Improving Collection and Analysis of Overall Survival Data.

Advances in anticancer therapies have provided crucial benefits for millions of patients who are living long and fulfilling lives. While these successes should be celebrated, there is certainly room to continue improving cancer care. Increased long-term survival presents additional challenges for determining whether new therapies further extend patients' lives through clinical trials, commonly known as the gold standard endpoint of overall survival (OS). As a result, there is an increasing reliance on earlier efficacy endpoints , which may or may not correlate with OS, to continue the timely pace of translating innovation into novel therapies available for patients. Even when not powered as an efficacy endpoint, OS remains a critical indication of safety for regulatory decisions and is a key aspect of the U.S. Food and Drug Administration's Project Endpoint. Unfortunately, in the pursuit of earlier endpoints, many registrational clinical trials lack adequate planning, collection, and analysis of OS data, which complicates interpretation of a net clinical benefit or harm. This article shares best practices, proposes novel statistical methodologies, and provides detailed recommendations to improve the rigor of using OS data to inform benefit-risk assessments, including incorporating the following in clinical trials intending to demonstrate the safety and effectiveness of a cancer therapy: prospective collection of OS data, establishment of fit-for-purpose definitions of OS detriment, and prespecification of analysis plans for using OS data to evaluate for potential harm. These improvements hold promise to help regulators, patients and providers better understand the benefits and risks of novel therapies.

Driving Diversity and Inclusion in Cancer Drug Development - Industry and Regulatory Perspectives, Current Practices, Opportunities, and Challenges.

In April 2022, the FDA issued draft guidance to help industry develop strategies to improve diversity in clinical trials. Historically, clinical trial sponsors have not systematically incorporated efforts to promote diversity, equity, and inclusion (DEI), particularly during the early design stages of clinical development plans and operational strategies. Unfortunately, a retrospective approach to DEI often results in clinical trial participants not being reflective of the diversity of patients intended to be treated with new therapies. A shift to prospective, intentional DEI strategies for clinical trials, including long-term engagement with diverse patients and communities throughout the development life cycle, is necessary to maximize the benefits and minimize the risks of new drugs and devices for all patients. Sponsors' current practices and opportunities for improving DEI address four major topics: institutional commitment, culture change, and governance; clinical development strategy; setting enrollment goals to ensure trial participant diversity; and development and implementation of the operational strategy. As DEI practices gain wider adoption in clinical trials, shared learning and collaboration among stakeholders on an ongoing and noncompetitive basis will lead to sustainable change. Prioritization of enrollment of diverse populations as an integral part of study start-up planning, clinical trial design, and recruitment capabilities will enhance the clinical development process for oncology therapies. Importantly, these efforts will help provide equitable access to clinical trials and innovative cancer therapies.

Electronic Nicotine Delivery Systems: An Updated Policy Statement From the American Association for Cancer Research and the American Society of Clinical Oncology.

Combustible tobacco use has reached historic lows, demonstrating the importance of proven strategies to reduce smoking since publication of the 1964 Surgeon General's report. In contrast, the use of electronic nicotine delivery systems (ENDS), specifically e-cigarettes, has grown to alarming rates and threatens to hinder progress against tobacco use. A major concern is ENDS use by youth and adults who never previously used tobacco. While ENDS emit fewer carcinogens than combustible tobacco, preliminary evidence links ENDS use to DNA damage and inflammation, key steps in cancer development. Furthermore, high levels of nicotine can also increase addiction, raise blood pressure, interfere with brain development, and suppress the immune system. The magnitude of long-term health risks will remain unknown until longitudinal studies are completed. ENDS have been billed as a promising tool for combustible tobacco cessation, but further evidence is needed to assess their potential efficacy for adults who smoke. Of concern, epidemiological studies estimate that approximately 15%-42% of adults who use ENDS have never used another tobacco product, and another 36%-54% dual use both ENDS and combustible tobacco. This policy statement details advances in science related to ENDS and calls for urgent action to end predatory practices of the tobacco industry and protect public health. Importantly, we call for an immediate ban on all non-tobacco-flavored ENDS products that contain natural or synthetic nicotine to reduce ENDS use by youth and adults who never previously used tobacco. Concurrently, evidence-based treatments to promote smoking cessation and prevent smoking relapse to reduce cancer incidence and improve public health remain top priorities for our organizations. We also recognize there is an urgent need for research to understand the relationship between ENDS and tobacco-related disparities.

Electronic Nicotine Delivery Systems: An Updated Policy Statement from the American Association for Cancer Research and the American Society of Clinical Oncology.

Combustible tobacco use has reached historic lows, demonstrating the importance of proven strategies to reduce smoking since publication of the 1964 Surgeon General's report. In contrast, the use of electronic nicotine delivery systems (ENDS), specifically e-cigarettes, has grown to alarming rates and threatens to hinder progress against tobacco use. A major concern is ENDS use by youth and adults who never previously used tobacco. While ENDS emit fewer carcinogens than combustible tobacco, preliminary evidence links ENDS use to DNA damage and inflammation, key steps in cancer development. Furthermore, high levels of nicotine can also increase addiction, raise blood pressure, interfere with brain development, and suppress the immune system. The magnitude of long-term health risks will remain unknown until longitudinal studies are completed. ENDS have been billed as a promising tool for combustible tobacco cessation, but further evidence is needed to assess their potential efficacy for adults who smoke. Of concern, epidemiological studies estimate that approximately 15% to 42% of adults who use ENDS have never used another tobacco product, and another 36% to 54% "dual use" both ENDS and combustible tobacco. This policy statement details advances in science related to ENDS and calls for urgent action to end predatory practices of the tobacco industry and protect public health. Importantly, we call for an immediate ban on all non-tobacco-flavored ENDS products that contain natural or synthetic nicotine to reduce ENDS use by youth and adults who never previously used tobacco. Concurrently, evidence-based treatments to promote smoking cessation and prevent smoking relapse to reduce cancer incidence and improve public health remain top priorities for our organizations. We also recognize there is an urgent need for research to understand the relationship between ENDS and tobacco-related disparities.

Comparison of the different mechanisms of cytotoxicity induced by checkpoint kinase I inhibitors when used as single agents or in combination with DNA damage.

Inhibition of the DNA damage response is an emerging strategy to treat cancer. Understanding how DNA damage response inhibitors cause cytotoxicity in cancer cells is crucial to their further clinical development. This review focuses on three different mechanisms of cell killing by checkpoint kinase I inhibitors (CHK1i). DNA damage induced by chemotherapy drugs, such as topoisomerase I inhibitors, results in S and G2 phase arrest. Addition of CHK1i promotes cell cycle progression before repair is completed resulting in mitotic catastrophe. Ribonucleotide reductase inhibitors such as gemcitabine also arrest cells in S phase by preventing dNTP synthesis. Addition of CHK1i re-activates the DNA helicase to unwind DNA, but in the absence of dNTPs, this leads to excessive single-strand DNA that exceeds the protective capacity of the single-strand-binding protein RPA. Unprotected DNA is subjected to nuclease cleavage, resulting in replication catastrophe. CHK1i alone also kills a subset of cell lines through MRE11 and MUS81-mediated DNA cleavage in S phase cells. The choice of mechanism depends on the activation state of CDK2. Low level activation of CDK2 mediates helicase activation, cell cycle progression, and both replication and mitotic catastrophe. In contrast, high CDK2 activity is required for sensitivity to CHK1i as monotherapy. This high CDK2 activity threshold usually occurs late in the cell cycle to prepare for mitosis, but in CHK1i-sensitive cells, high activity can be attained in early S phase, resulting in DNA cleavage and cell death. This sensitivity to CHK1i has previously been associated with endogenous replication stress, but the dependence on high CDK2 activity, as well as MRE11, contradicts this hypothesis. The major unresolved question is why some cell lines fail to restrain their high CDK2 activity and hence succumb to CHK1i in S phase. Resolving this question will facilitate stratification of patients for treatment with CHK1i as monotherapy.

Differential Sensitivity to CDK2 Inhibition Discriminates the Molecular Mechanisms of CHK1 Inhibitors as Monotherapy or in Combination with the Topoisomerase I Inhibitor SN38.

DNA damage activates checkpoints to arrest cell cycle progression in S and G2 phases, thereby providing time for repair and recovery. The combination of DNA-damaging agents and inhibitors of CHK1 (CHK1i) is an emerging strategy for sensitizing cancer cells. CHK1i induce replication on damaged DNA and mitosis before repair is complete, and this occurs in a majority of cell lines. However, ∼15% of cancer cell lines are hypersensitive to single-agent CHK1i. As both abrogation of S phase arrest and single-agent activity depend on CDK2, this study resolved how activation of CDK2 can be essential for both replication and cytotoxicity. S phase arrest was induced with the topoisomerase I inhibitor SN38; the addition of CHK1i rapidly activated CDK2, inducing S phase progression that was inhibited by the CDK2 inhibitor CVT-313. In contrast, DNA damage and cytotoxicity induced by single-agent CHK1i in hypersensitive cell lines were also inhibited by CVT-313 but at 20-fold lower concentrations. The differential sensitivity to CVT-313 is explained by different activity thresholds required for phosphorylation of CDK2 substrates. While the critical CDK2 substrates are not yet defined, we conclude that hypersensitivity to single-agent CHK1i depends on phosphorylation of substrates that require high CDK2 activity levels. Surprisingly, CHK1i did not increase SN38-mediated cytotoxicity. In contrast, while inhibition of WEE1 also abrogated S phase arrest, it more directly activated CDK1, induced premature mitosis, and enhanced cytotoxicity. Hence, while high activity of CDK2 is critical for cytotoxicity of single-agent CHK1i, CDK1 is additionally required for sensitivity to the drug combination.

Inhibition of checkpoint kinase 1 following gemcitabine-mediated S phase arrest results in CDC7- and CDK2-dependent replication catastrophe.

Combining DNA-damaging drugs with DNA checkpoint inhibitors is an emerging strategy to manage cancer. Checkpoint kinase 1 inhibitors (CHK1is) sensitize most cancer cell lines to DNA-damaging drugs and also elicit single-agent cytotoxicity in 15% of cell lines. Consequently, combination therapy may be effective in a broader patient population. Here, we characterized the molecular mechanism of sensitization to gemcitabine by the CHK1i MK8776. Brief gemcitabine incubation irreversibly inhibited ribonucleotide reductase, depleting dNTPs, resulting in durable S phase arrest. Addition of CHK1i 18 h after gemcitabine elicited cell division cycle 7 (CDC7)- and cyclin-dependent kinase 2 (CDK2)-dependent reactivation of the replicative helicase, but did not reinitiate DNA synthesis due to continued lack of dNTPs. Helicase reactivation generated extensive single-strand (ss)DNA that exceeded the protective capacity of the ssDNA-binding protein, replication protein A. The subsequent cleavage of unprotected ssDNA has been termed replication catastrophe. This mechanism did not occur with concurrent CHK1i plus gemcitabine treatment, providing support for delayed administration of CHK1i in patients. Alternative mechanisms of CHK1i-mediated sensitization to gemcitabine have been proposed, but their role was ruled out; these mechanisms include premature mitosis, inhibition of homologous recombination, and activation of double-strand break repair nuclease (MRE11). In contrast, single-agent activity of CHK1i was MRE11-dependent and was prevented by lower concentrations of a CDK2 inhibitor. Hence, both pathways require CDK2 but appear to depend on different CDK2 substrates. We conclude that a small-molecule inhibitor of CHK1 can elicit at least two distinct, context-dependent mechanisms of cytotoxicity in cancer cells.