The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

Abstract

On April 21, 2022, the Oncologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) will discuss class-wide safety findings observed with PI3K inhibitors in haematological malignancies. Dysregulated PI3K signalling promotes the survival and proliferation of malignant lymphocytes and is the rationale for therapeutic targeting of PI3K isoforms in haematological malignancies. Four PI3K inhibitors have received approval for indications involving relapsed or refractory indolent non-Hodgkin lymphoma or chronic lymphocytic leukaemia: idelalisib (Gilead Sciences), copanlisib (Bayer HealthCare Pharmaceuticals), duvelisib (Secura Bio), and umbralisib (TG Therapeutics; table). These inhibitors each inhibit the PI3Kδ isoform and some also inhibit other isoforms. Alpelisib, a PI3Kα-specific inhibitor approved in breast cancer and PIK3CA-related overgrowth spectrum, is not included in this Comment. Although the four PI3K inhibitors have shown durable overall response rates or improvements in progression-free survival, or both, they have also shown substantial toxicity. TableStatus of FDA-approved PI3K inhibitors for haematological malignancies Initial approval information* Indications are extracted; approval endpoints are from the US Prescribing Information on initial approval date. Post-approval trials Outcome Idelalisib (PI3Kδ inhibitor) Regular approval 2014: relapsed chronic lymphocytic leukaemia in combination with rituximab † Rituximab alone would be considered appropriate therapy due to comorbidities. based on a RCT of idelalisib plus rituximab vs placebo plus rituximab in relapsed chronic lymphocytic leukaemia: progression-free survival HR 0·18 (95% CI 0·10–0·31), overall survival immature 2016: three RCTs halted in chronic lymphocytic leukaemia or indolent non-Hodgkin lymphoma for increased deaths and serious toxic side-effects: idelalisib with bendamustine plus rituximab vs placebo plus bendamustine plus rituximab in untreated chronic lymphocytic leukaemia; idelalisib plus rituximab vs placebo plus rituximab in relapsed or refractory indolent non-Hodgkin lymphoma; idelalisib with bendamustine plus rituximab vs placebo with bendamustine plus rituximab in relapsed or refractory indolent non-Hodgkin lymphoma. Pooled analysis, idelalisib groups vs control: deaths 7·4% vs 3·5%, overall survival HR 2·29 (95% CI 1·26–4·18) 1 Gilead SciencesImportant drug warning: decreased overall survival and increased risk of serious infections in patients receiving Zydelig (idelalisib). http://cllsociety.org/docs/Zydelig%20Safety%20Update.pdfDate: March, 2016 Date accessed: February 16, 2022 Google Scholar Warning and limitations of use added to prescribing information (2016, 2018) Accelerated approval 2014: relapsed follicular lymphoma and small lymphocytic lymphoma after ≥2 systemic therapies based on single-arm trial: follicular lymphoma: overall response rate 54% (95% CI 42–66), duration of response median not reached; small lymphocytic lymphoma: overall response rate 58% (95% CI 37–77), duration of response median 11·9 months Required post-marketing trial: slow accrual to trial evaluating idelalisib dosage in relapsed or refractory follicular lymphoma Voluntary withdrawal of follicular lymphoma and small lymphocytic lymphoma indications (2022) Copanlisib (PI3Kα and PI3Kδ inhibitor) Accelerated approval 2017: relapsed follicular lymphoma after ≥2 systemic therapies based on single-arm trial: overall response rate 59% (95% CI 49–68), duration of response median 12·2 months CHRONOS-3: RCT of copanlisib plus rituximab vs placebo plus rituximab in relapsed indolent non-Hodgkin lymphoma: 2 Matasar MJ Capra M Özcan M et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22: 678-689 Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar progression-free survival HR 0·52 (95% CI 0·39–0·69), interim overall survival HR 1·07 (95% CI 0·63–1·82) Voluntary withdrawal of NDA based on CHRONOS-3 Duvelisib (PI3Kδ and PI3Kγ inhibitor) Regular approval 2018: relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after ≥2 therapies based on a RCT of duvelisib vs ofatumumab in relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma: progression-free survival HR 0·52 (95% CI 0·39–0·69), overall survival immature Final analysis, duvelisib vs ofatumumab: overall survival HR 1·11 (95% CI 0·80–1·53) 3 Secura BioCorrection of drug information: updated overall survival data for Copiktra (duvelisib) in patients with relapsed/refractory (R/R) chronic lymphatic leukemia (CLL) and small lymphocytic lymphoma (SLL). https://copiktrahcp.com/notice-to-hcps/Date: March 18, 2022 Date accessed: March 18, 2022 Google Scholar Under FDA review Accelerated approval 2018: relapsed or refractory follicular lymphoma after ≥2 systemic therapies based on single-arm trial: overall response rate 42% (95% CI 31–54), 43% of responses were ongoing at ≥6 months and 17% at ≥12 months Required post-marketing trial: RCT was not initiated for commercial reasons Voluntary withdrawal of follicular lymphoma indication (2021) Umbralisib (PI3Kδ and CK1ɛ inhibitor) Accelerated approval 2021: relapsed or refractory follicular lymphoma after ≥3 systemic therapies and relapsed or refractory marginal zone lymphoma after ≥1 anti-CD20-based regimen based on single-arm trial: follicular lymphoma: overall response rate 43% (95% CI 34–52), duration of response median 11·1 months; marginal zone lymphoma: overall response rate 49% (95% CI 37–62), duration of response median not reached UNITY-CLL: RCT of umbralisib plus ublituximab vs obinutuzumab plus chlorambucil in untreated and relapsed or refractory chronic lymphocytic leukaemia: progression-free survival HR 0·55 (95% CI 0·41–0·72); 4 Gribben JG Jurczak W Jacobs RW et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood. 2020; 136 (abstr).: 37-39 Crossref Google Scholar interim overall survival HR 1·23 5 TG TherapeuticsPress release: TG Therapeutics provides regulatory update. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-provides-regulatory-updateDate: Nov 30, 2021 Date accessed: March 7, 2022 Google Scholar ‡ Overall survival data reflect later data cutoff; 95% CI was not available publicly. Planned for discussion by ODAC, April 22, 2022 FDA=US Food and Drug Administration. HR=hazard ratio. NDA=new drug application. ODAC=Oncologic Drugs Advisory Committee. RCT=randomised controlled trial. * Indications are extracted; approval endpoints are from the US Prescribing Information on initial approval date. † Rituximab alone would be considered appropriate therapy due to comorbidities. ‡ Overall survival data reflect later data cutoff; 95% CI was not available publicly. Open table in a new tab FDA=US Food and Drug Administration. HR=hazard ratio. NDA=new drug application. ODAC=Oncologic Drugs Advisory Committee. RCT=randomised controlled trial. PI3K inhibitors in haematological malignanciesWe read the Comment in The Lancet Oncology by Nicholas Richardson and colleagues1 on PI3K inhibitors in patients with haematological malignancies with great interest. However, we are writing to correct two inaccuracies with respect to the discussion of copanlisib. Full-Text PDF PI3K inhibitors in haematological malignanciesPI3K signalling regulates several cellular activities, including growth and apoptosis.1 Therefore, inhibition of PI3K presented an intriguing and novel therapeutic avenue to treat several haematological malignancies, such as chronic lymphocytic leukaemia, follicular lymphoma, and marginal zone lymphoma. Given the paucity of novel treatments for these malignancies in the relapsed and refractory settings, there was considerable interest when the first PI3K inhibitor, idelalisib, was approved in 2014. Full-Text PDF PI3K inhibitors in haematological malignanciesWe are writing in response to the Comment by Nicholas Richardson and colleagues1 from the US Food and Drug Administration, which discussed the use of PI3K inhibitors in haematological malignancies. As investigators who have treated many patients with PI3K inhibitors, beginning with the phase 1 study of idelalisib in 2010, we can attest to the transformative and life-saving nature of these therapies. Many of the patients whom we have treated with PI3K inhibitors have derived great benefit for 5 years or more while on therapy. Full-Text PDF