On September 30, 2024 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company working to develop the world’s most potent vaccines, reported encouraging interim Phase 2 data from the ongoing Phase 2 study evaluating GRANITE, its individualized neoantigen targeting immunotherapy, in frontline microsatellite stable colorectal cancer (MSS-CRC) (Press release, Gritstone Bio, SEP 30, 2024, View Source [SID1234646924]). The randomized, controlled study is designed to evaluate the clinical benefit of maintenance therapy with GRANITE (GRT-C901/GRT-R902) in combination with immune checkpoint inhibitors in addition to fluoropyrimidine/bevacizumab versus fluoropyrimidine/bevacizumab alone.
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Overall progression-free survival (PFS) data show an encouraging benefit for GRANITE patients (HR=0.79 [95% CI, 0.42-1.50]). As expected, the greatest benefit was observed in the 50% of patients with lower disease burden at study entry, as measured by circulating tumor DNA (ctDNA) at study baseline. (HR=0.62 [95% CI, 0.23-1.70]). Continued follow-up is needed to fully assess GRANITE effects and determine whether a plateau of improved PFS (indicating durable clinical benefit) is achieved. The most recent ctDNA assessments for the 20 patients who remain without disease progression (per RECIST) were supportive of potential benefit from treatment with GRANITE: 12 of 13 GRANITE patients had stable ctDNA titers below the assay limit of quantitation (LOQ); 4 of 7 control patients exhibited the same characteristic.
"We are excited by the potential of GRANITE to extend both progression-free and overall survival in a disease where relentless progression is the rule with existing therapies," said Andrew Allen, MD, PhD, Co-Founder, President & CEO of Gritstone bio. "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. Success for immunotherapy typically manifests as an elevated plateau in PFS and overall survival 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 opportunity for even greater effects in tumors more typically amenable to immunotherapy."
Dr. Allen continued, "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."
Concurrently, Gritstone announced that it has engaged Raymond James as its financial advisor to support the Company in exploring and reviewing potential value-maximizing strategies. Gritstone does not intend to discuss or disclose further developments regarding the exploration of strategic alternatives unless and until its Board of Directors has approved a definitive action or otherwise determined that further disclosure is appropriate or required by law.
Key Findings from Interim Phase 2 Data in Front-Line Metastatic MSS-CRC
Data cut as of August 19, 2024
104 patients were randomized 1:1 in the study: 69 patients (39 GRANITE arm, 30 control arm) are included in the treated analysis below. Demographics and clinical characteristics were balanced between arms (stage, sidedness, presence of liver metastases), with the vast majority (80%) of patients having liver metastases in the treated analysis. Thirty-five patients did not advance to study treatment after oxaliplatin, most commonly due to withdrawing consent (n=15), disease progression (n=8), and other reasons (n=12) (12 in GRANITE arm; 23 in control arm).
Interim data demonstrated an emerging PFS benefit to all GRANITE recipients (study not statistically powered for PFS)
21% relative risk reduction of progression or death with GRANITE vs. standard of care (SOC) control in all treated population (HR=0.79 [95% CI, 0.42-1.50])
33% (13/39) GRANITE and 23% (7/30) of control patients remain on study and free of progression
Last ctDNA assessment is below the assay LOQ in 12/13 GRANITE and 4/7 control patients
Clinical benefit was most notable in patients with low disease burden (defined as patients with ctDNA equal to or below the trial population median value at study entry)
38% relative risk reduction of progression or death with GRANITE vs. SOC control with low ctDNA subgroup (HR=0.62 [95% CI, 0.23-1.70])
Low baseline ctDNA is a likely prognostic and predictive factor
Immune data were consistent with clinical activity
Functional neoantigen-specific T cells were observed in all 16/16 GRANITE patients tested by ELISPOT
Association of PFS and peak ex vivo ELISPOT responses was apparent, suggesting that ex vivo ELISPOT may be a surrogate for PFS
GRANITE demonstrated a favorable safety and tolerability profile
No patients discontinued study treatment due to an adverse event (AE)
Common adverse events were the mild systemic and local effects associated with any potent vaccine, i.e. transient flu-like illness
One treatment-related serious AE (fatigue) occurred in the GRANITE arm (patient continued GRANITE treatment without recurrence upon recovery)
Gritstone plans to review the PFS data with FDA in the coming months and agree on next steps to advance GRANITE, including a potential Phase 2 or 3 trial using ctDNA levels as eligibility criteria.