Kantar Health Blog

PI3 Kinase Inhibitors Provide Another Opportunity to Serve an Unmet Need; This Time It’s Endometrial Cancer

by User Not Found | Mar 26, 2012

Unmet needs often drive innovation in oncology, as shown by the success of two paradigm-changing drugs for metastatic melanoma:   Yervoy™ (ipilimumab, Bristol-Myers Squibb) and the tyrosine kinase inhibitor (TKI) Zelboraf® (vemurafenib, Roche).  Yervoy has kicked off the era of immunotherapy that is clearly active not only in melanoma but also potentially in a wide range of other cancers.  Zelboraf started the era of personalized medicine in melanoma when the drug was approved for patients whose tumors have a BRAF mutation. Because both drugs serve a disease state with high unmet need, the manufacturers are able to command a premium price (as illustrated in a previous blog, High Unmet Need in Hodgkin’s Disease Warrants High Price for Adcetris®), with Yervoy costing approximately $30,000 per injection for a maximum of four injections and the orally available Zelboraf costing approximately $9,400 for a 30-day supply. 

A biomarker-defined population like BRAF-mutated melanoma opens up another set of unmet needs since nearly all patients will eventually develop resistance to Zelboraf. Agents such as MEK inhibitors and PI3K inhibitors have gained attention as possible targets to overcome resistance to Zelboraf. Monotherapy and combination studies of MEK and PI3K inhibitors as well as BRAF with MEK inhibitors are currently ongoing. A further review of unmet needs in oncology being targeted by novel technologies can be found in the article “After an Eventful 2011, What’s in the Pipeline for Emerging Technologies in Oncology?” published in the March 2012 issue of OBR Green.

An unmet need in oncology that has not received much attention is one being targeted by manufacturers with a PI3K in their pipelines:  advanced or recurrent endometrial cancer.  To date, this disease has received little attention from manufacturers, who often focus in ovarian cancer – if they have any interest in gynecological cancers at all – since it is a larger population. Development in ovarian cancer has gone through a bit of a renaissance with the observation that it is particularly sensitive to VEGF-targeted agents. To date endometrial cancer has really only been sensitive to standard, blunt chemotherapy, contributing to it being a relatively unattractive market to manufacturers.

PIK3CA and PTEN mutations are common in endometrial cancers (Catasus, Modern Pathology, 2009), perhaps making the disease exquisitely sensitive to PI3K inhibitors. mTOR inhibitors, which hit a pathway related to PI3K, have already shown some activity in endometrial cancer (Mackay, ASCO 2011, Abstract 5013; Slomovitz, ASCO 2011, Abstract 5012; Oza, JCO, 2011), though the data likely will be insufficient for approval. At least 16 Class I PI3K inhibitors are in clinical development, but some differentiation exists between them – some are pan-PI3K inhibitors, some are isoform-specific inhibitors and some are dual PI3K and mTOR inhibitors. A more comprehensive review of PI3K inhibitors can be found in the article “PI3K Inhibitors: A Promising New Class of Cancer Therapeutics?” published in the July 2011 issue of OBR Green.  Notably, several PI3K inhibitors are currently in Phase I/II trials in endometrial cancer, with many of the trials evaluating tumor samples to determine whether the drugs respond best in patients with aberrant PIK3CA or PTEN.

Ongoing Phase II Trials with Experimental PI3K Pathway Inhibitors
in Endometrial Cancer

Drug

Target

NCT code

Sponsor

Est. enrollment/ primary endpoint

Tissue for pathway analysis

PF-04691502 or PF-05212384

PI3K/mTOR

NCT01420081

Pfizer

252 / CBR

Yes

MK-2206

AKT

NCT01312753

non-industry

90 / PFS

Yes

MK-2206

AKT

NCT01307631

non-industry

90 / PFS

Yes

BKM120

pan PI3K

NCT01289041

Novartis

140 / ORR

Yes

XL147

PI3K

NCT01013324

Sanofi

88 / PFS

No

BEZ235

PI3K/mTOR

NCT01290406

Novartis

140 / ORR

No

PI3K inhibitors, one of the hottest areas of development, have the potential to personalize therapy for endometrial cancer much like what occurred with melanoma in 2011; non-small cell lung cancer before that; colorectal cancer before that; and breast cancer before that. By having an active drug in an underserved, potentially biomarker-defined population like endometrial cancer, these developers will enjoy rapid uptake and a premium pricing.

Leave a comment