Inavolisib

Inavolisib, or GDC-0077, is an investigational, highly selective inhibitor and degrader of mutant phosphatidylinositol 3-kinase (PI3K) alpha. The PI3K-mediated signalling pathway has shown to play an important role in the development of tumours as dysregulation is commonly associated with tumour growth and resistance to antineoplastic agents and radiotherapy.

Due to inavolisib’s ability to inhibit the PI3K pathway through HER2-dependent degradation, it is currently undergoing clinical trials to potentially make use of it as an antineoplastic (anti-cancer) drug to treat breast cancer.

History
Compounds that act as inhibitors for components of the PI3K signalling pathway have been of interest due to their potential in treating solid tumours. Genentech, a subsidiary of Roche, has been generating inavolisib for clinical trials and research and it is part of their oncology discovery pipeline. As of 2023, inavolisib is currently still undergoing several clinical trials such as the phase I clinical trial NCT03006172, which was started on December 13, 2016, is estimated to complete on November 30, 2024, and aims to investigate inavolisib’s safety, tolerability, and pharmacokinetics when administered orally as a “single agent in participants with solid tumours in combination with endocrine and targeted therapies in participants with breast cancer”. Another example is the phase III study NCT04191499 which is underway since January 29, 2020 and aims to additionally evaluate the efficacy and safety of inavolisib in combination with palbociclib and fulvestrant in patients that have PIK3CA-mutated, locally advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer.

On December 4, 2023, Genentech announced positive results of the phase III INAVO120 (NCT04191499) trial, showing "statistically significant and clinically meaningful" progression-free survival improvement compared to the combination of palbociclib and fulvestrant. The overall survival data were immature (at the time of the analysis) but the data showed a "clear positive trend."

Structure, reactivity, and synthesis
Inavolisib is a synthetic, organic, small compound (the full structure can be seen here). When binding to phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (p110α), inavolisib’s carbonyl group can accept a hydrogen bond from the Tyr836 (conserved) in p110α. The difluoromethyl group can interact with the hydroxyl group presented on Ser774 (conserved) in p110α, which is 3.2Å nearer than of which on the equivalent residue Ser754 in p110δ. Additionally, the amide group can interact with Gln859 (non-conserved). This results in a very high selectivity regarding PI3Kα isoforms.

Compared to similar PI3K inhibiting compounds, inavolisib has a higher thermodynamic aqueous solubility that proved advantageous in the formulation process and aiding greater consistency in predictions of absorption.

There are multiple ways in which inavolisib can be developed. One way in which it can be developed is as a derivative of 1,3-oxazole. 1,3-oxazoles are a five-membered, monocylcic heteroarens class of compounds. They contain a nitrogen and oxygen atom. The chemical structures and the biological activities are very diverse which is beneficial for pharmacological purposes.

Another way in which inavolisib can be synthesized is by means of stereo-controlled N-arylation of alpha-amino acids. It features two consecutive reactions; these are Cu-catalysed C-N coupling reactions. The route for synthesis involves multiple steps. It starts with a chemoselective Ullmann-type coupling of a chiral difluoromethyl-substituted oxazolidinone. It then also involves a Cu-catalyzed N-arylation of L-alanine which presents great stereochemical integrity. Finally, it also entails an amide bond formation step using ammonia. This final step produces inavolisib with a high yield in >99.5 area% HPLC purity.

Metabolism and biotransformation
Inavolisib is an orally administered drug, though there is little knowledge about its metabolism. However, absorption, metabolism, and excretion data of taselisib, a molecule with a related chemical scaffold, suggest moderately slow absorption into the systemic circulation, metabolism to play a minor role in drug clearance, and biliary excretion to be the main route of excretion.

Molecular mechanisms of action
Inavolisib is a selective PI3K-p110α (PIK3CA) inhibitor, which may offer antineoplastic functionality. Therefore, it may serve as a new addition to combination therapy with conventional cancer treatment, such as chemotherapy. Combining inavolisib with palbociclib and fulvestrant might improve treatment of breast cancer.

Next to its inhibitory enzymatic ability, it is suggested that inavolisib binds to - and activates degradation of - mutated forms of p110α. Members of the PI3K family regulate cellular processes such as cell growth and proliferation, survival, remodelling, and intracellular transport of organelles. PI3K also plays an essential role for the immune system.

The class I isoform PI3K alpha (PI3Kα) is often times expressed in solid tumours through gene amplification or activated mutations. Mutations in PI3Kα can often be found in cancer cells, especially HR+ breast cancer, which causes a disruption of the PI3K pathway. This leads to increased tumour growth and metastasis. One of the most common mutations can be found in PIK3CA, which plays a significant role in tumour cell proliferation.

In preclinical studies, inavolisib has shown to specifically initiate the degradation of this p110α oncogene with the help of proteasomes. After binding to the mutant PI3Kα, inavolisib blocks phosphorylation of PIP2 to PIP3, thereby stopping downstream signalling.

Consequently, biomarkers in the PI3K pathway are reduced, cell proliferation inhibited, and the rate of PIK3CA-mutant breast cancer apoptosis increased (in comparison to the wild type). The exact mechanism of action of inhibitors like inavolisib on mutated PI3Kα and the inhibitors' influence on mutant structures are still unknown.

A new study in 2022 has discovered that inavolisib inhibits the PI3K pathway via HER2-dependent inhibition.[16 ] Thus, compared to other PI3K inhibitors, inavolisib is more potent and effective at suppressing tumour proliferation. This novel category of inhibitors, which selectively degrade the mutant oncoprotein, appears to be a promising candidate for helping treat patients with HER2-positive breast cancer.

Toxicity
Since clinical trials are still underway, there is still a lot unknown about inavolisib’s toxicity. Inavolisib is able to induce a strong cytotoxic response but this is directed towards tumour cells that contain the PI3K mutation, thereby inhibiting further tumour growth and leading to cell loss.

Inavolisib shows increased selectivity, limiting the amount of non-PI3K family kinases it inhibits to only one. Further, when tested at levels of 10 μM, no human receptors (CEREP human receptor panel, n = 71) were inhibited. Similarly, against ion channels (hERG, hNaV1.5, and hCaV1.2), it showed less than 20% inhibition at 10 μM. Additionally, inavolisib did not show to be a time-dependent or reversible inhibitor of CYP450 enzymes. As a result, there appears to be an overall lack in secondary pharmacology.

Efficacy and adverse effects
When tested in cancer cell lines, inavolisib showed a strong anti-proliferative effect in cells mutated either with H1047R or E545K mutations. When combined with standard-of-care treatments (aromatase inhibitors, CDK4/6 inhibitors, oestrogen antagonist), inavolisib shows promising efficacy in PIK3CA-mutant HER2-negative tumour reduction.

While not many specifics can yet be given about inavolisib, there are general concerns and complications with PI3K pathway inhibitors. Specifically PI3Kα inhibitors (such as inavolisib) are known to cause hyperglycaemia and rash. Hyperglycaemia is connected to the p110α isozyme which is involved in the uptake of glucose through an insulin-driven mechanism in the liver, muscle and fat cells. This occurs via the translocation through glucose transporters to the plasma membrane. Inhibition of PI3Kα obstructs insulin, further preventing the uptake of glucose in fat and muscle and increasing the breakdown of glycogen in the liver. This then causes an increased release of insulin from the pancreas in an attempt to balance out the glucose levels. A consequence of increased insulin levels may be limiting the PI3K inhibitor activity and reduction of its efficacy.

In phase 3, randomized, placebo-controlled INAVO120 trial, inavolisib more than doubled the time of survival before disease progression or death from any cause when combined with palbociclib and fulvestrant against the combination of placebo, fulvestrant, and palbociclib in patients whose breast cancer has (a) PIK3CA mutation(s), tested positive with hormone receptors but negative with HER2, and has advanced locally or metastasized (mPFS: 15.0 months vs 7.3 months, hazard ratio (HR): 0.43, p-value<0.0001). Although the survival rate of the combination of inavolisib, palbociclib, and fulvestrant didn't meet the pre-specified boundary for overall survival in the first interim analysis (p-value of 0.0098 or HR of 0.592), a positive trend was observed (HR 0.64, p=0.0338). Improvement was also seen in other secondary endpoints, such as objective response rate (58.4% in the inavolisib arm vs 25.0% in the placebo arm), clinical benefit rate (75.2% vs 47.0%), and duration of response. The rate of key side effects, which are associated with PI3K inhibition, like nausea, rash, stomatitis/mucosal inflammation, hyperglycemia, and diarrhea were all greater in the inavolisib group, only a few patients experienced adverse events leading them to discontinue the treatment.