CDK4/6 inhibitors as adjuvant therapy in early breast cancer? Uncertain benefits, guaranteed harms.

CDK4/6 inhibitors are oral agents inhibiting key molecules of the cell cycle regulation. In patients with endocrine receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy is an effective treatment in the metastatic setting. Now, two studies in the adjuvant setting - MonarchE (2 years of abemaciclib) and NATALEE (3 years of ribociclib) - report positive invasive disease-free survival. Here, we re-evaluate these seminal trials. First, an excess drop-out or loss-to-follow up occurred early in the control arms of both studies. Since both trials are open-label, there is concern that the patients who drop-out do not do so at random but based on socioeconomic factors and alternative options. Is it possible that the results merely appear favorable due to loss to follow up? Based on re-constructed Kaplan-Meier curves, we concluded the results of these studies remain fragile, being prone to informative censoring. Secondly, adverse events were notably higher in both trials, and some of them, like COVID-19 related deaths in NATALEE, raise serious concerns. Third, the potential costs associated with CDK4/6 inhibition given as adjuvant therapy are unprecedented. The NATALEE strategy, in particular, could affect up to 35 % of patients with newly diagnosed breast cancer, which is the cancer with the highest incidence worldwide. Without confirmatory data based on a placebo-controlled trial, or better identification of patients that would benefit from the addition of CDK4/6 inhibitors in the adjuvant setting, we argue against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer.

A novel framework to assess haematology and oncology registration trials: The THEOREMM project.

BACKGROUND: Methodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies-ESMO-MCBS and ASCO Value Framework-do not integrate these important shortcomings. METHODS: We propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)-that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework. RESULTS: Not applicable. CONCLUSIONS: Our proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

Postrecurrence Treatment in Neoadjuvant or Adjuvant FDA Registration Trials: A Systematic Review.

Importance: In oncology randomized clinical trials, suboptimal access to best available care at recurrence (or relapse) may affect overall survival results. Objective: To assess the proportion and the quality of postrecurrence treatment received by patients enrolled in US Food and Drug Administration (FDA) registration trials of systemic therapy in the adjuvant or neoadjuvant setting. Evidence Review: For this systematic review, all trials leading to an FDA approval from January 2018 through May 2023 were obtained from the FDA website and drug announcements. Randomized clinical trials of an anticancer drug in the neoadjuvant or the adjuvant setting were included. Trials of supportive care treatment and treatments given in combination with radiotherapy were excluded. Information abstracted for each trial included tumor type, setting, phase, type of sponsor, reporting and assessment of postrecurrence, and overall survival data. Findings: A total of 14 FDA trials met the inclusion criteria. Postrecurrence data were not available in 6 of 14 registration trials (43%). Of the 8 remaining trials, postrecurrence treatment was assessed as suboptimal in 6 (75%). Overall, only 2 of 14 trials (14%) had data assessed as appropriate. Conclusions and Relevance: This systematic review found that 43% of randomized clinical trials of anticancer treatment in the adjuvant or neoadjuvant context failed to present any assessable postrecurrence treatment data. In instances in which these data were shared, postrecurrence treatment was suboptimal 75% of the time. The findings suggest that regulatory bodies should enforce rules stipulating that patients have access to the best standard of care at recurrence.

Health-related quality of life in trials with high rates of early censoring: Caution advised.

Health-related quality-of-life (HRQoL) data are central to capturing the quality of patients' life, while endpoints like overall survival (OS) focus on the quantity of life. When analyzing HRQoL data gathered from patients in a randomized trial, a key consideration is the completion rate - indicating the proportion of patients remaining in the trial and with completed questionnaires. When completion rates are disproportionately low in one treatment arm, one likely explanation is that patients who did not complete questionnaires suffered more from toxicities, negatively impacting their HRQoL. This is likely the case when low completion rates occur in the more toxic arm within a randomized trial. If the HRQoL analysis is run as a complete-case analysis - only considering patients without missing data - a decrement in HRQoL can be missed. Conversely, when completion rates are high, the HRQoL data are thought to be more reliable, and informative censoring is less likely. We describe why this reasoning can be inadequate. In trials where high and imbalanced rates of early censoring affect progression-free survival or OS endpoints, the completion rates only apply to the fraction of patients remaining in the trial. In those, HRQoL results should be considered with caution, and reasons for censoring in the primary time-to-event analyses should be explored before making definite conclusions about HRQoL. This is even more relevant in trials with non-inferiority design, where a benefit in HRQoL could be used as a justification to modify practice.

[Interpreting a randomized trial in oncology: Key points for the clinician]. / Interpréter un essai randomisé en oncologie : éléments clés en clinique.

The analysis of randomized clinical trials presents a challenge for clinicians. A set of critical elements can facilitate their interpretation. One must question whether the inclusion and exclusion criteria accurately mirror clinical practice. Does the control arm align with what is currently recognized as best practice? Do patients in the control group have access to the best options when the cancer progresses or recurs? The degree of confidence with which phase II trial results can be interpreted also warrants consideration. Finally, informative censoring can be searched for by comparing early censoring rates between treatment arms. Faced with the challenges of interpreting scientific literature, these keys can help the clinician and guide the eventual integration of new results into shared medical decision-making.

L'analyse d'essais cliniques randomisés est un défi pour le clinicien. Une série d'éléments clés peuvent toutefois aider à l'interprétation. Tout d'abord, les critères d'inclusion et d'exclusion reflètent-ils la pratique quotidienne ? Ensuite, le bras contrôle correspond-il aux meilleures pratiques reconnues ? Est-ce que les patients du groupe contrôle ont un accès aux meilleures options lorsque le cancer progresse ou récidive ? Avec quelle confiance interpréter des résultats de phase II ? Enfin, la censure informative peut être recherchée en comparant les taux de censure précoce entre les bras de traitements. Face aux défis de l'interprétation de la littérature scientifique, ces clés peuvent être une aide pour le clinicien et guider l'intégration éventuelle de nouveaux résultats dans la décision médicale partagée.

Neoadjuvant followed by adjuvant pembrolizumab in melanoma: time biases in the data analysis of the SWOG S1801 trial.

The SWOG S1801 trial investigated the role of pembrolizumab, an anti-PD1 immune checkpoint inhibitor, in the perioperative setting of stage III or IV melanoma. This phase 2 trial compared two groups: one receiving pembrolizumab both before and after surgery (neoadjuvant-adjuvant), and another receiving it only post-surgery (adjuvant-only), with event-free survival (EFS) as the primary endpoint. Neoadjuvant strategies, involving pre-surgical drug administration, potentially offer rapid tumor control and a unique opportunity to assess tumor response. However, they may expose to toxicity and delay or preclude surgery. The study met its primary endpoint, with a 72 % EFS rate in the neoadjuvant-adjuvant group, and 49 % in the adjuvant group. Here, we question the results' applicability with three potential limitations. Key concerns include an arbitrary rule in event assignment, possibly affecting the event distribution over time. Second, different rates of early censoring between groups introduce the possibility of informative censoring, which could have led to an artefactual benefit in EFS. Lastly, phase 2 trial results, by definition, carry risk of fluke results, and should be confirmed in phase 3 trial before wide adoption. Collectively, these factors must be integrated into a careful interpretation of the SWOG S1801 trial outcomes. More robust data are needed to fully appraise strengths and limitations of neoadjuvant pembrolizumab in melanoma treatment.

Unveiling the Landscape of Uncommon EGFR Mutations in NSCLC-A Systematic Review.

Uncommon EGFR mutations represent a rare subgroup of NSCLC. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations are scattered and limited to mostly retrospective small cohorts because these patients were usually excluded from clinical trials. This was a systematic review on the efficacy of TKIs in patients harboring uncommon EGFR mutations, defined as mutations other than exon 20 insertions mutations or T790M. Response rates (RRs) for different generations of TKIs were determined for individual uncommon mutations, compound mutations, and according to classical-like and P-loop alpha helix compressing mutations classes. This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 1836 patients from 38 studies were included in the final analysis. Most available data (92.6%) were from patients treated with first- or second-generation TKIs. G719X, S768I, E709X, L747X, and E709-T710delinsD showed RRs ranging from 47.8% to 72.3% to second-generation TKIs, generally higher than for first- or third-generation TKIs. L861Q mutation exhibited 75% (95% confidence interval [CI]: 56.6%-88.5%) RRs to third-generation TKIs. Compound mutations with G719X, E709X, or S768I consistently showed RRs above 50% to second- and third-generation TKIs, although fewer data were available for third generations. For classical-like mutations, RRs were 35.4% (95% CI: 27.2%-44.2%), 51.9% (95% CI: 44.4%-59.3%), and 67.9% (95% CI: 47.6%-84.1%) to first-, second-, and third-generation TKIs, whereas for P-loop alpha helix compressing mutations classes mutations, RRs were 37.2% (95% CI: 32.4%-42.1%), 59.6% (95% CI: 54.8%-64.3%), and 46.3% (95% CI: 32.6%-60.4%), respectively. This systematic review supports the use of second-generation TKI afatinib for G719X, S768I, E709X, and L747X mutations and for compound uncommon mutations. For other uncommon mutations such as L861Q, third-generation TKI, such as osimertinib, could also be considered, given its activity and toxicity profile.

Progression-free survival estimates are shaped by specific censoring rules: Implications for PFS as an endpoint in cancer randomized trials.

Kaplan-Meier analysis hinges on the assumption that patients who are censored- lost to follow-up, or only recently enrolled on the study- are no different, on average, than patients who are followed. As such, censoring these patients- omitting their future information and taking the average of those who were followed- should not dramatically change the overall estimate. Yet, in a recent clinical trial, two sets of censoring rules- one favored by trialists and one favored by the US Food and Drug Administration- were applied to a progression-free survival (PFS) estimate. In response, the PFS estimate changed dramatically, increasing the median in the experimental arm from 32 to 43 months, while the control arm was essentially unchanged. In this commentary, we explore the reasons why PFS changed so dramatically. We provide a broad overview of censoring in oncology clinical trials, and suggestions to ensure that PFS is a more reliable endpoint.

Equal censoring but still informative: When the reasons for censoring differ between treatment arms.

In randomized controlled trials, informative censoring has been described as a potential bias, mainly affecting time-to-event composite endpoints, like progression-free survival (PFS). It is usually suspected in the presence of unequal attrition rates between arms. Early censoring occurs for different reasons: patients may withdraw from a trial because of toxicity, or because of disappointment with their allocation arm. If censoring is more frequent in one arm due to increased toxicity, this removes the frailest individuals and introduces a bias favoring this arm. Conversely, patients who withdraw because of disappointment of their allocation arm may be more affluent and healthy patients, who will seek treatment options outside the protocol. In trials with one treatment arm presenting higher toxicity rates, and the other arm potentially leading to patient disappointment, censoring can occur for different reasons in each arm however with the same rates. We modeled this hypothesis in a randomized controlled trial where modifying only 15% of censored patients' fate in each arm at early time-points made the PFS gain fade. Equal censoring but for different reasons is a hitherto unexplored form of informative censoring with potentially large implications across the cancer clinical trials landscape.

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.

Additional considerations before using a ctDNA-guided approach for informing adjuvant chemotherapy in colorectal cancer.

BACKGROUND: The DYNAMIC trial investigated the use of circulating tumor DNA (ctDNA) to guide adjuvant treatment decisions in stage II colon cancer. Despite the DYNAMIC trial's assertion that a ctDNA-guided approach could minimize the use of adjuvant treatment without compromising recurrence-free survival (RFS), we raised concerns regarding the trial's methodology and the practical implications of its findings in a Debate article. Here, we expand upon these concerns in a response to a correspondence by the authors of the DYNAMIC trial. MAIN BODY: We dispute the choice of a large non-inferiority margin in the DYNAMIC trial, simply because an 8.5 percentage points decrease in recurrence-free survival could result in significant harm to patients. We challenge the authors' comparisons of the DYNAMIC trial outcomes with observational studies. Such comparison is subject to selection bias and changes over time that limit their relevance. The prognostic role of ctDNA do not automatically imply that more treatment in patients with ctDNA positivity would improve outcomes, which we highlight. In real-world settings, we anticipate a potential rise in chemotherapy use due to clinicians utilizing ctDNA alongside existing clinicopathologic factors, rather than using ctDNA as an entire replacement. Lastly, a key concern in DYNAMIC was an 350% higher use of oxaliplatin in the ctDNA arm compared with standard management (9.5% versus 2.7%, respectively), which poses a risk for long-term neuropathy. CONCLUSION: We look forward improvements in patient selection in the adjuvant setting, but we maintain our reservations about the DYNAMIC trial and the real-life implementation of its results. As an alternative to exploring de-escalation strategies with large margins non-inferiority trials, we propose that superiority trials in stage II patients could be a more effective strategy.

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.