NEW YORK – The 40th Annual JP Morgan Healthcare Conference is being held virtually this week due to the ongoing coronavirus pandemic. Day four featured presentations from several firms operating in the precision oncology therapeutic space. Our coverage of presentations from day one, two, and three can be found here, here, and here.
Gritstone Bio CEO Andrew Allen shared updates on the firm's personalized neoantigen cancer vaccines, Granite and Slate, which are designed to treat immunologically "cold" tumors that may not respond to currently available checkpoint inhibitor therapy.
To accomplish this, Granite and Slate deliver personalized neoantigens — in the case of Granite the neoantigens are patient-specific, while in the case of Slate they are shared among multiple biomarker-defined tumors — to induce CD8 cytotoxic T-cell responses.
On Thursday, the Emeryville, California-based drugmaker announced that the first patient has been enrolled in the Phase II/III registration-directed clinical trial evaluating Granite combined with atezolizumab (Genentech's Tecentriq) and ipilimumab (Bristol Myers Squibb's Yervoy) as a first-line maintenance treatment for metastatic, microsatellite-stable, or MSS, colorectal cancer patients after induction chemotherapy.
Allen said Gritstone will test patients' circulating tumor DNA levels to track treatment responses in the study alongside the more traditionally used, imaging based RECIST criteria. Investigators will consider the therapy regimen to have antitumor activity in patients with at least a 50 percent decrease in ctDNA from baseline.
"[CtDNA] appears to be perhaps more reliable than RECIST radiology because we're driving T cells into lesions where we want T cells to expand when they meet their antigen," Allen explained. "Thus, measuring the lesion size may fail to capture clinical benefit if T-cell expansion is predominant within the lesion. Molecular response potentially gets us around that radiology problem."
Additionally, a Phase I/II study of Granite, which the company presented on during the European Society for Medical Oncology's annual meeting last fall, has updated overall survival data. According to Allen, the firm is now confident in that study's findings that patients' overall survival outcomes are closely related to the ctDNA decrease.
Indeed, as of Jan. 5, all the patients in the trial who were alive as of the ESMO data cutoff in August were still living. Extended overall survival results from the patients who experienced ctDNA responses were very encouraging, Allen pointed out. The trial enrolled patients with various advanced solid tumors, and among the MSS colorectal cancer patients specifically, those with ctDNA decreases following treatment with Granite continued to have an overall survival benefit. In comparison, patients whose ctDNA did not decrease on treatment did not have a survival benefit.
Beyond Granite, Gritstone expects to report Phase II data on its KRAS-dedicated Slate program in mid-2022. That "off-the-shelf" product targets neoantigens that are shared across tumors, and Gritstone is specifically studying it as a treatment for KRAS-mutated NSCLC and MSS colorectal cancer.
In 2022, Rain Therapeutics will begin new trials of the MDM2 inhibitor milademetan, its lead therapy candidate, according to CEO Avanish Vellanki. The Newark, California-based company will also unveil a drug candidate for a clinical program targeting RAD52 toward the end of the year.
The company is planning to start two milademetan studies, MANTRA-3 and MANTRA-4, in the second half of the year. In MANTRA-3, the firm will evaluate milademetan as a monotherapy in patients with Merkel cell carcinoma who are positive for the Merkel cell polyomavirus and have relapsed on checkpoint inhibitor treatment. In MANTRA-4, Rain will explore the combination of milademetan and the checkpoint inhibitor atezolizumab (Roche's Tecentriq) in patients with solid tumors with CDKN2A loss and wild-type p53.
The company has already begun enrolling patients in the Phase II MANTRA-2 basket trial evaluating milademetan in MDM2-amplified, p53-wild-type advanced or metastatic solid tumors. Vellanki is expecting early data readouts from this study in the second half of 2022.
These trials "encompass the clinical strategy for milademetan, representing wild-type p53 tumors that have unique mechanisms of MDM2 dependence," Vellanki said. "These all represent unique shots on goal."
Finally, Rain provided additional insights on its RAD52 therapeutic program. Vellanki said targeting RAD52 is synthetically lethal in tumors that express BRCA1/2 and PALB2, which offers a way to treat patients who do not respond to or have relapsed on PARP inhibitors. "We believe we're the only player in town with this RAD52 approach," he said.
After reviewing the clinical data on eprenetapopt, Aprea Therapeutics has gained a better idea of why the drug in combination with azacitidine failed to significantly increase complete remission rates in patients with TP53-mutant myelodysplastic syndromes compared to azacitidine alone. Furthermore, the company has made significant progress with the US Food and Drug Administration on the regulatory clinical holds the agency placed on the firm's other eprenetapopt studies in TP53-mutant myeloid and lymphoid malignancies, and this year it hopes to launch new studies in these settings.
Eprenetapopt, Boston-based Aprea's lead agent, is designed to reactivate the mutant tumor suppressor p53. The company announced that it failed to meet the complete remission endpoint in the Phase III MDS study back in December 2020. Out of concern for the drug's risk/benefit profile, the FDA placed a partial clinical hold on the company's program exploring the activity of eprenetapopt in TP53-mutant myeloid malignancies and placed a full clinical hold on a study of the drug in lymphoid malignancies. That made 2021 a challenging year for the company, Aprea CEO Chris Schade said, as it tried to figure out what went wrong in the Phase III MDS study and worked with the FDA to lift the clinical hold on its other trials.
Ultimately, a retrospective review of the MDS study showed that the company "narrowly missed" reaching statistical significance by failing to achieve complete remission in four patients in the experimental arm, Schade said. The endpoint miss, he said, may have been due to patients in the experimental arm receiving more dose reductions of azacitidine and having worse prognosis than patients in the control arm. Investigators weren't blinded, he noted, and therefore may have been unwilling to place sicker patients on the control arm.
After discussions with the FDA about the three myeloid trials of eprenetapopt on partial clinical hold, the company has agreed to conduct a dose optimization study of eprenetapopt in relapsed or refractory TP53-mutant MDS or AML patients. Aprea is hoping to start enrolling patients in Q2 and report results in the second half of the year, after which the firm plans to start a new randomized, controlled Phase II trial in TP53-mutant MDS.
Meanwhile, with regard to the FDA's full clinical hold on the eprenetapopt lymphoid study, Aprea has proposed to conduct a dose-optimization study in later-line non-Hodgkin's lymphoma patients and has proposed a new Phase I study in relapsed or refractory TP53-mutant Richter's transformed NHL. The FDA lifted the hold on the lymphoid program at the end of 2021. Aprea is planning to enroll the first patient in the Phase I trial in Q2 and test out an oral version of eprenetapopt in the trial.
The company was also advancing a next-generation p53 reactivator APR-548 in TP53-mutant MDS, but due to signals of ocular toxicity in preclinical models, the company decided to monitor for this adverse event in clinical studies. This made it difficult to enroll patients, and as such, Schade said the firm has decided to stop developing this drug. "At the same time, we'll be expediting the development of third-generation oral compounds," he said, adding that the firm is aiming to file an investigational new drug application for a lead molecule in Q4. "As you might anticipate, the third-generation molecule will incorporate our learnings from eprenetapopt and APR-548 … [and] balance the best features of its predecessors."
As of Dec. 31, Aprea projected it had between $50 million and $55 million in cash and cash equivalents, which it expects will fund its operations into 2023.