Patient-reported symptoms and functioning are valuable to understanding the tolerability of cancer treatments in clinical trials. Assessment of key side effects, physical and role functioning, and overall side effect bother in trials may be helpful for benefit-risk evaluation and useful to communicate in product labeling. Inclusion of these assessments has been supported in the literature and Food and Drug Administration guidance documents. In this article, the authors provide their perspective on the evolution of how this data has been considered in oncologic therapeutic evaluation and provide context for the research being presented by the National Cancer Institute Tolerability Consortium.

Treatment with PD-(L)1 blocking antibodies has dramatically improved outcomes across multiple cancer types. Such benefits must be carefully weighed against the risks of serious immune-related adverse events (irAEs) involving various organs, the occurrence patterns of which have not yet been well characterized. This large novel analysis of pooled clinical trial data submitted to FDA aims at uncovering and gaining deeper insights into the multiorgan patterns of irAEs associated with these agents. This retrospective pooled analysis is based on patient-level, monotherapy, PD-(L)1 blocking antibody data from 18 clinical trials completed between 2019 and 2023, supporting FDA approvals across 7 cancer types. Only FDA authors had access to and analyzed patient level data. Patients with irAEs were identified using each PD-(L)1 development program’s pre-defined definitions based on MedDRA preferred terms. Preferred terms were grouped into 30 irAEs based on the involved organs. IrAEs starting before or within 7 days of the end date of the preceding irAE, were considered co-occurring. Among the 5863 patients, 64% (n=3771) had at least one irAE; the most common irAEs (>10%) were skin reaction (53.5%), colitis/diarrhea (33.2%), hepatitis (23%), hypothyroidism (19.3%), and nephritis/renal dysfunction (11.7%). 50% (n= 1890) had more than one irAE type, with 59.7% experiencing 2, 24.8% experiencing 3, 9.7% experiencing 4, and 5.8% experiencing 5 to a maximum of 8 distinct irAE types, regardless of timing during their treatment course. Median time-to-onset of irAE in patients with a single type of irAE was 45 days while median time-to-onset of first irAE in subjects with more than one type of irAE was 30.5 days. Among the 1743 patients evaluable for co-occurrence analysis, 1285 (73.7%) experienced co-occurring irAEs. The 5 most frequently co-occurring irAEs were: skin reaction and colitis/diarrhea (15.8%); skin reaction and hepatitis (8.2%); skin reaction and hypothyroidism (7.5%); skin reaction and nephritis/renal dysfunction (4.8%); and colitis/diarrhea and hepatitis (4.2%). This is the largest study of patient level clinical trial data evaluating the incidence and occurrence patterns of multi-system irAEs. The study demonstrated that the median time-to-onset of the first irAE was shorter for patients who experienced multi-organ irAEs than in those with single organ irAEs. Notably, half of the patients with an irAE experienced more than one distinct irAE during treatment, the majority of whom demonstrated co-occurrence of irAEs. These findings underscore the importance of vigilant monitoring and comprehensive management strategies to address the interconnected nature of irAEs, aiding providers in understanding, predicting, and managing patients experiencing irAEs. Abhilasha Nair, Matthew J. Hadfield, Yue Huang, Flora Mulkey, Ilynn Bulatao, Marc R. Theoret, Kerry L. Reynolds. Characterization of multi-organ system involvement of immune-related adverse events after anti-PD-(L)1 monotherapies: A pooled analysis of clinical trial data submitted to FDA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3228.

FDA Oncology Center's @Falleh_Fallah and colleagues discuss loss of equipoise and other trial conduct challenges in an era of breakthrough therapies - via @JCO_ASCO.

Peripheral neuronal cells (Peri.4U) treated with docetaxel were found to have a significant decrease in sensitivity for A) mean process lengths but not for B) mean outgrowth intensity or C) relative straightness as measured after 24 hours post-drug treatment. For paclitaxel treatment at the same time point, the cells were also found to have significantly decreased sensitivity for D) relative mean process length and E) mean outgrowth intensity but not for F) relative straightness. Neurite parameters measured with MetaXPress® software were averaged from 3 independent experiments. Error bars represent the standard error of the mean from three independent transfection experiments. NTC = non-targeting control, UT= untransfected control.

Supplementary Figure 3. Blood count trajectory for patients with or without DS.

Sensitivity to mechanical stimuli with Von Frey filaments for C57BL/6J mice and litter-mates heterozygous for VAC14 prior to docetaxel treatment. The figure displays the estimate of the proportion of mice without a hind-paw withdrawal response to stimulation by each Von Frey fiber weight, e.g., no mice respond to fibers {less than or equal to}0.2 g and all mice respond to fibers{greater than or equal to}1.4 g. The VAC14 heterozygous mice (hatched line) are more likely than wild-type mice (solid line) to respond, meaning they are more sensitive to nociceptive stimuli (p=0.0012). Gray lines denote 95% confidence intervals.

1000 SNPs with greatest statistical association with cumulative docetaxel dose at grade 3+ neuropathy in CALGB 90401 discovery GWAS.

CONSORT diagram illustrating patient flow from enrollment on parent study to population included in pharmacogenetic discovery analysis and quality control filtering of SNPs from the Illumina HumanHap610-Quad into the pharmacogenetic analysis.

Supplemental Methods, Tables and Figures Table S1. Analyzed candidate genes Table S2. Gene sets and pathways used for candidate gene selection Table S3. Quality of sequencing reads per sample Table S4. Post-QC quality per sample Table S5. Replication cohorts Table S6. Gene-based analysis of rare and low frequency variants (MAF < 0.03) in candidate genes Table S7. Characteristics of replication patient subgroups Figure S1. Candidate gene analysis workflow. Figure S2. Associations with bevacizumab-induced hypertension in the SLC29A1-HSP90AB1 region. Figure S3. Top SLC29A1-HSP90AB1 SNPs are in predicted transcriptionally active regions in human umbilical vein endothelial cells. Figure S4. Proportion of high-grade hypertension in replication cohorts stratified by variant allele carrier status. Figure S5. Dose-dependent effects of adenosine on cyclic AMP and nitric oxide levels. Figure S6. Effects of adenosine receptor blockade on cyclic AMP and nitric oxide levels in HUVEC. Figure S7. Effect of ENT1 inhibition on cyclic AMP levels. Figure S8. Effect of SLC29A1-overexpression on cyclic AMP levels in HUVEC. Figure S9. Linkage disequilibrium plot of SLC29A1-HSP90AB1 intergenic region.

Most Highly Enriched Canonical Pathways

Number of patients who experienced neuropathy, completed treatment without neuropathy and discontinued treatment early without having neuropathy while on study and within each range of cumulative treatment.

<p>Supplementary Table 1 shows adverse reactions occurring at a frequency of 10% or higher in patients with SCLC who received lurbinectedin in Study B-005. Supplementary Table 2 shows select laboratory abnormalities as worsening from baseline and occurring at a rate of 20% or higher in patients with SCLC who received lurbinectedin in Study B-005.</p>

PURPOSE The US Food and Drug Administration approved abemaciclib in combination with endocrine therapy (ET) for the adjuvant treatment of adult patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score ≥ 20%. PATIENTS AND METHODS The approval was based on monarchE, a phase III, open-label, 2-cohort, multicenter trial of patients with EBC randomly assigned to receive abemaciclib plus ET (n = 2,808) or ET alone (n = 2,829). Abemaciclib was given at 150 mg orally twice daily for 2 years. RESULTS Invasive disease-free survival (IDFS) in the intent-to-treat population was statistically significant at the second IDFS interim analysis (IA; March 2020; hazard ratio [HR; 95% CI], 0.747 [0.598 to 0.932]; P = .0096); however, only 12.5% of patients had completed adjuvant therapy, and the HR for overall survival (OS) was > 1. A prespecified, controlled analysis of IDFS in patients with Ki-67 ≥ 20% in cohort 1 was statistically significant at the final IDFS analysis (July 2020; HR [95% CI], 0.643 [0.475 to 0.872]; P = .0042). At the first OS IA (April 2021), the majority of patients had completed adjuvant therapy, IDFS remained consistent, and potential detriment in OS was not observed for this subgroup (HR [95% CI], 0.767 [0.511 to 1.152]). The HR for OS in the intent-to-treat population at OS IA remained > 1 (HR [95% CI], 1.091 [0.818 to 1.455]). More patients in the abemaciclib plus ET arm experienced treatment emergent adverse events (all grades 98.4% v 88.8%, grade 3 ≥ 49.7% v 16.3%). CONCLUSION The approval of abemaciclib in adjuvant EBC was limited to patients with high risk of recurrence and Ki-67 ≥ 20%, given their favorable benefit:risk with a statistically significant IDFS advantage and no observed detriment on survival.

Abstract Purpose: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent. Patients and Methods: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment. Results: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097). Conclusions: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.

Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after six patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I/II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days to 4.1 years), median progression-free survival of 4.4 months (95% confidence interval [CI]: 3.0-18.4), and median overall survival of 34.3 months (95% CI: 19.2 to not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side-effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM.

Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10−6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10−8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10−7). The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).

On May 26, 2020, the FDA approved nivolumab with ipili-mumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n = 361) or four cycles of platinum-doublet chemotherapy (n = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months [95% confidence interval (CI), 13.2-16.2] compared with 10.7 months (95% CI, 9.5-12.5) for patients who received chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; P = 0.0006). Progression-free survival and overall response rate per blinded independent central review were also statistically significant. This was the first NSCLC application reviewed under FDA's Project Orbis, in collaboration with Singapore's Health Sciences Authority, Australia's Therapeutic Goods Administration, and Health Canada. The benefit-risk analysis supports FDA's approval of nivolumab with ipilimumab and chemotherapy.

Abstract On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The confirmed ORR determined by investigator assessment using RECIST 1.1 in the approved SCLC patient population was 35% [95% confidence interval (CI): 26–45], with a median DOR of 5.3 (95% CI: 4.1–6.4) months. The drug label includes warnings and precautions for myelosuppression, hepatotoxicity, and embryo-fetal toxicity. This is the first drug approved by the FDA in over 20 years in the second line for patients with metastatic SCLC. Importantly, this approval includes an indication for patients who have platinum-resistant disease, representing an area of particular unmet need.