JCO Precision Oncology

BackgroundFOLFIRINOX is a cornerstone regimen for eligible patients with pancreatic ductal adenocarcinoma (PDAC), but its clinical benefit is limited by substantial toxicity and frequent dose modification. In real-world practice, dose modifications are often individualized, and the clinical factors associated with these decisions remain incompletely characterized. ObjectiveTo develop and evaluate an electronic medical record (EMR)-based machine-learning framework for modeling cycle-specific FOLFIRINOX dose modification decisions in patients with PDAC. MethodsWe included patients with PDAC who received FOLFIRINOX at UCSF oncology clinics between November 2011 and December 2023. Predictors included demographic, clinical, laboratory, and treatment variables derived from the EMR. Logistic regression, random forest, and XGBoost models were trained using group-based 5-fold cross-validation to predict cycle-specific dose modifications for 5-fluorouracil, irinotecan, and oxaliplatin. Model performance was evaluated using area under the receiver operating characteristic curve. ResultsThe cohort included 514 patients receiving FOLFIRINOX across 5,041 treatment cycles. The mean age was 59 years, 60% of patients were White, 41% had a history of smoking, and patients received a median of 6 chemotherapy cycles. More than 60% of patients required at least one dose modification during treatment. XGBoost demonstrated the highest performance across component drugs, with AUCs ranging from 0.53 to 0.70. Clinically plausible predictors of irinotecan and oxaliplatin dose modification included hepatic and renal function markers, cumulative drug exposure, treatment-related symptoms, and demographic or behavioral characteristics. ConclusionWe developed an EMR-based machine-learning framework to model real-world FOLFIRINOX dose modification and identified clinically plausible, routinely available predictors, particularly for irinotecan and oxaliplatin. Variable model performance suggests that dosing decisions are only partially captured by structured EMR data, highlighting both the limitations of current data-driven approaches and clinical domains where ML-based models may support individualized dosing and toxicity surveillance. Future informatics efforts should incorporate dose-modification rationale, patient-reported and functional outcomes, and validation across diverse practice settings.

PurposeFLAURA2 demonstrated that adding chemotherapy to osimertinib improved overall survival compared with osimertinib monotherapy in metastatic epidermal growth factor receptor-mutated (EGFR-mut) non-small cell lung cancer (NSCLC). Notably, only 60% of patients in the osimertinib monotherapy arm received second-line therapy after discontinuing first-line osimertinib, raising the concern that FLAURA2 did not accurately reflect real-world practices at academic medical centers. We hypothesized that a higher proportion of patients on osimertinib monotherapy receive second-line therapy at academic medical centers in the United States (US). Patients and MethodsThis is a retrospective cohort study of 115 patients with metastatic EGFR-mut NSCLC treated with first-line osimertinib monotherapy at an academic medical center in the US from February 2018 to July 2024. Analyses included Kaplan-Meier survival estimation, the log-rank test, multivariate Cox regression, and the Kruskal-Wallis test. ResultsMost patients were female (74%) and had a history of never-smoking (69%). Fifty percent were Asian, and 93% of patients had adenocarcinoma histology. The median time to treatment failure (TTF) for all patients on first-line osimertinib was 25.3 months (95% CI: 18.6- 37.5). The median TTF was 16.3 months (CI: 13.3-22.0) for TP53-mutated patients and 42.3 months (CI: 36.9-NA) for TP53 wild-type patients (log-rank test, P < 0.001). Of the 115 total patients, 66 (57.4%) discontinued first-line osimertinib. Of these 66 patients, 26 (39.4%) either died or pursued hospice. Forty (60.6%) of the 66 patients experienced progression of disease and subsequently received second-line therapy. ConclusionsOnly 61% of patients with metastatic EGFR-mut NSCLC received second-line therapy after osimertinib at our institution, confirming that the second-line therapy rates in the control arm of FLAURA2 are similar to practice patterns at our US academic medical center.

Background: Osimertinib is the standard first-line treatment for EGFR- mutant non-small cell lung cancer (NSCLC) harboring common activating mutations, including exon 19 deletions and L858R. It is also active against tumors with acquired T790M resistance. However, the EGFR L858R+T790M compound mutation, where both variants co-occur within the same tumor, may confer distinct drug-sensitivity profiles not predicted by either mutation alone. Limited data exist on comparative treatment outcomes in this rare genotype. Methods: Using the MSK-CHORD clinicogenomic dataset (n=24,950), we identified patients with concurrent EGFR L858R and T790M mutations receiving erlotinib (Erlo) or osimertinib (Osi) monotherapy. Real-world progression-free survival (rwPFS) per treatment line was calculated using a strict definition requiring confirmed radiological progression events (rwPFS-strict), excluding lines with null endpoint data. Kaplan-Meier analysis, log-rank testing, Cox proportional hazards regression, and cross-cohort heterogeneity testing (Cochran's Q statistic) were performed. Two control cohorts, L858R-only (n=372) and T790M-only (n=76), were analyzed in parallel to assess mutation-context specificity of treatment response. Results: Thirty-one patients with EGFR L858R+T790M were identified; 21 contributed evaluable monotherapy lines, yielding 23 Erlo and 15 Osi treatment lines (14 unique patients per treatment group, 7 contributing to both). Median rwPFS numerically favored Erlo over Osi (7.10 vs 5.32 months; HR 1.29, 95% CI 0.66-2.52; log-rank p=0.46). This directional trend was reversed in the L858R-only control cohort, where Osi demonstrated significant superiority (9.03 vs 5.75 months; HR 0.70, 95% CI 0.55-0.89; p=0.003). The T790M-only cohort showed no significant difference (HR 1.32, p=0.12). An exploratory post-hoc heterogeneity test confirmed a significant cross-cohort interaction (Q=9.94, df=2, p=0.007). Conclusions: The expected osimertinib advantage was absent in L858R+T790M compound-mutant NSCLC. The opposing hazard ratio directions across mutation contexts (HR 1.29 vs 0.70), with a significant exploratory cross-cohort interaction (p=0.007), suggest that the EGFR L858R+T790M compound mutation may represent a pharmacologically distinct entity with differential TKI sensitivity. These hypothesis-generating findings warrant prospective validation.

IntroductionBRCA1/2 alterations are increasingly recognized as biologically and clinically relevant features in prostate cancer, yet the prognostic and therapeutic significance of zygosity status remains uncertain. Understanding differences between monoallelic and biallelic inactivation may refine risk stratification and guide therapeutic decision-making. Materials and MethodsA retrospective, desk-based observational analysis was performed using publicly accessible datasets from TCGA-PRAD (primary disease) and SU2C/PCF (metastatic disease). BRCA1/2 status was categorized as wild-type, monoallelic, or biallelic based on mutation, copy-number, and loss-of-heterozygosity profiles. Overall survival was evaluated using Kaplan-Meier estimates and Cox models. Systemic therapy outcomes were assessed by treatment class, incorporating exploratory interaction tests. ResultsIn TCGA-PRAD (n=300), OS did not significantly differ by zygosity (global log-rank p=0.45), with median OS of 80.0 months (wild-type), 78.0 months (monoallelic), and 55.0 months (biallelic). In SU2C/PCF (n=200), zygosity stratified outcomes significantly (global log-rank p=0.04): median OS was 22.0 months (wild-type), 14.0 months (monoallelic), and 16.0 months (biallelic). Treatment analyses showed ARSI exposure improved OS in wild-type disease (HR 0.60; 95% CI 0.38-0.95), while interaction testing suggested potential heterogeneity without statistical confirmation (interaction p=0.092). PARP inhibitor exposure showed directionally favorable HRs in wild-type and monoallelic groups but no significant interaction (interaction p=0.757). No therapy class demonstrated consistent effect modification by zygosity. ConclusionBRCA1/2 zygosity shows prognostic relevance in metastatic prostate cancer but not clearly in primary disease. While zygosity did not consistently modify systemic therapy associations in this dataset, findings support zygosity-aware reporting as a practical tool for molecular stratification and future research design.

PurposeThe addition of PARP inhibitors to chemotherapy has been assessed in [~]80 clinical trials across multiple malignancies, on the premise that PARP inhibitors will increase chemotherapy effectiveness regardless of whether cancers have underlying disruption of DNA repair pathways. Consequently, the majority of combination therapy trials have been performed on patients without biomarker selection, despite the use of homologous recombination deficiency to dictate use of PARP inhibitors in the maintenance setting. An unresolved question is whether biomarkers are needed to identify patients who respond to combination PARP inhibitors and chemotherapy. MethodsA systematic literature review identified studies using PARP inhibitors in combination with chemotherapy versus chemotherapy alone, where the study included a biomarker of DNA repair function (BRCA1, BRCA2, BRCAPRO, ATM, ERCC1, SFLN11). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance and fixed or random effects modelling. Subgroup analyses were conducted on biomarker selection and type of malignancy. ResultsNine studies comprising 2,084 patients met the inclusion criteria. Progression-free survival (PFS) was significantly better in patients with a DNA repair biomarker (HR 0.52, 95% confidence interval (CI) 0.43-0.63; p < 0.00001), but there was no benefit in patients who lacked a biomarker (HR 0.94, 95% CI 0.82-1.08; p = 0.38). Subgroup analysis showed that BRCA mutation and SFLN11 biomarkers could predict benefit, and biomarker-driven benefit occurred in ovarian, breast and small cell lung cancers. The addition of PARP inhibitors was associated with increased grade 3/4 side effects, and particularly neutropenia. ConclusionsCombination therapy only increases PFS in patients with identifiable DNA repair biomarkers. This indicates that PARP inhibitors do not sensitise patients to chemotherapy treatment, except where their cancer has a homologous recombination defect, or an alternative biomarker of altered DNA repair. While effective in patients with DNA repair biomarkers, there is a risk of high-grade haematological side-effects with the use of combination therapy. Thus, the benefit in PFS from combination therapy must be weighed against potential adverse effects, as individual arms of treatment can also confer benefit. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/23290442v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1c2dddcorg.highwire.dtl.DTLVardef@73d1e3org.highwire.dtl.DTLVardef@1d8cef0org.highwire.dtl.DTLVardef@fa22cc_HPS_FORMAT_FIGEXP M_FIG C_FIG

PurposeNational guidelines recommend next generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. We sought to describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race/ethnicity, and overall survival in US Veterans. Patients and MethodsThis retrospective cohort study included Non-Hispanic Black (NHB) and Non-Hispanic white (NHW) Veterans with mPCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. 45 genes in seven canonical or targetable mPCa pathways were evaluated in addition to TMB and MSI status. Multivariable logistic regression evaluated associations between race/ethnicity and genomic alteration frequencies. Cox proportional hazards models were used to determine associations between race/ethnicity, specific gene/pathway alteration, and overall survival. Results5,015 Veterans with mPCa who had NGS conducted were included (1,784 NHB, 3,231 NHW). NHB Veterans were younger, had higher PSA at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared to NHW Veterans. Nine of the top ten most commonly altered genes were the same in NHB v NHW Veterans; however, the frequencies of alterations varied by race/ethnicity. NHB race/ethnicity was associated with higher odds of genomic alterations in SPOP (OR 1.7 [1.2-2.6]) as well as immunotherapy targets (OR 1.7 [1.1-2.7]) including MSI high status (OR 3.1 [1.1-9.4]). Furthermore, NHB race/ethnicity was significantly associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR 0.6 [0.4-0.7]), AR axis (OR 0.7 [0.5-0.9]), and tumor suppressor genes (OR 0.7 [0.5-0.8]). Cox proportional hazards modelling stratified by race/ethnicity demonstrated alterations in tumor suppressor genes including TP53 were associated with shorter OS in both NHB (HR 1.54 [1.13-2.11] and NHW individuals (HR 1.52 [1.25-1.85]). ConclusionIn the equal access VA healthcare setting, Veterans undergoing NGS for mPCa exhibited differences in alteration frequencies in both actionable and non-actionable pathways that may be associated with survival. This analysis affirms the utility of genomic testing for identifying candidates irrespective of race/ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.

Abstract Introduction: MET tyrosine kinase (TKI) therapy has improved outcomes in patients with non-small cell lung cancer (NSCLC) harboring MET alterations. However, primary and acquired resistance ultimately limits durability of response. This study evaluated the safety and efficacy of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with metastatic MET-driven NSCLC who had progressed on prior treatment with at least one MET inhibitor. Methods: A multicenter phase I study evaluated capmatinib in combination with trametinib in patients with advanced stage NSCLC harboring activating MET alterations and prior exposure to at least one MET TKI. A 3+3 dose-escalation design was employed to assess safety and tolerability of the combination. Results: Three patients (n = 3) were enrolled in the study and completed a median of 3 cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and initiation of the third patient at a lower dose level. Ultimately, all patients discontinued therapy due to treatment-related adverse events. The study was terminated early due to poor accrual and TRAEs. No radiographic objective responses were observed. Conclusions: In this phase I trial, capmatinib plus trametinib was associated with significant treatment-related adverse events and treatment was discontinued in all participants. Based on these findings, further investigation of this combination of MET and MEK inhibitors is not recommended.

Backgroundintroduction of the poly(ADP-ribose) polymerase (PARP) inhibitors to clinical practice remarkably improved outcomes for advanced epithelial ovarian cancer (EOC) patients. We conducted this study to evaluate efficacy of frontline maintenance olaparib therapy in BRCA-mutated and/or HRD-positive EOC patients in real-world practice setting. Patients and methodswe enrolled patients with FIGO stage III-IV high-grade serous or endometrioid EOC with BRCA1/2 mutations and/or HRD-positive status with complete or partial response to frontline therapy, who were treated in 2014-2024. Main objective of this trial was to compare progression-free survival (PFS) of HRD+/BRCA-mutant advanced EOC patients treated with or without maintenance olaparib in well-balanced treatment arms. Cardinality matching was considered to ensure balancing of the study arms with 1:1 ratio of patients in trial arms. The groups were balanced according to the presence of residual tumor after initial treatment, platinum-free interval duration after frontline therapy, secondary local therapy for recurrent disease, treatment with platinum drugs for relapse and subsequent bevacizumab. The primary endpoint of the study was PFS. Resultscardinality matching with 1:1 ratio resulted in 282 matched patients for the analysis. Groups were well balanced in all baseline characteristics. Median age in both treatment arms was 50 years with no differences in patients age, surgical outcomes, prevalence of BRCA-mutated or HRD-positive disease and response to initial platinum-based therapy. With a median follow up of 37.2 mo. median PFS was 38.0 in the olaparib arm and 13.7 mo. in the control arm, respectively (HR 0.32; 95% CI 0.23-0.43; p<0.001). Estimated 3-year PFS was 50.9% and 11.5%, respectively. Median PFS2 was 49.5 mo. in the olaparib arm compared to 34.3 mo. in the control arm (HR 0.58; 95% CI 0.39-0.85; p=0.005). Conclusionthis study confirms the benefits of olaparib maintenance therapy in patients with HRD- -positive and/or BRCA-mutated advanced EOC in real-world setting. HighlightsO_LIUsing cardinality matching two cohorts of patients after frontline therapy were made (treated with maintenance olaparib vs not); C_LIO_LIMedian PFS was 38.0 in the olaparib arm and 13.7 mo. in the control arm, respectively (HR 0.32; 95% CI 0.23-0.43; p<0.001); C_LIO_LIThis data confirms efficacy of maintenance olaparib for BRCA/HRD-positive advanced epithelial ovarian cancer in routine clinical practice. C_LI

BackgroundOptimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting. PurposeTo synthesize and appraise evidence on systemic therapy for mCRPC patients stratified by prior therapy and HRR alterations informing a clinical practice guideline. Data SourcesMEDLINE and EMBASE (inception to 5 March 2025) using living search. Study SelectionRandomized clinical trials assessing systemic therapy in mCRPC. Data ExtractionPrimary outcomes assessed were progression free survival (PFS) and overall survival (OS). Data SynthesisThis report of the living systematic review (LSR) includes 143 trials with 17,523 patients (59 phase III/IV trials, 8,941 patients; 84 phase II, 8,582 patients). In the setting of prior androgen deprivation therapy (ADT) alone or ADT+docetaxel, treatment benefit was observed with poly (ADP-ribose) polymerase inhibitors (PARPi) in combination with androgen receptor pathway inhibitors (ARPI) for BRCA+ subgroup. In the setting of prior ADT+ARPI or ADT+ARPI+docetaxel, treatment benefit was observed with PARPi monotherapy for BRCA+ subgroup. Treatment benefit with PARPi may be observed for select non-BRCA homologous recombination repair (HRR) alterations (CDK12, PALB2). Treatment benefit was observed with abiraterone, enzalutamide, cabazitaxel, docetaxel (if no prior docetaxel), and Lu177 (if PSMA+) for patients without HRR alterations. LimitationsStudy-level data and indirectness in evidence. ConclusionFindings from the current LSR suggest that optimal treatment for mCRPC should be individualized based on prior therapy and HRR alterations. Current evidence favors PARPi alone (ARPI exposed) or in combination with ARPI (ARPI naive) for patients with BRCA alterations, while ARPI alone, chemotherapy, and Lu177 remain potential options for patients without HRR alterations. Registrationhttps://osf.io/46tjm Primary Funding SourceNIH U24 grant (U24CA265879-01-1).

AimIn this systematic review, the efficacy and safety of chronomodulated chemotherapy, defined as delivery of chemotherapy timed according to the human circadian rhythm, were assessed, and compared to continuous infusion chemotherapy for patients with advanced colorectal cancer. MethodsElectronic English-language studies published until October 2020 were searched. Randomised Controlled Trials (RCTs) compared chronomodulated chemotherapy with non-chronomodulated (Conventional) chemotherapy for management of advanced colorectal cancer were included. Main outcomes were the objective response rate (ORR) and system-specific and overall toxicity related to chemotherapy. Electronic database search in Ovid Medline, Ovid Embase, Cochrane CENTRAL and the Cochrane Database of Systematic Review (CDSR). ResultsIn total, 7 RCTs including 1137 patients were analysed. Males represented 684 (60%) of the study population. The median age was 60.5 (range: 47.2 - 64) years. There is no significant difference between chronomodulated and conventional chemotherapy in ORR ((risk ratio (RR) 1.15; 95%CI [0.87-1.53]). There was no significant difference in gastrointestinal toxicity under the random effect model RR 1.02; CI 95% [0.68 - 1.51]. No significant difference was found regarding neurological and skin toxicities, (RR 0.64,95%CI [0.32 - 1.27]) and (RR 2.11, 95%CI [0.33-13.32]), respectively. However, patients who received chronomodulated chemotherapy had fewer haematological toxicity, (RR 0.36, 95%CI [0.27-0.48]). ConclusionThere was no overall difference in ORR or toxicity but haematologic, between chronomodulated and non-chronomodulated chemotherapy used for patients with advanced colorectal cancer. Chronomodulated chemotherapy could be considered in patients at high risk of haematological toxicities.

The safety and efficacy of nivolumab in treating advanced renal cell carcinoma (aRCC) patients have been evaluated in real-world evidence (RWE) studies across various European countries, but no such data from Spain have been reported until now. We conducted a multicenter, retrospective study on 222 previously treated aRCC patients to assess the efficacy of nivolumab and the impact of pre-treatment factors on therapy outcomes in a real-world clinical practice scenario in Spain. Our results were then compared with other significant clinical experiences involving aRCC patients treated with nivolumab monotherapy. With a median follow-up of 14.6 months, the median overall survival (OS) was 18.1 months (95% confidence interval [CI], 14.2-23.7 months), and the median progression-free survival (PFS) was 4.96 months (95% CI, 3.98-7.13 months). The disease control rate was 51% (95% CI, 45-58%) and the objective response rate 23% (95% CI, 18-30%). Poor IMDC risk score was independently associated with worse OS, while prior nephrectomy with better OS. Poor IMDC risk score and [&ge;]3 metastatic sites were independently associated with worse PFS; [&ge;]3 metastatic sites was also associated with lower disease control. Consistent with prior clinical trials and RWE studies, this research confirms the efficacy and safety of nivolumab in daily clinical practice for a cohort of unselected previously treated aRCC patients in Spain.

PurposePrognosis in metastatic non-seminomatous germ cell tumors (mNSGCT) is currently guided by the IGCCCG classification, which incorporates tumor markers, organs involved with metastatic disease, and primary site but not histologic subtype. We aimed to evaluate whether specific histological components provide additional prognostic information in a large international mNSGCT cohort. Patient and MethodsWe analyzed clinical, pathologic, and outcome data from 662 patients with mNSGCT across multiple international centers. Cox regression and multivariable stepwise models were used to evaluate the impact of age, tumor histology, serum markers, primary site of disease, chemotherapy, IGCCCG, and post-chemotherapy surgery on overall survival. Analyses were performed using both complete-case and imputed datasets to account for missing values. ResultsThe presence of any percentage of embryonal carcinoma (EC) was independently associated with improved overall survival HR 0.603 (95% CI: 0.37-0.98, p=0.040), whereas yolk sac tumor (YST) predicted worse prognosis in complete-case analysis HR 2.27 (95% CI: 1.43 - 3.61 p = 0.001). Choriocarcinoma was also associated with a HR 1.58 (95% CI: 1.08 - 2.32 p= 0.019) adverse outcomes. IGCCCG risk classification remained a strong predictor of mortality HR up to 8.9 for Poor vs Good risk, (95% CI: 4.63 - 17.09 p < 0.001), but histologic components added significant independent prognostic value. Post-chemotherapy retroperitoneal lymph node dissection (RPLND) conferred a substantial survival benefit HR 0.44 (95% CI: 0.258 - 0.754 p=0.003). Interestingly, teratoma was not associated with mortality but was linked to younger age, testicular primaries, and higher likelihood of residual disease requiring surgery. ConclusionsHistological composition, particularly the presence of EC or YST, has a significant and independent impact on survival in mNSGCT, beyond established risk classifications. Integration of histological subtypes may enhance prognostic accuracy and guide individualized treatment strategies in advanced germ cell tumors.

Background Patients with advanced pancreatic ductal adenocarcinoma (aPDAC) often experience general health decline at diagnosis due to a high-symptom burden. The optimal management of symptoms and/or poor performance status (PS) in these patients remains an unmet medical need. Patients and Methods In this multicenter study, patients with PS[&ge;]2 and pathologically confirmed or imaging-suspected aPDAC were included at first oncology visit in a personalized 14-day emergency integrative supportive care program (14-EISCP) to manage pain, nutrition, diagnostics, and stenting procedures. The primary endpoint was the 14-EISCP success in feasibility of planned procedures and clinical benefit defined as post-EISCP PS[&le;]1, [&ge;]5 points improvement in fatigue, pain, global health-related quality of life (HRQoL) scores (EORTC QLQ-C15-PAL), or chemotherapy initiation within 30 days. Results A total of 106 patients were included; 93 evaluable patients considered for primary endpoint analysis (median age: 76 years [68-80], PS3: 20.9%, metastases: 61.3%). The median overall survival was 4.1 months (IC95% 2.6-5.6). The 14-EISCP was successful in 59.1% (n=55) of patients, meeting the primary objective (clinically relevant). The 14-EISCP feasibility was achieved in 70.9% of cases. Post-EISCP clinical benefit was observed in 79.6% of patients, with PS improvement to 0/1 in 13.2%, HRQoL improvement in 23.9%, and chemotherapy initiation [&le;]30 days in 73.1%. Among evaluable patients, 17.2% received mFOLFIRINOX or gemcitabine-nab-paclitaxel, 35.4% received FOLFOX, 25.3% had gemcitabine or 5-fluorouracil alone, and 22.2% received best supportive care. In patients with PS2 at baseline, the administration of doublet/triplet chemotherapy was associated with improved overall survival compared to single-agent. Discussion These results offer a promising framework for improving outcomes in aPDAC patients, bridging the gap between symptom management and systemic therapy administration. Conclusions In patients with PS[&ge;]2 and aPDAC, the personalized 14-EISCP was feasible and lead to meaningful clinical benefit, allowing doublet or triplet chemotherapy in half the patients.

BackgroundNUC-3373 is a novel thymidylate synthase (TS) inhibitor designed to directly deliver the active anti-cancer metabolite fluorodeoxyuridine-monophosphate (FUDR-MP or FdUMP) intracellularly. In addition to being a potent TS inhibitor, NUC-3373 has also been shown to cause DNA damage and promote the release of damage-associated molecular patterns. These diverse mechanisms position NUC-3373 as a potentially effective combination partner for several other anti-cancer agents. MethodsNuTide:303 was a Phase Ib/II open label, multi-arm, parallel cohort dose-finding and expansion study designed to evaluate optimal combination partners for NUC-3373. Module 1 planned to enroll up to 12 evaluable patients with advanced/metastatic solid tumors to determine the recommended dose for NUC-3373 in combination with leucovorin (LV) and pembrolizumab. Module 2 planned to enroll approximately 6-12 evaluable patients with advanced/metastatic non-small cell lung cancer (of any histology) or pleural mesothelioma to determine the recommended dose for NUC-3373 in combination with LV and docetaxel. A 3+3 dose escalation design was used in both modules, with safety parameters continually assessed and tumor assessments conducted at screening and every 8 weeks from C1D1 until progression. The study was terminated early and the Phase II part was not initiated; therefore, only results of the Phase Ib part of the study are presented. ResultsFifteen patients were enrolled in Module 1, of whom 13 received study treatment and were included in the safety population. Nine patients were evaluable for anti-tumor activity. No DLTs were observed in these heavily pre-treated PD-(L)1 experienced patients with a variety of different tumor types. An objective response rate of 22% and a disease control rate of 67% were reported. NUC-3373 + LV + pembrolizumab was well tolerated, the most common treatment-related adverse events (AEs) were nausea, vomiting, diarrhea, and fatigue and the majority of events were Grade 1 or 2. Four patients were enrolled in Module 2, all of whom received study treatment. Three evaluable for anti-tumor activity. Two patients treated at the first dose level achieved stable disease and completed >6 months of treatment. The most common treatment-related AE was fatigue (n=4) and the majority of events were Grade 1 or 2. ConclusionsThe results from the Phase Ib part of NuTide:303 suggest that NUC-3373 may be an effective combination partner for pembrolizumab in a variety of advanced solid tumors. The probability of being able to escalate to typical efficacious doses of docetaxel used in combination is low due to overlapping toxicity. The use of a different taxane in this combination is currently being considered.

PurposeDifferential tumor response to therapy is partially attributed to tumor heterogeneity. Additional efforts are needed to identify tumor heterogeneity parameters in response to therapy that are easily applicable in clinical practice. We aimed to describe tumor response-speed heterogeneity and evaluate its prognostic value in patients with metastatic colorectal cancer (mCRC). Patients and MethodsIndividual patient data from Amgen (NCT00364013) and Sanofi (NCT00305188; NCT00272051) trials were retrieved from Project Data Sphere. Patients in the Amgen 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) arm were used to establish response-speed heterogeneity. Its prognostic value was subsequently validated in the Sanofi FOLFOX arms and the Amgen panitumumab + FOLFOX arm. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. ResultsPatients with high response-speed heterogeneity in the Amgen FOLFOX cohort had significantly shorter (P<0.001) median progression-free survival (PFS) of 7.27 months (95%CI 6.12-7.96 months) and overall survival (OS) of 16.0 months (95%CI 13.8-18.2 months) than patients with low response-speed heterogeneity with median PFS of 9.41 months (95%CI 8.75- 10.89 months) and OS of 22.4 months (95%CI 20.1-26.7 months), respectively. Tumor response-speed heterogeneity was a poor prognostic factor of shorter PFS (HR 4.17, 95%CI 2.49-6.99, P<0.001) and shorter OS (HR 2.57, 95%CI 1.64-4.01, P<0.001), after adjustment for other common prognostic factors. Comparable findings were found in the external validation cohorts. ConclusionTumor response-speed heterogeneity to first-line chemotherapy was a novel prognostic factor associated with early disease progression and shorter survival in patients with mCRC. Implications for PracticeRoutine clinical decision making heavily relies on radiographic assessment of disease response to therapy. For patients with heterogeneous tumors, the degree and kinetics of individual tumor response to the same therapy can sometimes be vastly different. We explored a novel quantitative parameter to describe response-speed heterogeneity by utilizing individual patient data from previous clinical trials. This parameter was an independent prognostic factor associated with early disease progression and shorter survival. Complementary to existing molecular and radiographic tumor heterogeneity parameters, it may help practicing oncologists describe tumor response disparity and serve as a new prognostic factor for patients with mCRC.

Lung cancer remains the leading cause of cancer mortality worldwide. Immune checkpoint inhibitors targeting PD-1/PD-L1 have significantly improved outcomes in a subset of patients. OncoPrism, a clinical test employing a multidimensional predictive RNA-based immune biomarker, was evaluated for predicting immune checkpoint inhibitor (ICI) benefit in non-small cell lung cancer (NSCLC) patients. This study included data from 1,487 patients and evaluated OncoPrism across four NSCLC cohorts: one PD-L1 inhibitor cohort (n=195), one PD-1 inhibitor cohort (n=89), and two non-ICI cohorts (n=193 and n=1,010, respectively). In the PD-L1 inhibitor cohort, OncoPrism predicted progression-free survival (p<0.0001) and overall survival (p=0.043). In the PD-1 inhibitor cohort, an observational clinical trial, PREDAPT (NCT04510129) enrolling patients from 17 healthcare systems, OncoPrism predicted overall response rate (p=0.008), progression-free survival (p=0.004), and overall survival (p=0.011). PD-L1 Tumor Proportion Score (TPS) was not predictive of response, progression-free survival, or overall survival. OncoPrism did not predict overall survival across two non-ICI NSCLC cohorts (p=0.54, p=0.73), suggesting the test is specifically predictive of ICI benefit rather than being prognostic with more limited clinical utility. Overall, the data show OncoPrism high patients are likely to benefit from a two to three-fold increase in overall response rate, progression-free survival, and overall survival compared to those in other OncoPrism groups. These results underscore the impact of OncoPrism to address the current unmet need for ICI response prediction in NSCLC.

Background and ObjectivesIntravesical gemcitabine/docetaxel (Gem/Doce) is an effective therapy for Bacillus Calmette- Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem/Doce. MethodsPatients with BCG-unresponsive NMIBC treated with Gem/Doce were classified as responders (recurrence-free survival [RFS] >12 months) or non-responders (RFS <12 months). Whole-exome sequencing was performed on tumors prior to Gem/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT. Key Findings and LimitationsResponders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p<0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p<0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2/2 non-responders vs 0/1 responders; p=0.33). Phylogenetic analyses revealed clonal BAP1 and subclonal BRCA2 mutations in responders, whereas non-responders harbored clonal FGFR3 mutations. Limitations include small sample size and retrospective design. Conclusions and Clinical ImplicationsDistinct genomic features underlie differential response to Gem/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g., BRCA2) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials. Patient summaryIn this report we analyzed bladder tumors and found that some tumors respond well to treatment because they have defects in repairing DNA, making them more vulnerable to chemotherapy. In contrast, tumors that do not respond to chemotherapy harbor different genetic changes that help them survive and grow. These findings may help physicians choose more effective and personalized treatments in the future.

BackgroundThere are limited data comparing clinical and pathologic features and outcomes of rhabdomyosarcoma (RMS) between young children, adolescent/young adults (AYAs), and adults. Design/MethodsWe performed a retrospective chart review of patients with RMS treated at our institution between 2000 and 2017. We compared clinical and pathologic features, treatment modalities, and outcomes among three different age groups (young children: <15 years of age, AYA: 15-39 years of age, and older adults: >39 years of age). ResultsAmong 65 patients, 33 (50.8%) were young children, 14 (21.5%) were AYAs, and 18 (27.7%) were older adults. Head and neck was the most common tumor site among young children, AYAs tumor sites were variable, while extremities were the most frequent location for adults. AYAs were more likely to have stage 4 disease at presentation (64.3% vs. 21.2% in children, p=0.01, and vs. 27.8% in adults, p=0.08). Similarly, clinical group and risk classifications were higher among AYAs as compared to the other two age groups. Tumors in children were alveolar and embryonal histology, while AYAs primarily developed alveolar RMS. Older adults had tumors with diverse histologies, including pleiomorphic and spindle cell. Children and AYAs received multimodal therapy, but a subset of adults did not. Five-year overall survival (OS) varied by age at diagnosis (p=0.001), with highest OS among young children (81.8%) following by adults (50.0%), with the lowest OS among AYAs (14.29%). ConclusionThis study highlights the need for ongoing collaboration between pediatric and adult multidisciplinary teams to improve outcomes for patients with RMS across the age spectrum.

PurposeHomologous recombination deficiency (HRD) impacts cancer treatment strategies, particularly the effectiveness of PARP inhibitors. However, the variability different HRD assays has hampered the selection of oncology patients who may benefit from these therapies. Our study aims to assess the whole genome landscape to better define HRD in a pan-cancer cohort and to contribute to harmonization of HRD detection. MethodsWe employed a whole-genome sequencing WGS HRD classifier that included genome-wide features associated with HRD to analyze 580 tumor/normal paired pan-cancer samples. The HRD results were correlated retrospectively with treatment responses and were compared with commercial HRD tests in a subset of cases. ResultsHRD phenotype was identified in 62 samples across various cancers including breast (19%), pancreaticobiliary (17%), gynecological (15%), prostate (8%), upper gastrointestinal (GI) (2%), and other cancers (1%). HRD cases were not confined to BRCA1/2 mutations; 24% of HRD cases were BRCA1/2 wild-type. A diverse range of HRR pathway gene alterations involved in HRD were elucidated, including biallelic mutations in FANCF, XRCC2, and FANCC, and deleterious structural variants. Comparison with results from commercial HRD assays suggests a better performance of WGS to detect HRD, based on treatment response. ConclusionHRD is a biomarker used to determine which cancer patients would benefit from PARPi and platinum-based chemotherapy. However, a lack of harmonization of tests to determine HRD status makes it challenging to interpret their results. Our study highlights the use of comprehensive WGS analysis to predict HRD in a pan-cancer cohort, elucidates new genomic mechanisms associated with HRD, and enables an accurate identification of this phenotype, paving the way for improved outcomes in oncology care.

BackgroundDabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) are approved for BRAF V600E-mutated anaplastic thyroid cancer (ATC), but [~]60% of tumors do not harbor BRAF V600E, leaving these patients without effective treatment options. The combination of lenvatinib + pembrolizumab was studied in the ATLEP trial in Europe, demonstrating a response rate of 52%, and median progression-free survival (PFS) and overall survival (OS) of 10 and 11 months, respectively, in ATC. MethodsThis was a phase 2 study of patients with BRAF wild type ATCs were treated with concurrent lenvatinib 20 mg po daily and pembrolizumab 400 mg IV Q6 weeks. Those at high risk of bleeding could start on a reduced dose of lenvatinib. The primary endpoint was median OS and secondary endpoints were response rate and PFS. With historical median OS of 3 months with single agent lenvatinib, the trial aimed to improve OS by additional 3 months. ResultsTwenty-five patients with a median age of 62 years were enrolled, of which 64% were men. All patients had distant metastases at study entry. With a median follow-up time of 17.5 months (range 8.8-41.4) for alive patients, the median OS and PFS were 11.4 (95%CI: 7.8 to 35.6; p<0.025), and 5.4 months (95%CI: 3.8-11.0), respectively. Best overall response in target lesions was 36%, including 1 complete and 8 partial responses. ConclusionLenvatinib + pembrolizumab demonstrates efficacy in patients with metastatic, non-BRAF mutated ATC and should be considered a standard of care in this patient population.