Therapeutics: anticancer agent: alpelisib

Phosphoinositide 3-kinase enzymes are a group of intracellular signal transducers that phosphorylate the 3-hydroxyl group of phosphatidylinositol

Alpelisib

It is involved in the PI3K/AKT/mTor signalling pathway that is part of various metabolic and growth functions. The enzyme is believed to assist in rendering tumours insensitive to insulin and insulin-like growth factor 1 (IGF1).

Several drugs that inhibit various isoforms of PI3K enzymes are on the market and in development; alpelisib is another that is in the clinic as a targeted cancer therapy to suppress tumour growth. It is being developed by Novartis.

The drug is being tested on several types of cancer in which the PI3K pathway is activated, in combination with a variety of other cancer therapies.

For example, in a trial in oestrogen receptor positive advanced breast cancer, a condition wherein PI3K is frequently activated, it was given in combination with the selective oestrogen receptor degrader fulvestrant.

In the Phase Ib open label, single arm trial, 87 postmenopausal women whose cancer had progressed during or after antioestrogen therapy were given escalating doses of alpelisin, starting at 300 mg/day, and also fixed 500 mg doses of fulvestrant, in the dose escalation phase, and then the recommended Phase II dose plus fulvestrant in the dose expansion phase.1

The maximum tolerated dose in the combination was determined to be 400 mg, with the Phase II dose being set at 300 mg/day.

The most frequent serious adverse events were hyperglycaemia and rash, with a median progression-free survival at the maximum tolerated dose being 5.4 months. It was longer in patients with PIK3CA-altered tumours, at 9.1 months, than wild-type tumours, at 4.7 months.

The overall response rate in the altered group was 29%; there were no responses with the wild type. Novartis has also released positive early results of a Phase III trial with this combination in HR+/HER2- metastatic breast cancer via press release; it nearly doubled progression-free survival.

It has also been investigated in combination with paclitaxel in patients with advanced solid tumours. In the multicentre, open label dose finding study, 19 patients were given daily doses of 150–300 mg of alpelisib plus 80 mg/m2 paclitaxel.2

Dose limiting toxicities including hyperglycaemia and acute kidney injury led to the MTD being set at 150 mg with paclitaxel. The planned dose expansion phase was not done.

More success was achieved with the antibody-drug conjugate trastuzumab–DM1, as PI3K is an important resistance mechanism with anti-HER2 therapies.3

In all, 17 patients with metastatic breast cancer who had progressed on trastuzumab-based therapy were given daily doses of alpelisib, alongside 3.6 mg/kg of T-DM1 every 3 weeks.

The maximum tolerated dose was 250 mg, and 14 patients were evaluable for response; the objective response rate was 43%. Of those who had previously been treated with T-DM1 and progressed, it was 30%. The median progression free survival was 8.1 months. Trials continue.

References

  1. D. Juric, et al., JAMA Oncol. (2018): epub ahead of print, doi: 10.1001/jamaoncol.2018.4475.
  2. J. Rodon, et al., Oncotarget. 9, 31,709 (2018).
  3. S. Jain, et al., Breast Cancer Res. Treat. 171, 371 (2018).

Companies