS difference, particularly in a poor prognosis group of patients, indicates the potential for clinical benefit and provides the rationale for a confirmatory phase 3 trial, about which I am very excited. Furthermore, we are learning how to better analyze ctDNA continuously to study the efficacy of this novel immunotherapy. Expanding the scope of immunotherapy to a broader spectrum of [patients with] cancer is the ‘holy grail’ of oncology, especially for [MSS-CRC]. While early, these promising results suggest GRANITE has potential to deliver clinically meaningful benefit in MSS-CRC and other cold tumors,” he added.

In this phase 2/3 trial, 104 patients with MSS-CRC were randomly assigned 1:1 to receive GRANITE plus immune checkpoint blockade and fluoropyrimidine/bevacizumab or fluoropyrimidine/bevacizumab alone. Immunotherapy in the experimental arm included atezolizumab (Tecentriq) and ipilimumab (Yervoy).²

As of the data cutoff of March 8, 2024, 67 patients were assessed, which included 39 in the vaccine arm and 28 in the control arm. Investigators noted that demographics and clinical characteristics were comparable between treatment arms. Overall, approximately 75% of patients had liver metastases.

References

1. Gritstone bio announces positive preliminary progression-free survival and long-term circulating tumor DNA (ctDNA) data from phase 2 portion of ongoing phase 2/3 study of its personalized cancer vaccine, GRANITE, in front-line metastatic microsatellite stable colorectal cancer (MSS-CRC). News release. Gritstone bio, Inc. April 1, 2024. Accessed April 2, 2024. https://tinyurl.com/2n2uyasr
2. A study of a patient-specific neoantigen vaccine in combination with immune checkpoint blockade for patients with metastatic colorectal cancer. ClinicalTrials.gov. Accessed April 2, 2024. https://tinyurl.com/ea8d66c2