ASCO 2024: Brain Cancer Highlights
A few potential gems begin to sparkle
Each year in early June the American Society of Clinical Oncology (ASCO) holds its annual meeting in Chicago. If you have not attended, imagine a combination of the Super Bowl and a Taylor Swift concert all rolled up into one very intense week focused on “All Things Cancer”. It can be both overwhelming and physically exhausting as meetings, presentations and receptions often run from 6am to well after midnight. Whenever I attend, there is very little sleep, irregular meals and a backpack full of energy bars to get me through the day.
Usually brain cancer presentations and #Data at ASCO get lost in the enormity of the highlighted news releases associated with the larger oncology indications (lung, prostate, breast, melanoma, etc.). This year was not significantly different, but since MissionGBM is focused on brain cancer, we offer the below summaries and commentary regarding some of the more noteworthy brain cancer presentations.
Niraparib Makes a Splash in ndGBM
Niraparib (Zejula®) is a PARP inhibitor (PARPi) that has previously been approved for a number of non-brain cancer indications. PARP (Poly (ADP-ribose) polymerase) is a category of native enzymes that have evolved to repair DNA that becomes damaged by normal cell division processes or external treatment perturbations (e.g. radiation, chemotherapy). The PARP class has two principal subvariants (PARP1 and PARP2), and niraparib inhibits both. However, what makes niraparib interesting and differentiated for brain cancers is that it displays reasonable brain penetrance and pharmacology at oral dosing levels that can be tolerated by patients. Previous attempts to use PARPi’s to treat brain cancers have not been successful because (1) most PARPi are not sufficiently brain penetrant at tolerable doses; and (2) the therapeutic benefit of PARPi is really only obtainable when it is paired with a DNA damage agent (i.e. it does not well work as a monotherapy).
The Ivy Brain Tumor Center and the Barrow Neurological Institute (Phoenix) presented clinical data at ASCO that showed real promise for the combination of niraparib and RT for the treatment of ndGBM in uMGMT patients (see here and here). There are two key points that we would like to emphasize:
As we have written many times and which we validated in a thorough analysis of dozens of failed GBM trials with the brain cancer group at RA Capital, if the drug cannot get to the site of the brain tumor in sufficient concentration and dwell time to affect the targeted pharmacodynamic MoA, then the drug has ZERO chance of providing therapeutic benefit. Every serious biopharmaceutical drug developer knows this, and we can tell you from personal experience that no Development Committee at a Biopharma will advance a Development Candidate into IND-enabling studies or clinical development if the neuropharmacology #Data is absent, or is not supportive of obtaining adequate drug levels at the target. And yet, the field of clinical Neuro-Oncology, being Clinical Heavy and Science Lite, has repeatedly put drugs into patients without first doing the PK and neuropharmacology scientific work to rationally advance the drugs into patients. Uggggh!
Congratulations to Nader Sanai and the Ivy Brain Tumor Center team for designing the niraparib Phase 0/2 “trigger” trial and doing the rigorous non-clinical scientific work to understand the neuropharmacology of niraparib in the brain BEFORE blindly dosing GBM patients with yet another drug that is not very brain penetrant.
Bottom Line. Niraparib + RT should be advanced into a Phase 3 pivotal trial against an SoC Control group. Of course, making the investment decision to do so is a complicated mix of scientific, market and financial analysis conducted by the Sponsor, and is not as straightforward as the brain cancer community would like.
Dear Sponsor: If your Development Committee cannot prioritize funding of the Phase 3 trial of niraparib + RT, please get in touch. We have spent a career finding ways to solve partnering and financing challenges in order to accelerate drug development. Let’s talk and make this happen. The patients are waiting.
Shout out to the Ivy Brain Tumor Center for promoting and executing Phase 0 “Window of Opportunity” studies to quantitatively assess the PK and neuropharmacology of niraparib and other drugs for brain cancers. In the eyes of MissionGBM and experienced drug developers everywhere, you are doing things right, and providing much needed scientific leadership in a long neglected area of brain cancer science that has held back clinical development for decades.
METIS (EF-25) Phase 3 Trial of TTF in NSCLC Patients with Brain Metastases
Novocure presented the full clinical results from the Phase 3 METIS trial (see here). As we previously commented when the top line data was released, the results are intriguing (see here). Full Disclosure: We are fans of TTF when it is used in combination with therapeutic agents that catalyze and sustain TTF-induced in situ “vaccination” of the TME (see here and here). Going forward, we are hopeful that the company will (i) recognize and emphasize the true power of TTF to unlock synergistic combination MoAs (instead of purely emphasizing the historical cytodyskinesis monotherapy theory); (ii) conduct high quality scientific investigations that incorporate leading edge molecular biology to rigorously describe the most effective TTF-driven MoAs, and thereby, overcome the significant “pseudo-science” overhang that is holding back adoption of TTF by many brain cancer centers; and (iii) design future clinical trials and partnerships to accelerate the most effective TTF-driven MoAs even it means that the company has to share development control with other organizations that have a proven track record of efficient combination drug/device clinical development.
Interim report of a Phase 2 study of sonodynamic therapy (SDT) using SONALA-001 together with MR-guided low-intensity focused ultrasound (MRgFUS) in children with diffuse intrinsic pontine glioma (DIPG) (see here)
We continue to be intrigued by the promise of Sonodynamic Therapy (SDT); albeit the non-clinical and clinical #Data that we have reviewed to date as part of our syndicated investment activities have not been compelling enough to write a check. Nonetheless, we remain open-minded about the approach, and have periodically considered it as potential rGBM treatment for Julie when she eventually progresses. It is worth noting that the most compelling clinical #Data that we have seen to date has come from H3-mutant HGGs such as DIPG and DMG, which was the subject of the linked ASCO presentation. The #Data for non-H3-mutant HGGs (GBM, Grade 3/4 Astrocytomas) has not yet been as convincing. We think regularly about how to construct a viable investment case for SDT (or other therapeutic agents) in H3-mutant gliomas despite the very small number of affected patients. There has to be a way forward, if we work together to construct it.
We should point out that we have a deep background from our MIT/MGH days with related photodynamic therapy (PDT) using pulsed micro- and nanosecond lasers as well as picosecond time-resolved laser spectroscopy to quantitatively measure delta singlet oxygen and other reactive oxygen species induced by laser light in the presence of photosensitizers (see here, here and here). So hand-waving explanations of the SDT MoA do not cut it with us. We remain hopeful that companies working in the SDT space will conduct the rigorous science to elucidate the cytotoxic MoA of SDT and its potential synergistic linkage to immune system response.
A Phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients with recurrent high-grade glioma or uveal melanoma (UM) (see here)
The MissionGBM cohort has several MTAP dual-deletion GBM patients, who could potentially benefit from treatment with a brain-penetrant PRMT5 inhibitor, particularly in combination with a brain-penetrant CDK4/6 inhibitor. We have invested lots of time talking with a few (Bio)Pharma Chief Scientific Officers on behalf of MGBM patients in order to assess the possibility of conducting such a combination clinical study, or gaining use via Expanded Access (aka Compassionate Use) programs. It has been frustratingly slow because the current Regulatory framework virtually demands a single agent RCT prior to the design and conduct of a combination study. Sponsors simply cannot risk the ire of the FDA or the complication of a mandated and expensive factorial combo-vs-the-parts trial as their first clinical campaign. Thus, we wait – Uggggh!
While development of PRT811 has been discontinued by Prelude Therapeutics, we would advise that readers keep and eye on the development programs for Amgen’s AMG193 (see here and here) and TNG908 and TNG462 (Tango Therapeutics; see here).
Outcomes and immune response after peptide vaccination targeting human cytomegalovirus (CMV) antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma (see here)
It has been observed for a long time that the TME in brain tumors often stains positive for CMV-associated proteins. A spirited “chicken-versus-egg” debate continues apace regarding whether CMV plays a role in glioma initiation/progression -versus- CMV shows up later in the TME because the high degree of immunosuppression enables CMV to set up residence (just about all adults have been exposed to CMV). We all know that correlation does not equal causation, but there has not been definitive #Data reported to date to resolve the argument.
Nonetheless, there is no dispute regarding the potent immuno-inflammatory action of CMV antigen pp65, which is a known “Danger Signal” to the human innate immune system. Immunizing and subsequently boosting a human subject with a pp65 “vaccine” causes rapid and significant immune responses, which can often spiral out of control into high grade AEs requiring ICU admission, pressor support and a near-death experience. We have a couple of adult MissionGBM members who have come to us after receiving pp65 vaccines within Phase 1 clinical studies resulting in severe irAEs requiring months of recovery/salvage therapy (again – Where is the rigorous pre-clinical #Science, Neuro-Oncology community?). Thus, we read with interest the linked ASCO presentation in HGG and medulloblastoma. Of interest, the patient cohort was comprised of children and young adults, who typically have not had as much native exposure to CMV, and thus, tend to have less severe immunological reactions to CMV pp65 vaccines, which renders such an approach potentially safe enough to deploy clinically in younger patients after much more careful development.
On a related matter, the broader MissionGBM team has been involved in detailed conversations to determine whether a quite promising pp65 mRNA GBM vaccine approach (see here and here) can be developed to the point at which it can be safely tested in human clinical studies for adult HGG patients. It has been gratifying to connect our network of experts in mRNA cancer vaccines and the elucidation/mitigation of irAEs with the Sponsors in order to catalyze discussion and potential collaboration in the service of brain cancer patients. Stay tuned.
A Phase 0/1 trigger trial of BDTX-1535 in patients with recurrent high-grade glioma (HGG) with EGFR alterations or fusions (see here)
While we support the Phase 0/1 study designs that the Ivy Brain Tumor Center team is conducting, one simply cannot make a silk purse out of a sow’s ear. BDTX-1535 targets EGFR in HGG patients, which means that it will (i) show a transient depletion of EGFR-positive cells in HGG patients; and (ii) do nothing to alter the ultimate clinical course and mOS of the patients. Why? Because EGFR in HGG cells is principally resident on ecDNA, which will disappear quickly under therapeutic pressure, and confer a competitive advantage to the non-EGFR-positive cancer cells in the TME. We are growing weary of repeatedly advising against EGFR-targeted monotherapies in HGGs (see here and here…and just about every other post on MissionGBM). Doing the same thing over-and-over-again and expecting a different outcome is a sure path to bankruptcy. Dear Sponsor: Please suspend clinical development of BDTX-1535 for GBM right away, and reallocate the precious capital and patients to other programs until a brain-penetrant ecDNA pathway inhibitor can be advanced into the clinical to be used in combination protocols with a brain-penetrant EGFRi.