The complex balance of PI3K inhibition

Abstract

Phosphatidylinositol 3-kinase (PI3K) has all the characteristics of an appealing therapeutic target for breast cancer (BC): it is a targetable enzyme, and the catalytic subunit of one of its isoforms p110α (encoded by the PIK3CA gene) is the most frequently altered oncogene in BC. In fact, activating mutations of PIK3CA are present in 30% of advanced, hormone receptor-positive (HR+) disease.1Bertucci F. Ng C.K.Y. Patsouris A. et al.Genomic characterization of metastatic breast cancers.Nature. 2019; 569: 560-564Crossref PubMed Scopus (212) Google Scholar Despite a strong rationale and huge scientific efforts undertaken to develop PI3K inhibitors, relevant clinical results have been difficult to deliver, as underscored by the report in this issue of Annals of Oncology from Dent et al. of the SANDPIPER randomized clinical trial.2Dent S. Cortés J. Im Y.-H. et al.Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial.Ann Oncol. 2021; 32: 197-207Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was the first drug inhibiting the PI3K/AKT/mTOR pathway to be approved in HR+ advanced BC in 2012. It was shown to improve progression-free survival (PFS) with an impressive hazard ratio (HR) of 0.45, regardless of genomic alterations when given with exemestane in patients with hormone-resistant disease, but failed to significantly improve overall survival and adverse events (AEs) led to treatment discontinuation in 19% of patients.3Baselga J. Campone M. Piccart M. et al.Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer.N Engl J Med. 2012; 366: 520-529Crossref PubMed Scopus (2044) Google Scholar,4Treilleux I. Arnedos M. Cropet C. et al.Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer.Ann Oncol. 2015; 26: 120-125Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar After these important results, development of PI3K inhibitors was eagerly expected. Unfortunately, these drugs were, from the onset, crippled by a poor therapeutic index and AEs reflecting the importance of PI3K signaling in most normal cells. The first generation of PI3K inhibitors, the pan-class I PI3K inhibitors pictilisib and buparlisib, were particularly impacted by these dose-limiting toxicities, mostly transaminitis, hyperglycemia, rash and mood alterations.5Di Leo A. Johnston S. Lee K.S. et al.Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2018; 19: 87-100Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 6Krop I.E. Mayer I.A. Ganju V. et al.Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Oncol. 2016; 17: 811-821Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 7Campone M. Im S.-A. Iwata H. et al.Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: Overall survival results from BELLE-2.Eur J Cancer. 2018; 103: 147-154Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 8Baselga J. Im S.-A. Iwata H. et al.Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 904-916Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar Although development of both drugs was discontinued, pictilisib for insufficient efficacy and buparlisib for excessive toxicity, clinical trial data suggested that meaningful improvement in PFS would be mostly restricted to patients with somatic PIK3CA mutations. The second generation of PI3K inhibitors was developed to be more selective for specific isoforms of PI3K. This led to successful development of the p110γ- and/or δ-specific duvelisib and idelalisib in chronic lymphocytic leukemia and other hematological malignancies.9Flinn I.W. O'Brien S. Kahl B. et al.Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies.Blood. 2018; 131: 877-887Crossref PubMed Scopus (133) Google Scholar,10Furman R.R. Sharman J.P. Coutre S.E. et al.Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.N Engl J Med. 2014; 370: 997-1007Crossref PubMed Scopus (1275) Google Scholar Isoform-specific inhibitors of p110α were developed to improve therapeutic index in PIK3CA-mutant tumors as compared with pan-PI3Ki. The two pioneering compounds are alpelisib (highly specific for the P110α isoform) and taselisib (sometimes referred as β-sparing, inhibiting p110α, p110-γ and p110-δ, 30-fold more than p110β11Juric D. Krop I. Ramanathan R.K. et al.Abstract LB-64: GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human phase Ia dose escalation study.Cancer Res. 2013; 73 (LB-64)Google Scholar). Both showed promising results in early phase clinical trials, especially in PIK3CA-mutant tumors, and were rapidly brought forward in phase III trials in combination with fulvestrant (versus fulvestrant and placebo): alpelisib in the SOLAR-1 trial12André F. Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC).Ann Oncol. 2020; 31: S1142-S1215Google Scholar,13André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.N Engl J Med. 2019; 380: 1929-1940Crossref PubMed Scopus (711) Google Scholar and taselisib in the SANDPIPER trial. These trials are strikingly similar in design: they included a similar population of aromatase inhibitor pretreated, HR+, human epidermal growth factor receptor 2-negative advanced BC patients, with no prior exposure to mTOR-inhibitors (and few patients had received CDK4/6 inhibitors at the time of inclusion). Investigator-assessed PFS in the PIK3CA-mutant cohort was the primary endpoint in both studies. SOLAR-1 aimed for an HR of 0.65 in favor of alpelisib, while SANDPIPER aimed for an HR of 0.70 in favor of taselisib. Comparisons of two independent trials should always be cautious, but despite different definitions of endocrine sensitivity (patients with a documented clinical benefit from the most recent endocrine treatment in the metastatic setting are considered as ‘hormone sensitive’ in the SANDPIPER trial while they are ‘secondary resistant’ in the SOLAR-1 study), the median PFS of the control arm is quite similar in the two studies. However, although the initial benefit seems similar, absolute differences favor SOLAR-1 over SANDPIPER (median PFS increased from 5.7 to 11 months versus 5.4 to 7.4 months, respectively). Furthermore, the curves for the two arms of the SANDPIPER study converged after 8 months, leading the authors to conclude that the benefit was not clinically meaningful. How can we explain these results? First, despite increased isoform specificity, the spectrum of AEs remains, in most cases, consistent with PI3K inhibition and includes hyperglycemia, gastrointestinal disorders (diarrhea, nausea, stomatitis), rash, pneumonitis, while other AEs are less specific like headache and asthenia. These AEs have a direct effect on exposure and efficacy. In a retrospective analysis of SOLAR-1, dose-reductions following protocol recommendations for toxicity management were associated with decreased efficacy. The median alpelisib dose intensity was 248 mg/day (versus 300 mg/day starting dose), and median PFS decreased from 12.5 to 9.6 months for patients receiving ≥248 mg/day versus those receiving <248 mg/day, respectively.14Rugo H.S. André F. Yamashita T. et al.Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.Ann Oncol. 2020; 31: 1001-1010Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar A similar safety/dose-intensity/efficacy correlation may exist for taselisib, and, as a consequence, only a small difference in the therapeutic index of these two compounds may explain the observed significant differences in clinical utility of both drugs. This reminds us that despite strong scientific rationales and high expectations, clinical trials are required to assess the true value of any new drug. These results also raise the issue of long-term tolerability, which is often not adequately captured during early phase trials where drug exposure is often short and the patients' motivations may lead to an underestimation of toxicity. How can we move forward? As theses toxicities are mostly ‘on target’, it is unlikely that we will gain much by new, more isoform-selective drugs. Only innovative mutant-selective inhibitors, sparing the wild-type enzyme, are likely to improve the therapeutic index significantly, as shown with osimertinib and sotorasib in EGFR-mutant and KRAS G12C-mutant non-small-cell lung cancer, respectively.15Hong D.S. Fakih M.G. Strickler J.H. et al.KRASG12C inhibition with sotorasib in advanced solid tumors.N Engl J Med. 2020; 383: 1207-1217Crossref PubMed Scopus (324) Google Scholar,16Soria J.-C. Ohe Y. Vansteenkiste J. et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018; 378: 113-125Crossref PubMed Scopus (1965) Google Scholar By contrast, higher therapeutic index can be achieved by better toxicity management and patient selection.17Hortobagyi G.N. Opportunities and challenges in the development of targeted therapies.Semin Oncol. 2004; 31: 21-27Crossref PubMed Scopus (27) Google Scholar Indeed, the incidence of alpelisib-related grade 3 hyperglycemia and rash can be halved when practice guidelines are used to manage these specific AEs.10Furman R.R. Sharman J.P. Coutre S.E. et al.Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.N Engl J Med. 2014; 370: 997-1007Crossref PubMed Scopus (1275) Google Scholar With regard to patient selection, subgroup analyses of the SANDPIPER study suggest that patients with detectable PI3KCA mutation in circulating tumor DNA (ctDNA) at baseline (78% of patients with PIK3CA-mutant tumors) and those with two or more detectable PIK3CA mutations in ctDNA may derive more benefit from PI3K inhibitors.18Vasan N. Razavi P. Johnson J.L. et al.Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.Science. 2019; 366: 714-723Crossref PubMed Scopus (79) Google Scholar This suggests that, as with all modern targeted treatment, therapeutic progress for our patients with PIK3CA-mutated advanced BC requires improved practice guidelines, better patient selection and refined drug design. We thank the contributors of PI3K inhibitor for their huge work, and our team for their daily care of the patients.