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Breakthrough Therapy Cancer Drugs and Indications With FDA Approval: Development Time, Innovation, Trials, Clinical Benefit, Epidemiology, and Price

Daniel Tobias Michaeli and Thomas Michaeli

Background: The breakthrough therapy designation (BTD) facilitates the development of drugs with a large preliminary benefit in treating serious or life-threatening diseases. This study analyzes the FDA approval, trials, benefits, unmet needs, and pricing of breakthrough and nonbreakthrough therapy cancer drugs and indications. Patients and Methods: We analyzed 355 cancer indications with FDA approval (2012–2022). Breakthrough and nonbreakthrough indications were compared regarding their FDA approval, innovativeness, clinical trials, epidemiology, and price. Data were extracted from FDA labels, the Global Burden of Disease study, and the Centers for Medicare & Medicaid Services. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) of tumor response were meta-analyzed across randomized controlled trials. Objective response rates (ORRs) were meta-analyzed for single-arm trials. Results: We identified 137 breakthrough and 218 nonbreakthrough cancer indications. The median clinical development time was 3.2 years shorter for breakthrough drugs than for nonbreakthrough drugs (5.6 vs 8.8 years; P=.002). The BTD was more frequently granted to biomarker-directed indications (46% vs 34%; P=.025) supported by smaller trials (median, 149 vs 326 patients; P<.001) of single-arm (53% vs 27%; P<.001) and phase I or II design (61% vs 31%; P<.001). Breakthrough indications offered a greater OS (HR, 0.69 vs 0.74; P=.031) and tumor response (RR, 1.48 vs 1.32; P=.006; ORR, 52% vs 40%; P=.004), but not a PFS benefit (HR, 0.53 vs 0.58; P=.212). Median improvements in OS (4.8 vs 3.2 months; P=.002) and PFS (5.4 vs 3.3 months; P=.005) but not duration of response (8.7 vs 4.7 months; P=.245) were higher for breakthrough than for nonbreakthrough indications. The BTD was more frequently granted to first-in-class drugs (42% vs 28%; P=.001) and first-in-indication treatments (43% vs 29%; P<.001). There were no differences in treatment and epidemiologic characteristics between breakthrough and nonbreakthrough drugs. Breakthrough drugs were more expensive than nonbreakthrough drugs (mean monthly price, $38,971 vs $22,591; P=.0592). Conclusions: The BTD expedites patient access to effective and innovative, but also expensive, new cancer drugs and indications.

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Life Years Gained From the FDA Accelerated Approval Program in Oncology: A Portfolio Model

Ágnes Benedict, Gábor Szabó, Kinga Marczell, Bridget Doherty, and Silas Martin

Background: Although the FDA Accelerated Approval Program (AAP) has come under scrutiny, the population-level health benefit of the program has not been quantified. Therefore, the objective of this study was to estimate the number of life years gained among patients with cancer that can be attributable to the therapies receiving FDA accelerated approvals in oncology between 2006 and 2022 in the United States. Methods: The data sources used were FDA listings, FDA approval letters and labels, published clinical trial data and other publications including relative effectiveness estimates, and the Ipsos Oncology Uptake Tool for product uptake. Data for 130 oncology treatments approved by the FDA under the AAP were extracted and validated. We developed a decision analytic model to estimate the survival gain for each indication and to accumulate life years gained for consecutive cohorts of patients receiving the therapies. Life year gains were estimated with and without the AAP, and the incremental life years gained were attributed to the program. Results: The analysis estimated that through December 2022 in the United States, the program gained approximately 263,000 life years across 69 products for which overall survival data were available, for approximately 911,000 patients with cancer. Conclusions: Policy discussions about the evaluation of AAP cannot be complete without assessing its impact on its most important target outcome: patient survival. To date, there has been no estimation of the life year gain delivered by the AAP. Our research shows that substantial number of life years were gained for patients with high unmet need by the cancer therapies approved through the program.

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Health Care Lobbying and Oncology

Nirmal Choradia, Aaron Mitchell, and Ryan Nipp

Background: The health care industry spends more on lobbying than any other industry, with more than $700 million spent in 2022. However, health care lobbying related to cancer has not been characterized. In this study, we sought to describe overall health sector lobbying spending and oncology-related lobbying spending across patient and clinician organizations. Methods: We obtained lobbying data from and the Federal Election Commission. Overall health sector lobbying spending was categorized by OpenSecrets into 4 groups: pharmaceuticals/health products, health services/health maintenance organizations (HMOs), hospitals/nursing homes, and health professionals. We then identified and categorized 4 oncology-related lobbying groups: oncology physician professional organizations (OPPOs), prospective payment system (PPS)–exempt cancer hospitals, patient advocacy organizations, and provider networks (eg, US Oncology Network). We described temporal trends in lobbying spending from 2014 to 2022, in both overall dollar value (inflation-adjusted 2023 dollars) and in per-physician spending (using American Association of Medical Colleges [AAMC] data for number of hematologists/oncologists) using a Mann-Kendall trend test. Results: Among the overall health sector lobbying, pharmaceuticals/health products had the greatest increase in lobbying spending, with an increase from $294 million in 2014 to >$376 million in 2022 (P=.0006). In contrast, lobbying spending by health professionals did not change, remaining at $96 million (P=.35). Regarding oncology-related lobbying, OPPOs and PPS-exempt cancer hospitals had a significant increase of 170% (P=.016) and 62% (P=.009), respectively. Per-physician spending also demonstrated an increase from $60 to $134 for OPPOs and from $168 to $226 for PPS-exempt cancer hospitals. Overall, OPPO lobbying increased as a percentage of overall physician lobbying from 1.16% in 2014 to 3.76% in 2022. Conclusions: Although overall health sector lobbying has increased, physician/health professional lobbying has remained relatively stable in recent years, spending for lobbying by OPPOs has increased. Continued efforts to understand the utility and value of lobbying in health care and across oncology are needed as the costs of care continue to increase.

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Barriers and Facilitators Impacting Lung Cancer Screening Uptake Among Black Veterans: A Qualitative Study

Neelima Navuluri, Tiera Lanford, Abigail Shapiro, Govind Krishnan, Angela B. Johnson, Isaretta L. Riley, Leah L. Zullig, Christopher E. Cox, and Scott Shofer

Background: Racial disparities in lung cancer screening (LCS) are well established. Black Veterans are among those at the highest risk for developing lung cancer but are less likely to complete LCS. We sought to identify barriers and facilitators to LCS uptake among Black Veterans. Patients and Methods: A qualitative study using semistructured interviews was conducted with 32 Black Veterans to assess for barriers, facilitators, and contextual factors for LCS and strategies to improve screening. Veterans were purposively sampled by age, sex, and LCS participation status (ie, patients who received a low-dose CT [LDCT], patients who contacted the screening program but did not receive an LDCT, and patients who did not connect with the screening program nor receive an LDCT). Interview guides were developed using the Theoretical Domains Framework and Health Belief Model. Data were analyzed using rapid qualitative analysis. Results: Barriers of LCS uptake among Black Veterans include self-reported low LCS knowledge and poor memory, attention, and decision processes associated with the centralized LCS process. Facilitators of LCS uptake among Black Veterans include social/professional role; identity and social influences; perceived susceptibility, threat, and consequences due to smoking status and military or occupational exposures; emotion, behavioral regulation, and intentions; and high trust in providers. Environmental context and resources (eg, transportation) and race and racism serve as contextual factors that did not emerge as having a major impact on LCS uptake. Strategies to improve LCS uptake included increased social messaging surrounding LCS, various forms of information dissemination, LCS reminders, balanced and repeated shared decision-making discussions, and streamlined referrals. Conclusions: We identified addressable barriers and facilitators for LCS uptake among Black Veterans that can help focus efforts to improve disparities in screening. Future studies should explore provider perspectives and test interventions to improve equity in LCS.

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Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer

Ranjit Manchanda, Li Sun, Monika Sobocan, Isabel V. Rodriguez, Xia Wei, Ashwin Kalra, Samuel Oxley, Michail Sideris, Caitlin T. Fierheller, Robert D. Morgan, Dhivya Chandrasekaran, Kelly Rust, Pavlina Spiliopoulou, Rowan E. Miller, Shanthini M. Crusz, Michelle Lockley, Naveena Singh, Asma Faruqi, Laura Casey, Elly Brockbank, Saurabh Phadnis, Tina Mills-Baldock, Fatima El-Khouly, Lucy A. Jenkins, Andrew Wallace, Munaza Ahmed, Ajith Kumar, Elizabeth M. Swisher, Charlie Gourley, Barbara M. Norquist, D. Gareth Evans, and Rosa Legood

Background : Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)–based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. Methods: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. Results: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year’s testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. Conclusions: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

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Racial Differences in Germline Genetic Testing Completion Among Males With Pancreatic, Breast, or Metastatic Prostate Cancers

Jeffrey W. Shevach, Danielle Candelieri-Surette, Julie A. Lynch, Rebecca A. Hubbard, Patrick R. Alba, Karen Glanz, Ravi B. Parikh, and Kara N. Maxwell

Background: Germline genetic testing is a vital component of guideline-recommended cancer care for males with pancreatic, breast, or metastatic prostate cancers. We sought to determine whether there were racial disparities in germline genetic testing completion in this population. Patients and Methods: This retrospective cohort study included non-Hispanic White and Black males with incident pancreatic, breast, or metastatic prostate cancers between January 1, 2019, and September 30, 2021. Two nationwide cohorts were examined: (1) commercially insured individuals in an administrative claims database, and (2) Veterans receiving care in the Veterans Health Administration. One-year germline genetic testing rates were estimated by using Kaplan-Meier methods. Cox proportional hazards regression was used to test the association between race and genetic testing completion. Causal mediation analyses were performed to investigate whether socioeconomic variables contributed to associations between race and germline testing. Results: Our cohort consisted of 7,894 males (5,142 commercially insured; 2,752 Veterans). One-year testing rates were 18.0% (95% CI, 16.8%–19.2%) in commercially insured individuals and 14.2% (95% CI, 11.5%–15.0%) in Veterans. Black race was associated with a lower hazard of testing among commercially insured individuals (adjusted hazard ratio [aHR], 0.73; 95% CI, 0.58–0.91; P=.005) but not among Veterans (aHR, 0.99; 95% CI, 0.75–1.32; P=.960). In commercially insured individuals, income (aHR, 0.90; 95% CI, 0.86–0.96) and net worth (aHR, 0.92; 95% CI, 0.86–0.98) mediated racial disparities, whereas education (aHR, 0.98; 95% CI, 0.94–1.01) did not. Conclusions: Overall rates of guideline-recommended genetic testing are low in males with pancreatic, breast, or metastatic prostate cancers. Racial disparities in genetic testing among males exist in a commercially insured population, mediated by net worth and household income; these disparities are not seen in the equal-access Veterans Health Administration. Alleviating financial and access barriers may mitigate racial disparities in genetic testing.

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Volume 22 (2024): Issue 3 (Apr 2024)

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Aligning With the National Cancer Plan

Erin Frantz, Rachel Darwin, Kimberly Callan, and Wui-Jin Koh

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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024

William G. Wierda, Jennifer Brown, Jeremy S. Abramson, Farrukh Awan, Syed F. Bilgrami, Greg Bociek, Danielle Brander, Matthew Cortese, Larry Cripe, Randall S. Davis, Herbert Eradat, Bita Fakhri, Christopher D. Fletcher, Sameh Gaballa, Muhammad Saad Hamid, Brian Hill, Paul Kaesberg, Brad Kahl, Manali Kamdar, Thomas J. Kipps, Shuo Ma, Claudio Mosse, Shazia Nakhoda, Sameer Parikh, Andrew Schorr, Stephen Schuster, Madhav Seshadri, Tanya Siddiqi, Deborah M. Stephens, Meghan Thompson, Chaitra Ujjani, Riccardo Valdez, Nina Wagner-Johnston, Jennifer A. Woyach, Hema Sundar, and Mary Dwyer

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent’s toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

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Clinical Risks for Chronic Lymphocytic Leukemia

Jennifer R. Brown

Our understanding of risk factors for the development of chronic lymphocytic leukemia (CLL) is still incomplete and includes genetic and environmental factors. CLL is one of the most familial of all cancers, yet common high-penetrance risk alleles have not been identified. Genome-wide association studies have identified many common variants with low relative risks, whereas exome-wide rare variant analysis has implicated ATM in CLL causation. Environmental factors have also been challenging to identify given the limited understanding of the relevant time period of exposure relative to diagnosis, and the inability to quantify past exposures. Agent Orange and glyphosate herbicides have perhaps the most data to support their role. CLL is preceded by a precursor condition called monoclonal B-cell lymphocytosis (MBL), which could therefore be considered a risk factor, but which itself is likely caused by the same risk factors that ultimately give rise to CLL. Although virtually all people with CLL have a preceding MBL phase, most people with MBL will not develop CLL.