Assessing Patient Risk, Benefit, and Outcomes in Drug Development: Insights From Afatinib Clinical Trials Across Diverse Cancer Indications.

PURPOSE: In 2013, afatinib was approved for non-small-cell lung cancer with subsequent indication expansion. We investigated published afatinib clinical trials to assess risk and benefit profiles for the drug in its approved indication of non-small-cell lung cancer as well as in off-label uses. Previous literature demonstrates excessive patient burden and limited benefit as afatinib has spread into more indications. A trial analysis is needed to establish efficacy and risk. METHODS: In this investigation, we screened literature databases and clinical trial registries for trials of afatinib as monotherapy or in combination interventions for cancer treatment. We extracted participant demographics, adverse event characteristics, as well as clinical and surrogate endpoints for each trial. Studies were deemed positive, negative, or indeterminate based on their achieving of primary endpoints as well as their safety. RESULTS: Our search yielded 2444 articles; we excluded 2352 articles for a final inclusion of 92 trials of 8859 patients. Our sample had 49 (53%) positive trials, 27 (29%) negative trials, and 16 (17%) indeterminate trials. The most common off-label indications for afatinib were breast cancer and squamous cell carcinoma of head and neck. The median OS for all trials was 8.4 months, median PFS 3.4 months, and the total ORR was 29.6%. Our study found that trials performed in disease states beyond the initial indications were largely negative with little patient benefit. The adverse events within our trial sample appear to be in line with expectations for toxicity. IMPLICATIONS: These results are consistent with other studies that present similar findings, such as in Carlisle et al which indicate limited efficacy in nonapproved indications. Future trials should keep this potential evidence and patient burden in mind before initiation of those trials. This study contributes to the understanding of afatinib's risk-benefit profile across many clinical applications.

Assessing patient risk, benefit, and outcomes in drug development: A decade of ramucirumab clinical trials.

OBJECTIVE: This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. BACKGROUND: The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. METHODS: On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. RESULTS: Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. CONCLUSION: We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Lenvatinib Clinical Trials: A Systematic Review.

IMPORTANCE: Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking. OBJECTIVE: This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time. EVIDENCE REVIEW: On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint). FINDINGS: Expansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials. CONCLUSION AND RELEVANCE: Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.

Characteristics and outcomes of new molecular oncology drug approvals, in combination or monotherapy.

IMPORTANCE: Understanding the factors that are associated with new molecular entity (NME) cancer drug approvals as a single agent and in combination, and European Society for Medical Oncology (ESMO) scores, can aid in identifying suitable factors to consider in trial designs for future drugs. In addition, the association between the various outcomes can aid in determining benefit when surrogate outcomes are used in approval consideration. OBJECTIVE: This study aims to (1) use the measures used in evaluating clinical trials by ESMO scores to determine the differences in the characteristics of 2013-2022 Food and Drug Administration (FDA) oncology NME drug approvals for those approved for use in combination or as a monotherapy, and (2) analyze the association between survival outcomes and the response rate for monotherapy NME drugs and/or drugs approved in combination. DESIGN: Cross-sectional analysis. SETTING: US FDA Oncology Drug Approvals (2013-2022) PARTICIPANTS: US FDA Oncology Drug Approvals (2013-2022) EXPOSURES: Trial-level characteristics (tumor types, basis of approval, randomized or not, phase) and associations between overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) and whether NME drugs were approved as monotherapy or in combination . RESULTS: Drugs approved for use as a monotherapy are less likely to be approved using a randomized study (p < 0.001) and more likely to be approved via the accelerated pathway (p = 0.012) and be open-label (p < 0.001). Drugs approved for use as a combination or monotherapy significantly differed on their approval basis (p = 0.002), phase of trial at the time of approval (p = 0.02), and ESMO scores (p = 0.02). There was low correlation between response rate and either PFS or OS metrics. However, nearly all of the drugs with large improvements in OS (> 5months) were drugs with robust ORR. CONCLUSIONS AND RELEVANCE: Drugs approved as monotherapy with a low response rate are likely to have marginal benefit in OS and PFS.

Systematic Review and Meta-Analysis of Randomized Trials Testing Interventions to Reduce Physician Burnout.

BACKGROUND: Physicians deal with intense professional pressures, which may contribute to increasing burnout. We sought to evaluate the efficacy of interventions designed to reduce burnout in physicians, physicians-in-training, and other health care professionals. METHODS: We searched PubMed and Embase (through January 6, 2023) and reference lists. We included all randomized studies assessing an intervention designed to reduce professional burnout in physicians and other health care personnel. We adhered to the PRISMA reporting guidelines. We abstracted data on study and participant characteristics, study outcomes, and study quality. We used a random-effects model to pool mean differences in burnout change (pre- and post-intervention) between intervention and control arms. RESULTS: Thirty-one of the 38 eligible studies (81.6%) used the Maslach Burnout Inventory (MBI) questionnaire to assess burnout. When comparing the intervention and control groups, the mean difference in the emotional exhaustion component of the MBI was -1.11 (95% confidence interval [CI], -2.14 to -0.09; I2: 74.5%; 20 studies); the mean difference in the depersonalization component of the MBI was -0.32 (95% CI, -0.63 to -0.01; I2: 54.2%; 17 studies); and the mean difference in the personal accomplishment component of the MBI was 1.11 (95% CI, -0.21 to 2.43; I2: 94.3%; 16 studies). CONCLUSIONS: Studies testing interventions to decrease physician burnout led to significant numerical improvements in some domains of burnout, but it is unlikely that these changes result in meaningful changes in clinical burnout. Further, the limited follow-up time, biased assessments, and heterogeneity in intervention efficacy suggest that a more nuanced understanding of the causes of burnout is needed to develop more effective interventions.

Assessing patient burden and benefit: A decade of cabozantinib clinical trials.

Drug development is complex and costly. Clinical trial participants take on risks, making it essential to maximize trial efficiency and maintain participant safety. Identifying periods of excessive burden during drug development can inform trial design, ensure patient benefit and prevent harm. This study aims to examine all published clinical trials for cabozantinib to assess patient benefit and burden over time. We conducted a retrospective cross-sectional review of interventional clinical trials of cabozantinib for solid cancer treatment. We searched PubMed/MEDLINE, Embase, Cochrane (CENTRAL) and ClinicalTrials.gov. We extracted adverse event rates, median progression-free survival (PFS), median overall survival and objective response rate (ORR) for each included trial. We calculated frequencies of trial characteristics, cumulative grade 3-5 adverse event rates and cumulative ORRs. Out of 1735 studies, 54 publications were included that involved 6372 participants and 21 cancers. Of the 54 studies in our sample, 31 (57.41%) were single-arm trials and 23 (42.60%) had negative results. Trials among and within various indications had conflicting results over time. Cumulative risk to participants increased over time, and clinical benefit decreased. The findings suggest that the risk profile of cabozantinib increased from 2011 to 2016 and has remained elevated but stable while benefit has decreased over time. The use of non-randomized and single-arm trials is concerning, and more methodologically rigorous trials are needed. The results of trials for different indications are inconsistent, and empirical administration may reduce the drug's efficacy.

Cancer Drug Price and Novelty in Mechanism of Action.

Importance: Many economic theories point to regulatory issues and subsidization of research and development costs as the primary factor in the high cancer drug prices in the US. Even so, the association between the median annual cost and novelty of cancer drugs approved in the US remains unclear. Objective: To evaluate the association between the median annual cost and novelty of cancer drugs approved in the US over a 6-year period. Design, Setting, and Participants: This cross-sectional study included all cancer drugs approved by the US Food and Drug Administration (FDA) from January 1, 2015, to December 31, 2020. Drug names, indications, manufacturer, dosage, and measures of activity/efficacy were extracted from the FDA announcement. The search was performed in December 2021. Data were analyzed from January 2022 until April 2022. Main Outcomes and Measures: Annual cost of treatment was calculated based on average wholesale price collected from the 2021 Micromedex Red Book database. Mechanism of action was inferred from trial publication or its references. Results: There were 224 cancer drug approvals across 119 individual drugs, with a median annual cost of $196 000 (IQR, $170 000-$277 000). Gene and viral therapies were the most expensive (median, $448 000 [IQR, $448 000-$479 000]), followed by small molecule therapy (median, $244 000 [IQR, $203 000-$321 000), and biologics (median, $185 000 [IQR, $148 000-$195 000]). There was no significant difference in cost between first-in-class, next-in-class, and subsequent approvals of an already approved drug. Conclusions and Relevance: Findings of this study indicate that the median annual price of anticancer drugs in the US is not associated with the novelty of their mechanism of action.

Eligibility for Human Leukocyte Antigen-Based Therapeutics by Race and Ethnicity.

Importance: The development of therapeutics for patients who are positive for specific human leukocyte antigen (HLA) subtypes evokes the question of whether certain racial and ethnic groups are more or less likely to be eligible for novel products. Objective: To determine whether racial and ethnic inequities were present with regard to trial eligibility in trials investigating a therapeutic restricted to patients with specific HLA subtypes. Design, Setting, and Participants: This cross-sectional study included all clinical trials registered in ClinicalTrials.gov through March 18, 2022, that investigated an interventional study of a therapeutic strategy and restricted participants to those with at least 1 HLA subtype. Data were analyzed from May 8 to July 1, 2022. Main Outcomes and Measures: The type of therapeutics used in trials, the condition under study, the HLA subtypes used, and the likelihood of being enrolled in such a trial according to race and ethnicity. Results: Of 2135 trials identified, 263 met inclusion criteria. Overall, the estimated likelihood of being eligible for an HLA-based trial was 50.3%. Individuals of African American descent had the lowest likelihood of eligibility (33.0%), while being an individual of European descent conferred the highest (53.0%; 1.6 times more likely than African American individuals). Most trials studied anticancer therapeutics (258 [98.1%; 95% CI, 96.4%-99.7%]), and most were a therapeutic vaccine (179 [68.1%; 95% CI, 62.4%-73.7%]). The HLA-A*02:01 allele and the HLA-A2 serotype were the most frequent HLA subtypes for trial eligibility. The frequency of the HLA-A*02:01 allele in the population varied, with 11.9% (95% CI, 11.8%-12.0%) in African or African American individuals and 27.1% (95% CI, 27.1%-27.1%) in individuals of European descent. Conclusions and Relevance: The findings of this cross-sectional study suggest that enrollment restrictions for clinical trials investigating novel HLA therapeutics may be associated with racial and ethnic inequities with regard to trial eligibility. Overcoming these restrictions poses biological challenges, but solutions must be implemented to provide equal access to innovative strategies regardless of race or ethnicity.

Progression-free survival, disease-free survival and other composite end points in oncology: improved reporting is needed.

Composite outcome measures such as progression-free survival and disease-free survival are increasingly used as surrogate end points in oncology research, frequently serving as the primary end point of pivotal trials that form the basis for FDA and EMA approvals. Such outcome measures combine two or more distinct events (for example, tumour (re)growth, new lesions and/or death) into a single, time-to-event end point. The use of a composite end point can increase the statistical power of a clinical trial and decrease the follow-up period required to demonstrate efficacy, thus lowering costs; however, these end points have a number of limitations. Composite outcomes are often vaguely defined, with definitions that vary greatly between studies, complicating comparisons of results across trials. Altering the makeup of events included in a composite outcome can alter study conclusions, including whether treatment effects are statistically significant. Moreover, the events included in a composite outcome often vary in clinical significance, reflect distinct biological pathways and/or are affected differently by treatment. Therefore, knowing the precise breakdown of the component events is essential to accurately interpret trial results and gauge the true benefit of an intervention. In oncology clinical trials, however, such information is rarely provided. In this Perspective, we emphasize this deficiency through a review of 50 studies with progression-free survival as an outcome published in five top oncology journals, discuss the advantages and challenges of using composite end points, and highlight the need for transparent reporting of the component events.

Cost of Drug Wastage From Dose Modification and Discontinuation of Oral Anticancer Drugs.

Importance: Oral chemotherapy is often dispensed to patients as a 1-month supply, with pill dose and package size predetermined by the drug manufacturer; thus, changing the patient dosage may waste the remaining initial drug supply. The cost of pills wasted due to dose modification and discontinuation is often unreported. Objective: To estimate the cost of pill wastage due to dose modification and discontinuation for oral anticancer drugs that were recently approved by the US Food and Drug Administration (FDA) or that are commonly prescribed. Design, Setting, and Participants: This retrospective cross-sectional economic evaluation initially identified 26 oral anticancer drugs newly approved between January 1, 2020, and August 31, 2022, from the FDA website and the top 50 best-selling pharmaceuticals in 2021 abstracted from the Drug Discovery Trends website managed by Drug Discovery and Development. The monthly costs of each agent were extracted from the Micromedex RED BOOK database. The FDA package insert, and in some cases PubMed, of each identified drug and indication was searched (matching on trial registration number) for information on registration trials. Information extracted for each drug included the name of the drug approved, drug target, cost of the drug, number of pills per bottle, available strengths, indication, name of the trial, number of patients exposed to treatment drug, number of dose level reductions, median duration of treatment, percentage of patients who received dose reduction, and percentage of dose discontinuation. All variables included in calculations were derived from the package insert or original trial publication. Main Outcomes and Measures: The cost of wastage for selected oral anticancer drugs due to dose reduction or discontinuation and the percentage of wastage in comparison with the total cost of treatment. Results: After removing duplicates, 22 oral anticancer medications were included in the study. Because some drugs had more than 1 indication, data from 35 clinical trials were analyzed. Eight of the medications (covering 9 indications) had pill strengths divisible at each dose-reduction level; thus the cost of reduction for these pills was assumed to be zero. Two medications did not allow for dose reduction. The median cost of wastage from dose reduction and discontinuation was $1750 (range, $43-$27 200), with a mean cost of $4290 (SD, $5720) per patient. The median percentage of wastage from the total cost of treatment was 1.04% (range, 0.04%-10.80%) with a mean of 1.78% (SD, 2.21%). Conclusions and Relevance: This economic evaluation found that due to both the high cost per pill and limited pill strength availability, the mean cost of wastage associated with dose reduction or discontinuation was $4290 per patient. These results suggest that to reduce the financial burden for patients with cancer, regulatory bodies should enforce availability of pill strengths that will limit pill wastage during dose modification or recommend that drug manufacturers issue credit for unused pills.

Scoping Review of Published Oncology Meta-analyses in High-Impact Oncology Journals.

Importance: Many meta-analyses have been conducted on a wide array of topics, and many of these have focused on treatment efficacy of drugs or bias in interventional studies on a specific topic. Objective: To examine the factors associated with having a positive study conclusion in meta-analyses in the field of oncology. Evidence Review: All meta-analyses published between January 1, 2018, and December 31, 2021, on 5 oncology journal websites were identified and study characteristics, study results, and information on study authors were abstracted. The meta-analysis authors' conclusions were coded as positive, negative, or equivocal, and each article subject matter was coded as one that could affect profits and marketing of a company. Whether an association existed between study characteristics and authors' conclusions was also examined. Findings: Database searches resulted in 3947 potential articles, of which 93 meta-analyses were included in this study. Of the 21 studies with author funding from industry, 17 studies (81.0%) reported favorable conclusions. Of the 9 studies that received industry funding, 7 (77.8%) reported favorable conclusions, and of the 63 studies that did not have author or study funding from industry, 30 (47.6%) reported favorable conclusions. Studies that were funded through nonindustry sources and authors who had no relevant conflict of interest had the lowest percentage of positive conclusions and the highest percentage of negative and equivocal conclusions compared with studies with other sources of potential conflict of interest. Conclusions and Relevance: In this cross-sectional study of meta-analyses published in oncology journals, multiple factors were associated with having a positive study conclusion, which suggests that future research should be performed to elucidate reasons for more favorable conclusions among studies with study or author industry funding.

Profile of the Oncology Physician Workforce and the Characteristics of Attrition.

PURPOSE: To determine the prevalence of attrition and the frequency of transition from a primarily clinical role to an industry-related role among oncology physicians. METHODS: We tracked yearly Centers for Medicare & Medicaid Services (CMS) billing between 2015 and 2022 to estimate attrition of oncology physicians. A subanalysis of a random sample of 300 oncologists with fewer than 30 years of experience and who had stopped billing were used to conduct a more thorough assessment of current employment. Employment was primarily found through LinkedIn; otherwise a secondary search was done through a Google search. Type of employer was categorized as industry (pharmaceutical or biotechnology), nonindustry (academic/clinical/government), others, or no information found. The results are provided separately by sex. RESULTS: Of the 16,870 oncologists who billed to CMS in 2015, 3,558 (21%) had stopped billing by 2022. Among a randomly selected 300 oncologists, we found current employment information for 223 (74%); 78 of the 223 (35%) were most recently employed within industry. Among all CMS-billing oncologists, 30% (5,126 of 16,870) identified as female. Women stopped billing at the rate of 18% (929 of 5,126) by 2022. Surgical oncologists had the lowest overall attrition (17%, 149 of 855). Radiation oncologists had 21% (881 of 4,244) overall attrition and 7% (5 of 71) sampled attrition to industry. CONCLUSION: By 2022, 21% of oncology physicians billing to CMS in 2015 had stopped. 78 of the 300 sampled physicians were found to be working in industry. In total, 1 in 17 oncologists (5%) moved to industry over a 5-year period.

Frequency and Characteristics of Trials Using Medical Writer Support in High-Impact Oncology Journals.

Importance: The practice of using medical writers to communicate scientific information has gained popularity, but it may affect how and what information is communicated. Objective: To assess characteristics of oncology trials that use medical writers and whether there is an association between the use of medical writers and trial success or the primary outcome evaluated. Design, Setting, and Participants: This cross-sectional study included oncology trials testing a tumor-targeting intervention that were published in The Lancet, The Lancet Oncology, JAMA, JAMA Oncology, Journal of Clinical Oncology, and The New England Journal of Medicine between May 1, 2021, and May 1, 2022. Exposures: Assistance of medical writers or no assistance. Main Outcomes and Measures: The main outcomes were the percentage of studies with medical writers, the percentage of trial successes reported with medical writers, the association between trial success and medical writer use, and the association between a primary end point and medical writer use. Results: Among 270 studies, 141 (52.2%) included a medical writer and 129 (47.8%) did not include a medical writer. Of the studies that included a medical writer, 83 (58.9%) were successful. Of the studies that did not include a medical writer, 64 (49.6%) were successful (P = .16 for difference). Studies with medical writers were less likely than studies without medical writers to have the end point of overall survival (15 [10.6%] vs 17 [13.2%]) and disease-free or event-free survival (16 [11.3%] vs 29 [22.5%]), whereas studies with a medical writer were more likely to have the end point of progression-free survival (32 [22.7%] vs 17 [13.2%]). Use of medical writer was associated with the conclusions being presented favorably in all studies (113 [80.1%] vs 89 [69.0%]; odds ratio [OR], 1.81 [95% CI, 1.04-3.19]), but when adjusted for other variables, there was no association (OR, 1.84 [95% CI, 0.92-3.72]). Conclusions and Relevance: In this cross-sectional study, trials using medical writers were more likely to report surrogate end points, such as progression-free survival, and favorable conclusions, but when adjusted for trial phase, randomization, and study funding, there was no association with favorable conclusions. These findings suggest that journals need heightened scrutiny for studies with medical writers and that authorship should be properly acknowledged.

Umbrella review of basket trials testing a drug in tumors with actionable genetic biomarkers.

BACKGROUND: The utilization of basket trials in oncology has gained popularity because of the drive for precision medicine and the increasing ease of genetically profiling tumors. However, it is unknown if this has translated into patient benefit, either through higher response rates because of precision treatment or because of increasing options for less-common tumor types that are less represented in oncology drug trials. We sought to characterize basket studies for oncology drugs targeting a genetic biomarker, determine the responses for various tumor types and genetic biomarkers, and test for correlation between the number of participants in each tumor basket and the incidence of the respective tumor. METHODS: We conducted a retrospective cross-sectional review of oncology basket trials on Embase or clinicaltrials.gov with published data. We included studies that reported on oncology drugs that target a genetic biomarker. We examined the response for basket trial participants, stratified by tumor type and genetic biomarker and the correlation between the number of participants in each tumor basket and the incidence of the respective tumor. RESULTS: The overall response rate for all 25 included trials was 23%. The response for each genetic biomarker ranged from 0 to 69%, and for half of the genetic biomarkers, the response rate ranged from 0 to 100%, depending on tumor type. There is low correlation between the number of participants in each tumor basket and the incidence of the respective tumor (66.41 + -0.20x, R2 = 0.003, p = 0.75). CONCLUSION: While there has been an increase in the number of published basket trials and individuals included in these trials, the response rate is low, but varies widely, depending on tumor type and genetic biomarker.

A systematic review of basket and umbrella trials in oncology: the importance of tissue of origin and molecular target.

INTRODUCTION: We sought to characterise oncology basket and umbrella trials that have been implemented, determine how many have been completed, and calculate the response rate, by tumour type and drug target. METHODS: We conducted a retrospective, cross-sectional review of PubMed, Embase, and clinicaltrials.gov for all oncology basket and umbrella trials. We included all trials and publications reporting on the results of these trials, and we calculated overall response rates, stratified by tumour type and drug target. RESULTS: Most basket and umbrella trials are phase II and non-randomised in design. Of the 180 basket trials, 99 (55.0%) had published results and 81 (45.0%) did not. Of the 73 umbrella trials, 28 (38.4%) had published results and 45 (61.6%) did not. The median response rate was 14.0 (IQR: 4.2, 31.2) for basket trials and 17.8 (IQR: 3.8, 40.4) for umbrella trials. These responses varied, depending on tumour type and drug target. CONCLUSIONS: Understanding what is known about these trials, especially given the limited but heterogenous response reported in these trials, provides context about the strengths and limitations of drugs, especially since several drugs have been approved in recent years for tumour-agnostic indications, based on the results of these types of trials.

Eventual success rate and predictors of success for oncology drugs tested in phase I trials.

Previous estimates of the likelihood of a drug tested in phase I trials obtaining FDA clearance are out of date. In the intervening years, newer pharmaceuticals have been developed, resulting in new delivery systems and lines of therapies. We sought to explore and update these estimates by comprehensively searching drugs tested in phase I trials and to determine the factors associated with later receiving FDA approval. In a cross-sectional analysis, we searched for anti-tumor drugs tested in phase I trials and published in scientific journals or presented at hematology/oncology conferences. For each drug, we searched PubMed for phase II and phase III studies testing the drug for the same indication tested in phase I studies. We found 51 drug approvals; four were withdrawn. The probability of a drug tested in 2015 being approved by 2021 was 6.2%. Drugs tested as monotherapy were more likely to receive approval than drugs tested in combination, and monoclonal antibodies were more likely to receive approval than drugs of other mechanisms. In adjusted models, response rates higher than 40% in phase I studies, demonstrating an improvement in overall survival (OS) in phase III studies, and drugs tested as monotherapy were associated with receiving FDA approval. When looking at all drugs tested during a single year, most drugs were not approved, and among those that are approved, almost 8% are withdrawn. Response rates higher than 40%, testing a drug as monotherapy, and demonstrating an improvement in OS were associated with receiving FDA approval.

Association Between US Drug Price and Measures of Efficacy for Oncology Drugs Approved by the US Food and Drug Administration From 2015 to 2020.

This cross-sectional study estimates all US Food and Drug Administration anticancer approvals in recent years and evaluates if an association exists between their cost and efficacy.

Crossover in Adjuvant Trastuzumab Trials: Sparing Toxicity in Patient Care.

OBJECTIVES: Design and reporting of randomized control trials for drug therapies in the adjuvant setting require a nuanced consideration of patient crossover. Adjuvant trials can be susceptible to the misuse of crossover and may distort the interpretation of findings. We sought to investigate and describe crossover and/or postprogression access to trastuzumab within adjuvant trastuzumab randomized control trials for human epidermal growth factor receptor 2-positive breast cancer patients. METHODS: Seven clinical trials for adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer were identified through a meta-analysis published in the Lancet . Primary study publications were located through MEDLINE, Google Scholar, and trials were identified, when possible, using Clincialtrials.gov. RESULTS: Sixteen publications, describing 7 studies, were reviewed. Four (57%) trials reported offering patients within the control arm the opportunity to crossover and receive trastuzumab in the adjuvant setting. Two (29%) trials did not report nor discuss crossover within the publication. Five (71%) trials reported the total number of patients who crossed over among the control arms. No trials specified the proportion of control patients who received trastuzumab at recurrence. CONCLUSIONS: Trials for adjuvant trastuzumab did not disambiguate between crossover (1) in the adjuvant setting or (2) at recurrence. Due to the low reported rate of crossover, it is questionable if participants received the standard of care.