PI3K Inhibitors: A Promising New Class of Cancer Therapeutics?

By Tatiana Spicakova, PhD – Associate Consultant, CancerMPact®, Head of Emerging Technologies, Kantar Health

Targeted therapy has revolutionized the way cancer is treated and manufacturers continue to invest substantial resources in the development of new technologies, of which phosphoinositide-3 kinase (PI3Ks) inhibitors, either alone or in combination with MEK inhibitors, appear as the most promising next wave of targeted therapeutics.

Aberrant PI3K signaling has a known role in carcinogenesis, caused by several mechanisms such as activation of the upstream receptor tyrosine kinase, overexpression or mutational activation of PI3K, or mutational inactivation or loss of phosphatase and tensin homolog (PTEN, a negative regulator of PI3K). Given the importance of activated PI3K signaling in cancer, Class I PI3Ks are currently one of the hottest drug targets in oncology, with several small molecules in early stages of clinical development.

Given the number of PI3K inhibitors entering the clinic, selecting the right therapeutic area will be key for companies to ensure successful market entry. Preclinical data provide some guidance as to which tumor types might be sensitive to PI3K inhibition. For example, preclinical models suggest that breast tumors harboring HER2 amplifications require PI3K signaling after acquiring resistance to anti-HER2 therapies. Hence, a combination of PI3K inhibitors with Herceptin® (trastuzumab, Roche) may result in an effective therapy in this patient population. Recognizing the opportunity for PI3K inhibitors in breast cancer, several companies have initiated clinical trials in this tumor type: XL147 (Exelixis/sanofi-aventis) is in a Phase I/II trial in combination with Herceptin or Herceptin plus paclitaxel; GDC-0941 (Genentech/Roche) is in Phase I trial in combination with trastuzumab-DM1 (an antibody-drug conjugate) and in combination with paclitaxel and Avastin® (bevacizumab, Genentech/Roche); and BKM120 (Novartis) is in Phase I/II trial in combination with Herceptin and a Phase I trial combined with BEZ235 (Novartis) and paclitaxel with or without Herceptin.

Non-Small Cell Lung Cancer (NSCLC) is also likely to emerge as a therapeutic area of interest for PI3K inhibitors. It was previously shown that NSCLC tumors can become resistant to EGFR-targeted inhibitors via activation of or maintaining downstream PI3K signaling. Hence, these tumors represent an attractive opportunity for PI3K inhibitors either following progression on EGFR-targeted agents or in combination with EGFR-targeted agents in earlier settings. Not wasting any time, Genentech/Roche initiated a Phase I trial to evaluate GDC0941 in combination with Tarceva® (erlotinib, OSI/Astellas/Genentech/Roche) in NSCLC patients previously treated with chemotherapy, and Exelixis initiated Phase I trials to evaluate XL147 or XL765 in combination with Tarceva in NSCLC patients previously treated with Tarceva or Iressa® (gefitinib, AstraZeneca). Determined to lead the race, Novartis plans to open a Phase II trial to evaluate BKM120 in metastatic NSCLC with activated PI3K pathway. Unlike XL147, the drug will not be used in combination with Tarceva; instead, patients with squamous histology will either receive BKM120 or docetaxel, and patients with non-squamous histology will receive either BKM120 or docetaxel or Alimta® (pemetrexed, Eli Lilly).

Selection of other tumor types will likely depend on whether the tumors are known to harbor PI3K mutations/amplifications or PTEN mutations/deletions such as endometrial or brain tumors. Comprehensive mutational analysis of tumors from patients enrolled in PI3K inhibitor clinical trials and stratification by mutation status will be key in teasing out which genetic abnormalities are most likely to result in meaningful clinical outcomes.

Although the majority of PI3K inhibitors are under development in solid tumors, hematological malignancies also represent a therapeutic area of interest, especially for isoform-specific PI3K inhibitors. For example, constitutive activation of PI3K signaling pathway is commonly found in acute myeloid leukemia (AML), with the p110d isoform always expressed. In acute promyelocytic leukemia (APL), both p110d and p110b isoforms are expressed. Interestingly, activating mutations in the p110a catalytic subunit – that are commonly present in solid tumors – have not yet been identified in AML. Given the importance of p110d and p110b isoforms in hematological malignancies, p110d isoform specific inhibitors such as AMG319 (Amgen) and CAL101 (renamed as GS1101 following acquisition of Calistoga Pharmaceuticals by Gilead Sciences) could potentially have efficacy and safety advantages over pan-PI3K inhibitors. Acting on the evidence for the role of PI3K in hematological malignancies, Amgen plans to evaluate AMG319 in a Phase I trial in relapsed/refractory lymphoid malignancies, with the expansion cohort enrolling patients with chronic lymphocytic leukemia (CLL).

Calistoga Pharmaceuticals, acquired by Gilead Sciences earlier this year, is so far leading the race of isoform-specific PI3K development with several clinical trials ongoing in hematological malignancies. Calistoga initiated the clinical development of CAL-101 in relapsed/refractory hematological malignancies, and currently offers patients who are deriving benefit with CAL-101 the opportunity to continue treatment. Following Calistoga’s acquisition, Gilead appears to fully support the development of CAL-101 in hematological malignancies. A Phase I trial is evaluating the compound in combination with chemotherapy and CD20-targeted antibody in relapsed/refractory indolent B-cell non-Hodgkin’s lymphoma (NHL) or CLL; a different Phase I trial is evaluating CAL-101 monotherapy in previously untreated low-grade lymphoma; a Phase II trial is evaluating CAL-101 in combination with Rituxan® (MabThera® in Western Europe, rituximab, Biogen Idec/Genentech/Roche) in elderly patients with previously untreated CLL or small lymphocytic lymphoma (SLL), and a Phase II trial is evaluating CAL-101 in indolent B-cell NHL. Calistoga was also developing CAL-120, a dual inhibitor of p110d and p110b, which was expected to enter Phase I development in solid tumors based on the emerging role of p110b isoform in PTEN null tumors, but following the acquisition, it has not been disclosed whether Gilead still plans on taking CAL-120 into clinical development.

The excitement surrounding PI3K inhibitors was certainly evident at this year’s ASCO where data from early clinical development were presented for all 3 categories of PI3K inhibitors: (1) pan-PI3K inhibitors that target all p110 isoforms; (2) isoform-specific PI3K inhibitors that target a specific p110 isoform; and (3) PI3K/mTOR dual inhibitors that inhibit all p110 isoforms as well as mTOR.

To learn more about the presented safety and preliminary efficacy data, please refer to the full article in the July issue of OBR green.

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  1. PX-866 has been reviewed by Kantar Health and is included in the article we created for the July issue of OBR Green. To view the full article, please click here: http://www.oncbiz.com/journal-obrgreen-201107.php and go to page 16.

    Pathway Therapeutics received funding at the end of May 2011 to conduct a Phase I on PWT33597 (PI3Kalpha/mTOR inhibitor); we will continue to monitor its progress as well as the other isoform-specific inhibitors in preclinical development by Pathway Therapeutics.

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