[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.

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.

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.

Quality of life in the adjuvant setting: A meta-analysis of US Food and Drug Administration approved anti-cancer drugs from 2018 to 2022.

BACKGROUND: In oncology, quality of life (QoL) questionnaires were historically designed to be used in the advanced or metastatic setting. We sought to determine the effects of contemporary treatments on QoL in the adjuvant setting and to determine if the QoL instruments used in these studies provide a relevant assessment. METHODS: We conducted a systematic identification of all anti-cancer drugs used in the adjuvant setting and approved by the US Food and Drug Administration from January 2018 to March 2022. We conducted a quality evaluation and a meta-analysis of reported QoL results. We used the global QoL results when multiple QoL outcomes were reported. RESULTS: There were 224 FDA approvals reviewed, of which 12 met the inclusion criteria. The placebo was the control arm in 10 out of 12 trials. Of those, 11 trials (92 %) assessed QoL, and ten (83 %) reported results. In reports with QoL results, a moderate-risk of bias was found in 3 out of 10 (30 %) and a high-risk of bias in 6 out of 10 (60 %) of reports, respectively. No trial reported a meaningful difference between arms. The meta-analysis found an overall detrimental effect on QoL in the experimental arm, though it was not statistically different. CONCLUSION: This study identified 12 FDA registration trials in the adjuvant setting between 2018 and 2022. We found a moderate- to high-risk of bias in 90 % of the ten trials reporting QoL data. Our meta-analysis suggested a detrimental effect on QoL in the experimental arm, questioning the relevancy, in the adjuvant setting, of thresholds that were mostly developed in the advanced or metastatic setting. POLICY SUMMARY: Future works should focus on specificities of the adjuvant setting when considering QoL evaluation.

PARP inhibitors and overall survival in ovarian cancer, reevaluation advised in all settings.

PARP inhibitors in ovarian cancer have been a breakthrough therapy of the past decade, driven by positive trial results, and supported by an original pharmacological rationale. However, with mature data, detrimental survival results led to the withdrawals, in 2022, of all approved PARP inhibitors in the most advanced settings' indication (as monotherapy in third or subsequent lines) by the US Food and Drug Administration (FDA). Two other indications, as maintenance after relapse, were also restricted. In this work, based on pooled meta-analysis in each setting, we question a unique situation in oncology: a survival benefit is seen in front-line settings, with, at the same time, a survival decrement in later lines. Either this original feature is explained by the unique biological action of PARP inhibitors-through synthetic lethality-in patients with ovarian cancer and homologous repair deficiency. Another explanation may be trial design: decrement in later lines could partly explain why beneficial results were seen in early settings, simply by avoiding late exposure to PARP inhibitors in the experimental arm in those trials. High crossover rates seen in some trials further support this alternate hypothesis. We contend our analysis and recent survival results of PARP inhibitors warrant a whole reassessment of the place of these compounds in the landscape of ovarian cancer treatments.

Post-progression treatment in cancer randomized trials: a cross-sectional study of trials leading to FDA approval and published trials between 2018 and 2020.

BACKGROUND: Suboptimal treatment upon progression may affect overall survival (OS) results in oncology randomized controlled trials (RCTs). We aim to assess the proportion of trials reporting post-progression treatment. METHODS: This cross-sectional analysis included two concurrent analyses. The first one examined all published RCTs of anti-cancer drugs in six high impact medical/oncology journals between January 2018 and December 2020. The second studied all US Food and Drug Administration (FDA) approved anti-cancer drugs during the same period. Included trials needed to study an anti-cancer drug in the advanced or metastatic setting. Data abstracted included the tumor type, characteristics of trials, and reporting and assessment of post-progression treatment. RESULTS: There were 275 published trials and 77 US FDA registration trials meeting inclusion criteria. Assessable post-progression data were reported in 100/275 publications (36.4%) and 37/77 approvals (48.1%). Treatment was considered substandard in 55 publications (n = 55/100, 55.0%) and 28 approvals (n = 28/37, 75.7%). Among trials with assessable post-progression data and positive OS results, a subgroup analysis identified substandard post-progression treatment in 29 publications (n = 29/42, 69.0%) and 20 approvals (n = 20/26, 76.9%). Overall, 16.4% of publications (45/275) and 11.7% of registration trials (9/77) had available post-progression data assessed as appropriate. CONCLUSION: We found that most anti-cancer RCTs do not report assessable post-progression treatment. When reported, post-progression treatment was substandard in most trials. In trials reporting positive OS results and with assessable post-progression data, the proportion of trials with subpar post-progression treatment was even higher. Discrepancies between post-progression therapy in trials and the standard of care can limit RCT results' applicability. Regulatory rules should enforce higher requirements regarding post-progression treatment access and reporting.