Genomic instability is the hallmark of various cancers with the increasing accumulation of DNA damage. The application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of cancers. However, the adverse effects including normal tissues injury are also accompanied by the radiotherapy and chemotherapy. Targeted cancer therapy has the potential to suppress cancer cells’ DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response functions. Obviously, understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy, in particular, raising novel hypothesis or theory in this field on the basis of previous scientists’ findings would be important for future promising druggable emerging targets. In this review, we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed, then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy, highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors, also, the DNA damage baseline drift leads to the harmful intrinsic targeted cancer therapy. In addition, clinical therapeutic drugs for DNA damage and repair including therapeutic effects, as well as the strategy and scheme of relative clinical trials were intensive discussed. Based on this background, we suggest two hypotheses, namely “environmental gear selection” to describe DNA damage repair pathway evolution, and “DNA damage baseline drift”, which may play a magnified role in mediating repair during cancer treatment. This two new hypothesis would shed new light on targeted cancer therapy, provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for patients.

DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy.

Phosphoinositide 3-kinase (PI3K) signaling regulates cellular proliferation, survival and metabolism, and its aberrant activation is one of the most frequent oncogenic events across human cancers. In the last few decades, research has focused on the development of PI3K inhibitors, from preclinical tool compounds to the highly specific medicines approved to treat patients with cancer. Herein we discuss current paradigms for PI3K inhibitors in cancer therapy, focusing on clinical data and mechanisms of action. We also discuss current limitations in the use of PI3K inhibitors, including toxicities and mechanisms of resistance, with specific emphasis on approaches aimed at improving efficacy. Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance.

The present and future of PI3K inhibitors for cancer therapy

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 

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

Purpose: Marginal zone lymphoma (MZL) is an uncommon non–Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Patients and Methods: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111–214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Results: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Conclusions: Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

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The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient's goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.

Prospects in the management of patients with follicular lymphoma beyond first-line therapy.

Summary Background Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Methods CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov , NCT02367040 and is ongoing. Findings Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4–28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8–33·0) versus 13·8 months (10·2–17·5; hazard ratio 0·52 [95% CI 0·39–0·69]; p Interpretation Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Funding Bayer.

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

Ross Baker

Papers

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