JCO Precis Oncol. 2022; 6: e2100370. Published online 2022 Mar...

JCO Precis Oncol. 2022; 6: e2100370.
Published online 2022 Mar 31. doi: 10.1200/PO.21.00370

Excellent research just released from the University of Colorado.....which discusses other PI3K inhibitors in development. Highly relevant information - in any discussion about Paxalisib and its potential to become the illusive much sought after, general purpose PI3K Inhibitor. (general purpose PI3K drug, is words used by a leader in the field, Jean Zhao from Harvards, Dana Farber).

It was Jeans 2016/17 study that lead to Paxalisib being selected in a Dana Farber breast brain cancer trial that started in 2019 (initial data still to be released). Subsequent to that.... Pax has been sought out for several other brain cancer studies, by the world absolute best cancer hospitals.

But will Pax work outside the brain ? and become the No 1 in this drug class. Nothing from the company and nothing from the current market to suggest that, in the least. After all these years ....of many here following this stock - nobody knows, other than to read this public information and match it up with what is known about Paxalisib.

Surely it is a dream that Paxalisib could reach such grand heights, as the general purpose PI3K drug. Problem is - read this article and kindly advise WHY not. (Instead of somebody saying, move on, if you are not happy, I might add. )

In fact, the closer you review this information... only one conclusion can be drawn. I concede much more work lies ahead, but current cap $150m verse a likely $80b with major success. Very worthwhile to read this stuff below, understand it where possible and appreciate what is at stake here.

Copanlisib and taselisib are the 2 drugs which seem mostly likely - Copanlisib PI3K-α and PI3K- does not cross BBB ----- taselisib has shown brain activity, but lacks beta (Dana Farber PI3k b to reverse loss of PTEN) . Copanlisib verse Taselisib verse Paxalisib.....would seemingly be a no race, with that big head start of CNS penetration , apparently safety mTOR, AKT and all 4 isoforms, that Pax offers..

Frustrated and not overly happy - you bet. But only a fool would move on from here.

Enjoy this great information.



CHALLENGES IN DEVELOPING EFFECTIVE AND TOLERABLE PI3K INHIBITORS
Despite the key role of PI3K in numerous tumor types, development of effective and safe PI3Ki has been a major challenge. Reasons include off-target effects of nonselective PI3Ki leading to intolerable toxicities, drug resistance because of activation of alternative oncogenic pathways, mutations in PI3K downstream effectors, or PTEN inactivation.³⁶

Pan-PI3Ki suppress activity of all PI3K class I isoforms and include buparlisib,^37-39 pictilisib,^40,41 pilaralisib,⁴² copanlisib,^43,44 PX866,^45,46 CH5132799,⁴⁷ and SF1126.⁴⁸ With the exception of copanlisib, no pan-PI3Ki have been approved for clinical use because of a lack of clinical activity and/or significant safety concerns.³⁶ One of the most extensively tested pan-PI3Ki is buparlisib, which has results available from three randomized trials in HR+/HER2– MBC.^37-39 Although it showed antitumor efficacy, including activity in brain metastases, its clinical development was abandoned because of toxicity. More than 20% of patients on buparlisib had grade ≥ 3 elevation of liver enzymes, and there were cases of severe depression leading to suicide attempts.³⁸ Another pan-PI3Ki pictilisib failed to show improvement in PFS in HR+ breast cancer, perhaps because 24% of patients in the pictilisib arm discontinued treatment and an additional 24% required dose reduction because of adverse events (AEs).⁴⁰ Development of pilaralisib, PX-866, and CH5132799 has been stopped because of lack of activity, whereas SF1126 is still in clinical trials.³⁶

Unlike other pan-PI3Ki, copanlisib is administered intravenously and has a better therapeutic index,³⁶ with hyperglycemia and nausea being the most frequent yet manageable AEs.⁴³ The drug demonstrated low incidence of high-grade GI and liver toxicity.⁴⁹ Copanlisib showed activity in patients with hematologic malignancies, breast cancer, and endometrial cancer.⁴³ Copanlisib is US Food and Drug Administration (FDA)–approved in patients with relapsed refractory follicular lymphoma irrespective of PI3K mutational status on the basis of the results of the CHRONOS-1 trial that showed durable responses in 59% of patients.⁴⁹ Copanlisib is now being studied in solid tumors and hematologic malignancies in combination with chemotherapy, antihormonal therapy, targeted agents, or immunotherapy.³⁶

Further efforts to suppress the PI3K pathway progressed primarily in two directions. To improve efficacy and overcome drug resistance, dual PI3K/mTOR inhibitors were formulated, such as apitolisib, dactolisib, and gedatolisib. Alternatively, to improve the toxicity profile, isoform selectivity was prioritized and selective inhibitors were developed, such as taselisib (inhibiting p110α, p110γ, and p110δ, but sparing the p110β isoform) and alpelisib (selective p110α inhibitor).

Dual PI3K/mTOR inhibitors, dactolisib and apitolisib, have not achieved the hoped-for clinical efficacy, mainly because of frequent dose-limiting toxicities, such as diarrhea, hyperglycemia, mucositis, and liver toxicity.^50-52 Broadening the spectrum of inhibition seemed to increase the toxicity of these inhibitors disproportionately to antitumor activity, likely because of the fundamental role of PI3K/mTOR pathway in normal tissues. Gedatolisib differs from other PI3K/mTOR inhibitors because of its intravenous administration and is better tolerated. Although studies of gedatolisib in endometrial cancer (NCT01420081)⁵³ and hematologic malignancies (NCT02438761) were terminated because of low activity, studies evaluating combinations of gedatolisib with antihormonal drugs and targeted inhibitors of HER2, poly(ADP-ribose) polymerase, and CDK4/6 are ongoing in breast cancer (NCT03911973, NCT02626507, NCT03698383) as well as lung, pancreatic, and head and neck cancers (NCT03065062).

The first selective inhibitor of PI3K (taselisib) spared the p110β subunit, while inhibiting p110α, γ, and δ. From a signaling standpoint, this approach could alleviate the severity of some AEs without sacrificing antitumor efficacy. However, a phase III clinical trial of taselisib (SANDPIPER) showed only modest activity and a challenging safety profile (diarrhea, nausea, vomiting, abdominal pain, stomatitis, fatigue, hyperglycemia, and rash),⁵⁴ leading to cessation of its clinical development.

On the basis of the strong association with RTK signaling and frequent mutations in human cancers, PI3K p110α has become the clear target for inhibition. The selective PI3K p110α inhibitor alpelisib demonstrated a manageable safety profile and prolonged PFS among patients with the PIK3CA-mutant, HR+ MBC in the phase III clinical trial SOLAR-1.⁵⁵ Main side effects were hyperglycemia, diarrhea, and rash. At a median follow-up of 20 months, PFS was 11 months (95% CI, 7.5 to 14.5) in the alpelisib-fulvestrant group compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group.⁵⁵ Alpelisib received FDA approval for the HR+ MBC in May 2019, becoming a milestone of success on the difficult path toward PI3K inhibition in cancer. Although patients with brain metastases were not included in SOLAR-1, case reports indicate potential activity of alpelisib in brain metastatic disease.⁵⁶
Given the challenges of developing effective and tolerable PI3Ki, researchers have explored inhibition of PI3K downstream effectors AKT and mTOR. A first-generation mTOR inhibitor everolimus is FDA-approved in HR+ MBC on the basis of the BOLERO-2 study,⁵⁷ whereas the second-generation mTOR inhibitor, sapanisertib, and AKT inhibitors, capivasertib and ipatasertib, are in early clinical trials. Compared with everolimus, which predominantly inhibits mTORC1, sapanisertib may have an advantage because of combined inhibition of mTORC1 and mTORC2.⁵⁸ mTORC2 directly phosphorylates AKT, and this escape pathway is suppressed by sapanisertib.⁵⁸
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CURRENT CLINICAL TRIALS OF INHIBITORS OF THE PI3K PATHWAY IN HER2+ DISEASE

Agents suppressing PI3K pathway were studied in several clinical trials in patients with HER2+ MBC (Table (Table2).2). The first-generation mTOR inhibitor, everolimus, has been tested in HER2+ disease in phase III randomized placebo controlled clinical trials BOLERO-1⁵⁹ and BOLERO-3.⁶⁰ BOLERO-1 evaluated everolimus versus placebo in combination with trastuzumab and paclitaxel as a first-line therapy for HER2+ MBC. PFS did not differ between the everolimus and placebo groups. Although in the subgroup of patients with HR-/HER2+ disease PFS was 7.2 months longer on everolimus compared with placebo, it did not meet the prespecified criteria for significance.⁵⁹ In BOLERO-3, women with HER2+ transtuzumab-resistant MBC previously treated with taxanes were randomly assigned to everolimus or placebo in combination with vinorelbine and trastuzumab. Median PFS was 7.0 months in the everolimus and 5.8 months in the placebo group (P = .0067). However, this small improvement in PFS came at the cost of increased toxicity, such as cytopenias, stomatitis, and fatigue, in the everolimus group. Serious AEs were reported in 42% of patients on everolimus and 20% of patients on placebo.⁶⁰ Both BOLERO-1 and BOLERO-3 trials were conducted in a biomarker-unselected population of patients. These trials were not practice-changing because of two possible reasons: (1) the relatively weak activity of everolimus in suppressing the PI3K pathway, with mTORC2 mediating sustained AKT activation, and (2) the absence of a biomarker selection strategy. Subsequent exploratory analysis of the combined BOLERO-1 and BOLERO-3 trials suggested that patients with HER2+ MBC with aberrant PI3K pathway activation could derive significant PFS benefits from everolimus, whereas patients whose tumors lacked such activation do not benefit from mTOR inhibition.⁶¹