Personalized Vaccine Shows Early Promise in Metastatic Colorectal Cancer


A phase 2/3 study of GRANITE vaccine in combination with standard therapy shows encouraging early signs of efficacy and safety in patients with metastatic microsatellite-stable colorectal cancer.

Colorectal cancer image: © mi_viri - stock.adobe.comNormal

Colorectal cancer image: © mi_viri - stock.adobe.comNormal

GRANITE (GRT-C901/GRT-R902), a personalized neoantigen cancer vaccine, demonstrated positive early progression-free survival (PFS) and long-term circulating tumor DNA (ctDNA) responses compared with fluoropyrimidine/bevacizumab (Avastin) alone in front-line metastatic microsatellite-stable colorectal cancer (MSS-CRC), according to positive preliminary data from the phase 2 portion of a phase 2/3 study (NCT05141721).1

As of the clinical data cutoff date of March 8, 2024, and the ctDNA data cutoff date of March 12, 2024, 104 patients were randomized in a 1:1 fashion. A total of 67 were included in this treated analysis, including 39 in the GRANITE arm and 28 in the control arm, and 36 patients left the study prior to randomized treatment due to early progressive disease or withdrawal of consent. Additionally, 1 patient has yet to begin study treatment.

An early trend in PFS data was seen with GRANITE (HR, 0.82; 95% CI, 0.34-1.67; 62% censored). There was also an extended PFS benefit in patients who are at high risk (HR, 0.52; 95% CI, 0.15-1.38; 44% censored).

“These preliminary results indicate that GRANITE is inducing a potentially significant immune response in a disease that has been felt to be immunologically cold. 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,” said J. Randolph Hecht, MD, professor of clinical medicine and director of the UCLA Gastroinestinal Oncology Program and an investigator in the GRANITE phase 2/3 study, in the press release.

“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 cancer patients is the ‘holy grail’ of oncology, especially for MSS colorectal cancer. While early, these promising results suggest GRANITE has potential to deliver clinically meaningful benefit in MSS-CRC and other cold tumors,” added Hecht.

ctDNA responses also aligned with the positive PFS trend with GRANITE over those given fluoropyrimidine/bevacizumab alone. In the high-risk group of patients, between first blood draw and last blood draw, ctDNA shifted from high (>2% VAF) to low (≤2% VAF) in 56% of patients treated with GRANITE vs 22% given fluoropyrimidine and bevacizumab. In this group, progressive disease was observed in 44% vs 78% of patients.

In the low-risk group of patients whose ctDNA was negative after induction chemotherapy, ctDNA also favored treatment with GRANITE vs the control as a sustained ctDNA negativity was seen in 67% vs 38% of patients, and progressive disease was observed in 11% vs 38%, respectively.

Further, short-term ctDNA response analysis did not show a difference between those in the GRANITE (30%) vs control arms (42%).

For safety, findings suggest GRANITE is well-tolerated with a favorable safety profile. Most of the adverse effects (AEs) observed were mild and deemed grade 1 or 2. These AEs were similar to those experienced with other vaccines, and notably, no patients discontinued treatment due to their AEs.

“We believe these preliminary findings put us in a strong position to share mature PFS data in the third quarter and then enter regulatory discussions regarding phase 3. The growing body of evidence favoring GRANITE in this trial, including positive PFS and long-term ctDNA trends in both high and low-risk populations, is exciting and suggests GRANITE is working in this notoriously underserved patient population,” said Andrew Allen, MD, PhD, co-=founder, president, and chief executive officer of Gritstone Bio, in a press release.

The Phase 2/3 Study of GRANITE in MSS-CRC

In the randomized, controlled, open-label study, investigators are assessing the clinical benefit of maintenance therapy with GRANITE when given with immune checkpoint blockade in addition to fluoropyrimidine/bevacizumab compared with fluoropyrimidine/bevacizumab alone in the frontline for patients with MSS-CRC.2

For phase 2 of the trial, the primary end point being assessed is molecular response defined as ≥ 30% decrease from baseline in ctDNA. In phase 3, the primary end point is PFS. Secondary end points for both phase 2 and 3 include incidence of treatment-emergent AEs, immune-related AEs, treatment-related AEs, serious AEs, AEs leading to death, AEs leading to dose delays, and AEs leading to discontinuation of study treatment, PFS as assessed by the investigator and independent review committee, overall survival, overall response rate, duration of response, clinical benefit rate, deepening of response, and the feasibility of manufacturing a patient-specific vaccine.

Enrollment was open to patients 18 years of age or older with histologically confirmed metastatic CRC, measurable and unresectable metastatic disease according to RECIST v1.1, availability of formalin-fixed paraffin-embedded tumor specimens, an ECOG performance status of 0 or 1, and adequate organ function.

Among those enrolled, the demographics and clinical characteristics were well balanced between treatment arms. Approximately 75% of patients have liver metastases.

  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.
  2. A study of a patient-specific neoantigen vaccine in combination with immune checkpoint blockade for patients with metastatic colorectal cancer. Updated December 22, 2023. Accessed April 2, 2024.
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