In April 2024 Gritstone bio announced “positive” preliminary data from an ongoing Phase II portion of the Phase II/III study to evaluate GRANITE. GRANITE is Gritstone’s personalised neoantigen cancer vaccine and is being evaluated in front-line metastatic microsatellite stable colorectal cancer (MSS-CRC). The study is designed to quantify the clinical benefit of maintenance therapy with GRANITE in combination with immune checkpoint blockade and fluoropyrimidine/bevacizumab compared to fluoropyrimidine/bevacizumab alone.
Gritstone takes on cancer
Gritstone outlines how its founders identified that, in patients with solid tumours who respond to checkpoint inhibitors, new targets called tumour-specific neoantigens are produced. These are unique to the tumour cells and can be “recognised and targeted for destruction by the patient’s own immune system”. Although these neoantigens present a critical target, identifying them is a “key therapeutic challenge”.
“Some tumours have hundreds of mutations, but only a minority result in true tumour-specific neoantigens found on the surface of tumour cells – making them difficult to find and target appropriately.”
New progress
Gritstone “successfully manufactured” GRANITE product candidate for every eligible patient; 104 patients were randomised in the study and 67 patients were included in the treated analysis shared. 36 patients left the study before randomised treatment due to early progressive disease or withdrawal of consent, and 1 patient is yet to begin study treatment start.
Key highlights from the data include:
- Progression Free Survival (PFS) – an early trend in PFS benefit was observed for GRANITE recipients.
- Biomarker results – Circulating Tumour DNA (ctDNA) – short-term molecular response is “uninformative” but long-term ctDNA responses “align with PFS trends and favour GRANITE”.
- Safety and tolerability – GRANITE demonstrated a “favourable” safety and tolerability profile.
Encouraging results
Dr Andrew Allen, Co-founder, President, and CEO of Gritstone bio commented that the preliminary Phase II results are “highly encouraging” and “represent the first randomised trial evidence, albeit early, that a personalised neoantigen-directed vaccine can potentially drive efficacy in a metastatic ‘cold’ tumour”.
“The overall trend of PFS improvement in GRANITE recipients is great to see, and the exploratory PFS hazard ratio of 0.52 in the high-risk group, a more mature dataset, is a striking signal.”
Dr Allen reflected that “pioneering new spaces carries inherent risks”, suggesting that regarding defining molecular response, “we simply got it wrong”. As ctDNA levels in both arms “decreased on chemotherapy for longer than we anticipated”, the protocol measure of ctDNA change was “uninformative”.
“Fortunately, long-term analysis demonstrates the expected correlation of ctDNA with clinical benefit and favours GRANITE patients. 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.”
Dr Allen described the “growing body of evidence” that favours GRANITE as “exciting”, stating that it “suggests GRANITE is working in this notoriously underserved patient population”.
Dr J. Randolph Hecht, Professor of Clinical Medicine and Director of the UCLA GI Oncology Programme, is an investigator in the Phase II/III study.
“Up to 97% of patients with metastatic colorectal cancer, 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.”
Considering the preliminary results, Dr Hecht infers that GRANITE is “inducing a potentially significant immune response in a disease that has been felt to be immunologically cold”. Not only does the PFS difference, in a “poor prognosis group of patients”, indicate the “potential for clinical benefit”, but the team is learning “how to better analyse 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 tumours.”
It was great to hear more from Dr Allen at the Congress in Washington as he joined us to chair and present, and we look forward to further updates from the Gritstone team. For more like this, don’t forget to subscribe here.
