Preliminary Data Hint at PFS Benefit With Personalized Neoantigen Vaccine in Metastatic MSS CRC

The addition of the personalized neoantigen cancer vaccine GRANITE (GRT-C901/GRT-R902) to maintenance therapy with ipilimumab (Yervoy) and atezolizumab (Tecentriq) plus 5-flourouracil (5-FU) and bevacizumab (Avastin) following induction therapy with FOLFOX or FOLFOXIRI plus bevacizumab showed an early trend in progression-free survival (PFS) benefit vs induction therapy followed by maintenance 5-FU and bevacizumab alone in patients with metastatic microsatellite stable colorectal cancer (MSS-CRC), according to topline data from the ongoing phase 2 portion of a phase 2/3 study (NCT05141721).^1,2

At a data cutoff of March 8, 2024, treatment with GRANITE (n = 39) led to an 18% reduction in the risk of disease progression or death vs the control (n = 28) in all patients (HR, 0.82; 95% CI, 0.34-1.67) and a 48% reduction in the risk of disease progression or death in high-risk patients (HR, 0.52; 95% CI, 0.15-1.38). In the latter population, in which over 90% of patients had liver metastases, the median PFS was 11.57 months (95% CI, 7.36-not available [NA]) with GRANITE vs 7.06 months (95% CI, 2.04-NA) with the control.²

Circulating tumor DNA (ctDNA) was also evaluated. At a data cutoff of March 12, 2024, results showed that more high-risk patients in the GRANITE arm achieved low variant allele frequency (≤2 %) from the time of random assignment to the most recent study visit vs those in the control arm, at 56% (n = 9/16) and 22% (n = 2/9), respectively. Moreover, fewer patients in the GRANITE arm experienced progressive disease vs those in the control arm (44% vs 78%).¹

Additionally, a higher percentage of patients whose ctDNA was negative after induction chemotherapy were able to sustain undetectable levels of disease with GRANITE vs the control, at 67% (n = 6/9) vs 38% (n = 3/8), respectively. The rates of progressive disease were 11% (n = 1) and 38% (n = 3) with GRANITE and the control, respectively.

“Today’s preliminary phase 2 results are highly encouraging and represent the first randomized trial evidence, albeit early, that a personalized neoantigen-directed vaccine can potentially drive efficacy in a metastatic ‘cold’ tumor. The overall trend of PFS improvement in GRANITE recipients is great to see, and the exploratory PFS HR of 0.52 in the high-risk group, a more mature dataset, is a striking signal,” Andrew Allen, MD, PhD, cofounder, president, and chief executive officer of Gritstone bio, said in a press release.

“Pioneering new spaces carries inherent risks, and with regard to defining molecular response, we simply got it wrong. ctDNA levels in both arms decreased on chemotherapy for longer than we anticipated, generating similar short-term molecular response rates across arms and rendering our protocol measure of ctDNA change uninformative. Fortunately, long-term analysis demonstrates the expected correlation of ctDNA with clinical benefit and favors GRANITE patients," Allen said. "We believe these preliminary findings put us in a strong position to share mature PFS data in the third quarter [of 2024] and then enter regulatory discussions regarding phase 3 [research]. 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.”¹

The registrational study enrolled patients with previously untreated metastatic MSS-CRC who were eligible for standard-of-care therapy with FOLFOX or FOLFOXIRI plus bevacizumab. In the investigational arm, patients received induction chemotherapy and underwent GRANITE vaccine manufacturing, after which patients received maintenance chemotherapy with 5-FU plus bevacizumab, GRANITE, ipilimumab, and atezolizumab. In the control arm, patients received induction chemotherapy followed by maintenance chemotherapy with 5-FU plus bevacizumab.^2,3

A total of 104 patients were randomly assigned 1:1 to treatment with GRANITE vs the control, 36 of whom withdrew from the study prior to the randomized portion because of early disease progression or change in consent.²

The primary end points of the phase 2 portion of the study are molecular response, PFS, overall survival (OS), and safety.

Baseline demographics and clinical features were balanced between the treatment arms in terms of stage, sidedness, and presence of liver metastases.

Regarding safety, GRANITE was well tolerated. Most adverse effects (AEs) were grade 1 or 2 and presented as mild systemic and local effects that are commonly associated with vaccinations. Additionally, no patients discontinued therapy because of an AE.

“Up to 97% of patients with metastatic CRC, the second most common cause of cancer death, are MSS. Unlike patients with melanoma and lung cancer, they have not benefited from standard immunotherapies, such as checkpoint inhibitors. These preliminary results indicate that GRANITE is inducing a potentially significant immune response in a disease that has been felt to be immunologically cold,” J. Randolph Hecht, MD, professor of clinical medicine and director of the UCLA GI Oncology Program, said in the press release.¹

“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" Hecht added. "Expanding the scope of immunotherapy to a broader spectrum of cancer patients 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.”

Mature PFS and OS data in all patients are expected in the third quarter of 2024 and the first half of 2025, respectively.²

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. April 1, 2024. Accessed April 2, 2024. https://ir.gritstonebio.com/news-releases/news-release-details/gritstone-bio-announces-positive-preliminary-progression-free
2. Preliminary phase 2 randomized data evaluating GRANITE, a neoantigen-directed personalized cancer vaccine, in patients with front-line metastatic MSS-CRC. Gritstone bio. April 1, 2024. Accessed April 2, 2024. https://ir.gritstonebio.com/static-files/d61b6379-09d9-4051-9505-ea1baf8f880e
3. 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 April 2, 2024. https://clinicaltrials.gov/study/NCT05141721