To Treatment Failure Research Articles

Predictors of response to CDK4/6i retrial after prior CDK4/6i failure in ER+ metastatic breast cancer

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8–16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2–5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7–6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

Real-world effectiveness and safety of trastuzumab-deruxtecan in Japanese patients with HER2-positive advanced gastric cancer (EN-DEAVOR study).

Trastuzumab-deruxtecan (T-DXd) was approved for the treatment of HER2-positive patients with advanced gastric cancer in Japan based on the results of the DESTINY-Gastric01 trial. This study aimed to collect real-world data and evaluate the effectiveness and safety of T-DXd. Patients aged ≥ 20years at the start of T-DXd administration with a histopathologically confirmed diagnosis of HER2-positive unresectable advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma that had worsened after chemotherapy were enrolled in this retrospective cohort study. Key outcomes included T-DXd treatment status, overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response rate and frequency of grade ≥ 3 adverse events (AEs). Of the 312 patients included in the analysis, 75.3% were male, the median (range) age was 70.0 (27.0-89.0) years, 12.2% had an ECOG PS ≥ 2, 43.3% had ascites and the initial T-DXd dose was > 5.4- ≤ 6.4mg/kg in 78.2% of patients. The median (95% confidence interval) OS, rwPFS and TTF (months) was 8.9 (8.0-11.0), 4.6 (4.0-5.1) and 3.9 (3.4-4.2), respectively. The response rate was 42.9% in patients with a target lesion. In total, 48.4% of patients experienced a grade ≥ 3 AE, 2.6% experienced grade 5 AEs and 60.9% experienced AEs leading to T-DXd dose adjustments (reduction: 36.9%, interruption: 34.0% or discontinuation: 23.7%). No new safety signals were detected. T-DXd was effective and had a manageable safety profile as a third- or later-line treatment for patients with HER2-positive gastric or GEJ cancer in Japanese clinical practice. UMIN000049032.

FLAIR: A Phase II, Open Label, Randomized Study of Osimertinib Plus Bevacizumab Versus Osimertinib in Recurrent or Metastatic Treatment-Naïve NSCLC Patients Harboring EGFR 21L858R Mutation

IntroductionOsimertinib, the 3rd generation EGFR-TKI, has emerged as standard first-line treatment for patients with advanced EGFR mutated nonsmall cell lung cancer (NSCLC). Patients with exon 21 L858R mutation showed lower efficacy with EGFR-TKIs than those with 19Del mutation, even with osimertinib, it remains an unmet medical need to further improve the efficacy in L858R population. We present the rationale and design for FLAIR (NCT04988607), which will investigate the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation. Materials and MethodsFLAIR is a prospective, multicenter, randomized, open label study, which is initiated by Chinese Thoracic Oncology Group (CTONG2002). Patients age ≥18 years with primary recurrent or metastatic nonsquamous NSCLC who are treatment-naïve with documented EGFR exon 21 L858R mutation is eligible. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily plus bevacizumab 15mg/kg every 3 weeks or osimertinib monotherapy 80 mg once daily until progression or another discontinuation criterion is met. The primary endpoint is investigator-assessed progression free survival (PFS). Secondary endpoints include: overall survival rate at 24 months, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), central nervous system (CNS) PFS, CNS ORR and safety. ResultsFLAIR has completed the enrollment, and results are expected in the fourth quarter of 2025 (depending on the actual event rate). ConclusionsThis study will offer better perspectives on the efficacy and safety of osimertinib plus bevacizumab combination therapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation, providing valuable guidance for clinical practice.

Prospective therapeutic studies of disseminated extranodal large B-cell lymphoma including intravascular large B-cell lymphoma.

This study aimed to establish a standard treatment for disseminated extranodal large B-cell lymphoma, including intravascular large B-cell lymphoma (DEN-LBCL/IVL), and to validate the clinical diagnostic criteria we proposed. Between 2006 and 2016, 22 patients were enrolled in a clinical trial conducted by the Hokuriku Hematology Oncology Study Group. The first cycle of chemotherapy consisted of dose-reduced cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with delayed administration of rituximab. From the second to the sixth cycle, patients received conventional rituximab and CHOP therapy. The primary endpoint was overall survival (OS), while the secondary endpoints included the complete response (CR) rate and time to treatment failure (TTF). The results showed a CR rate of 73%, a median OS of 65 months, and a median TTF of 45 months. These findings indicate that patients with DEN-LBCL/IVL were effectively treated with our new chemoimmunotherapy regimen. Our clinical diagnostic criteria are useful for identifying patients who require early intervention.

Capmatinib efficacy for METex14 non-small cell lung cancer patients: Results of the IFCT-2104 CAPMATU study

BackgroundCapmatinib is a selective MET inhibitor with demonstrated efficacy in a phase II study of non-small cell lung cancer (NSCLC) patients harboring METex14 mutations. However, the real-world outcomes of capmatinib are largely unknown. From June 2019, the French Early Access Program (EAP) provided capmatinib to METex14 NSCLC patients who were ineligible for or for whom first-line standard therapies had failed. MethodsIFCT-2104 CAPMATU was a multicenter study that included all METex14 NSCLC patients who received capmatinib as part of the EAP until August 2021. The primary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). ResultsA total of 146 patients were included. The median age was 74.9 years, 56.6 % were never-smokers, and 32.4 % had brain metastases. The median TTF, median PFS and median OS from capmatinib initiation were 5.1 months (95 % CI 4.2–6.0), 4.8 months (95 % CI 4.0–6.0) and 10.4 months (95 % CI 8.3–13.2), respectively. Evaluation of the best response to capmatinib was available for 134 patients and resulted in an ORR of 55.3 % (95 % CI 46.8 %-63.6 %). The median PFS was 7.7 months for treatment-naïve patients and 6.0 and 4.1 months for patients who had received one or 2 + prior lines of treatment, respectively. For patients with brain metastases, the median PFS was 3.0 months. Capmatinib had a known and manageable safety profile, with grade 3 to 4 adverse events, mostly peripheral edema (8.2 %), occurring in 17.8 % of patients. ConclusionIn this large real-world study of METex14 NSCLC patients, the efficacy of capmatinib was confirmed, with a manageable safety profile, even in patients with brain metastases and in those who received several lines of treatment. This study reinforces the key role of capmatinib for these patients.

Hypomagnesemia as a predictor of the efficacy of combination EGFR-targeted drugs versus EGFR ADCs alone in HNSCC.

146 Background: EGFR-targeted drugs and ADCs in combination with EGFR-conjugated chemotherapy drugs can both cause hypomagnesemia. However, the predictive value of hypomagnesemia in response to treatment for head and neck squamous cell carcinoma (HNSCC) is unclear. Methods: This study retrospectively analyzed patients who participated in clinical trials of EGFR-targeted drugs and EGFR ADCs for HNSCC and solid tumors, from February 24, 2022, to March 25, 2024. The primary endpoint of the study was time to treatment failure (TTF). Results: This study conducted a retrospective analysis of 68 patients . All patients exhibited normal baseline serum magnesium levels prior to treatment, but following two cycles of treatment, varying degrees of hypomagnesemia were observed among them. Among the 46 patients who received 2 cycles of combination therapy with EGFR-targeted drugs, 33 were hypomagnesemia and 13 were normal serum magnesium, ORR[90.9%vs. 8.5%,(P=0.002)] (Table), TTF [151 days (95% CI: 212-380) vs. 87 days (95% CI: 52-230), HR 0.576 (95% CI: 0.270–1.230,P = 0.021)]. Among the 22 patients who received EGFR ADC alone for 2 cycles, 8 were hypomagnesemia and 14 were normal serum magnesium, ORR [37.5% vs.28.6%, (P=0.549)] (Table), TTF [97.5 days (95% CI: 68-300) vs. 108.5 days (95% CI: 60-160), HR of 0.877 (95% CI: 0.339–2.263; P = 0.547)]. Conclusions: The study demonstrates that, the occurrence of hypomagnesemia is associated with ORR and TTF following two cycles of combination of EFGR-targeted drugs, not observed in patients receiving EGFR ADCs as monotherapy in HNSCC. [Table: see text]

Challenges of liquid panel in genomic profiling of esophageal squamous cell carcinoma (ESCC): Insights from an analysis of over 1000 cases.

86 Background: Genomic analysis of ctDNA from cancer patients can allow identification of actionable alterations of tumor without an invasive biopsy. ctDNA analysis has been reported to be superior for global summary of tumor heterogeneity and a short turnaround time compared to tissue analysis,however, there are potential issues including the detection sensitivity, threshold to determine TMB-H, and clonal hematopoiesis of indeterminate potential (CHIP). In order to elucidate the impact of ctDNA analysis on personalized cancer treatment, we decided to examine the genetic landscape and clinical outcomes of ESCC cohort registered in the C-CAT database. Methods: We retrospectively analyzed data from 1059 cases of ESCC registered in the C-CAT from June 2019 to February 2024. Clinical characteristics, TMB status, pathological gene variants, and time to treatment failure (TTF) of first-line treatment were examined. Results: The panels applied to eligible patients consisted of 925 tumor tissue panels (87.3%) and 134 liquid panels (12.7%). Pathological gene mutations were detected in 924 cases (99.8%) in tissue panels and 133 cases (99.2%) in liquid panels. The top 10 detected genes were TP53 (93.4%), CDKN2A (57.8%), CDKN2B (45.5%), CCND1 (43.9%), FGF19 (41.0%), PIK3CA (29.0%), NFE2L2 (28.3%), BCL6 (16.5%), NOTCH1 (13.5%), and KMT2D (12.2%). The detection rate for these genes excluding NOTCH1 and KMT2D were significantly higher in tissue panels than in liquid panels (P≤0.01). The median TMB was 5.00 Muts/Mb for both. In first-line treatment, the TTF for immune checkpoint inhibitors (ICIs) and chemotherapy was significantly longer in TMB-H (≧10 Muts/Mb) compared to TMB-L (3.1M vs. 1.9M, P<0.01) in patients evaluated by tissue panels, but it was not proven in patients evaluated by liquid panels (P=0.38). Furthermore, the results suggest that patients with CDKN2A, CCND1, and FGF19 variants benefit more by adding ICIs to chemotherapy than patients without these variants and while the opposite was true for BCL6 and NOTCH1 and KMT2D. Conclusions: In this ESCC cohort, detection rates in the liquid panels were generally lower than in the tissue panels, suggesting that sufficient ctDNA could not be obtained in many cases. The appropriate patient selection for the liquid panels and the timing of blood collection should be discussed. Furthermore, the ideal threshold for determining TMB-H in the liquid panels needs to be further investigated.

46 Radiological tumor burden is an independent risk factor for survival in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with first line immunotherapy (IO)-based regimens

Abstract Background IO-based regimens (IO + IO or IO + VEGF inhibitor) represent current standard of care systemic therapies for the management of patients with mRCC. IMDC is the current standard to assess prognosis in patients with mRCC of clear cell histology. Baseline radiological tumor burden (BRTB) is a readily available measurement to calculate using routine CT-scans. Here we describe the utility of BRTB as prognostic factor in patients with mccRCC treated with first line IO-based regimens. Methods We reviewed data of 183 patients with mccRCC treated at Dana-Farber Cancer Institute from August 2014 to October 2023 and who received ≥ 1 dose of an IO-based regimen (IO + IO or IO + VEGF inhibitor). Patients with available CT-scan reports within 1 month prior to first line treatment initiation were included in our analysis. BRTB was assessed by a single operator as the sum of all measurable lesions as listed on the RECIST v1.1 report. The primary outcome was overall survival (OS), and secondary outcomes were time to treatment failure (TTF) and time to next therapy (TTNT). To evaluate the impact of BRTB on OS, TTF and TTNT, we used univariable and multivariable Cox regression models accounting for IMDC risk group, history of nephrectomy, and presence of either bone, liver, or brain metastases prior to first line initiation. Results A total of 150 patients satisfied the inclusion criteria and were included in our final analysis, of which 80% of patients were male (120/150). 9% (13/150) had favorable risk, 51% (77/150) had intermediate risk and 20% (30/150) had poor risk by IMDC criteria. Overall, 73% (109/150) of patients had nephrectomy prior to first line therapy initiation and 41% (61/150) had either brain, bone, or liver metastasis. Median follow-up was 44.8 months. Every 1 cm increase in BRTB was associated with a 5% increase in risk of death (HR: 1.05; 95% CI: 1.03 – 1.08; p < 0.0001). On multivariable analysis, radiological tumor burden was significantly associated with OS (HR: 1.04; 95%CI: 1.00 – 1.08; p = 0.03). After categorizing BRTB by tertiles, tertile 1 included 0 - 7.5 cm, tertile 2: 7.6– 15.3 cm and tertile 3: 15.4 – 47.7 cm. The 4-year OS estimates were 84% (95%CI: 74 – 97%), 60% (95%CI: 45 – 81%) and 43% (95%CI: 29 – 66%), respectively, for the 1st, 2nd and 3rd tertile (log-rank P < 0.0001). BRTB did not show a significant association with TTF on univariable (HR: 1.00; 95%CI: 0.99 – 1.01; p = 0.783), or multivariable analysis (HR: 0.99; 95%CI: 0.97 – 1.01; p = 0.428). As for TTNT, BRTB also did not show a significant association on univariable (HR: 1.01; 95%CI: 1.0 – 1.02; p = 0.234) or multivariable analysis (HR: 1.01; 95%CI: 0.99 – 1.03; p = 0.453). Conclusions Baseline radiological tumor burden is an independent prognostic factor for OS in patients with mccRCC treated with first line immunotherapy-based regimens. However, tumor burden is not significantly associated with TTF or TTNT. Figure: Kaplan-Meier curves representing OS based on baseline radiological tumor burden assessed by RECIST v1.1 (Tertile 1: 0 - 7.5 cm; Tertile 2: 7.6 - 15.3 cm; Tertile 3: 15.4 – 47.7 cm). P value is derived from the log-rank test.

20 Evaluating intermediate endpoints for overall survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors: an IMDC study

Abstract Background In Phase 3 trials, the assessment for primary endpoint of overall survival (OS) necessitates extended follow-up periods, a larger pool of events, and higher associated costs. Hence, we sought to determine whether shorter intermediate (IEs) such as Objective Response (OR), Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients receiving immune checkpoint (ICI)-based therapy. Methods We included all International mRCC Database Consortium (IMDC) patients who received contemporary first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last follow-up. OR included investigators-assessed complete or partial response per RECIST1.1 criteria. First, we assessed the endpoint correlations across all follow-up times of individual patient data using Kendall’s Tau (KT) correlation by a Clayton copula. A KT >0.49 indicates a strong correlation (Wicklin R., 2023). Then we evaluated associations of OS with TTF and TTNT status at the 6-month landmark using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by ICI type and years of ICI start. The KT correlation was estimated by the R GJRM package (https://www.r-project.org/). All other statistical analyses were done with SAS 9.4 software (SAS Institute, Cary, NC). Results The cohort consisted of 1667 patients with a median follow-up of 15.4 months (IQR: 7.1-28.6). For the 6-month landmark analysis in OS, patients who died or had less than 6 months of follow-up were excluded, affecting 278 for OR, 373 for TTF, and 380 for TTNT. Median age at 1L start was 63 years (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. A total of 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Over the entire follow-up of individual patient data, the Kendall’s Tau correlation was 0.49 (95%CI: 0.45-0.52) for TTF with OS and 0.67 (95%CI: 0.64-0.69) for TTNT with OS. The Kendall’s Tau correlations between endpoints were also similar in subgroup analyses by IMDC risk group and type of regimen and the strongest in the ICI+TKI subgroup with a Kendall’s Tau correlation of 0.73(0.66-0.78). On the 6-month OS landmark analysis (Table), patients who discontinued their 1L regimen had poor OS (adjusted HR: 2.77 (95%CI: 2.16-3.55)). Additionally, those who transitioned to a 2L therapy within the first 6 months showed worse OS, reflected by an HR of 2.82 (2.22-3.59). Patients who did not have an objective response also had worse OS (adjusted HR: 2.74 (95%CI: 2.15-3.49)). On the other hand, patients with an objective response had an 18-month OS rate (equivalent of 12-month OS post the 6-month landmark) of 91% (95%CI: 88%-93%) vs 74% (95%CI: 70%-78%) for those with no response at 6 months. Table. Landmark analysis of OS from 6 months of post therapy initiation, according to OR, TTF and TTNT event status at 6 months, in whole cohort and by IMDC and treatment groups. Conclusions Our study explored TTF, TTNT and OR as clinical IEs for OS. TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating treatment efficacy in ICI-based regimens.

35 Efficacy of treatments post-lenvatinib in patients with advanced renal cell carcinoma (aRCC)

Abstract Background Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of therapies post-lenvatinib in patients with aRCC. Methods We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Patients having received treatment post-lenvatinib exposure were eligible and divided into two cohort: patients post-1st line lenvatinib (2nd line cohort) and patients post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results Overall, 84 patients received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. The median duration of prior lenvatinib was 9.7 months. All patients received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 19.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most patients were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The median follow up from 2nd-line treatment initiation was 4.9 months. The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed patients (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. The median duration of prior lenvatinib was 5.9 months. Most patients received 2nd line everolimus + lenvatinib (97%) (ORR 31%, median TTF 9.2 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most patients were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The median follow up from 3rd-line treatment initiation was 14.9 months. The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for patients progressing on lenvatinib-based therapies.

Survival outcome and prognostic factors in patients with chemotherapy-naive metastatic castration-resistant prostate cancer treated with abiraterone acetate – real-world experience in Vietnam

Introduction and aim. In real life, metastatic castration-resistant prostate cancer patients (mCRPC) had more complex clinical presentation than patients in the COU-AA-302 trial. This study primarily aimed to describe the overall survival of chemotherapy-naive mCRPC treated with abiraterone acetate plus prednisone (AAP). Other relevant outcomes and baseline characteristics of these patients were also evaluated. Material and methods. This retrospective, observational study collected data from chemotherapy-naive mCRPC patients treated with AAP in Vietnam. Kaplan-Meier curves were used to estimate time to treatment failure (TTF), and overall survival (OS). The impact of baseline characteristics on OS was explored using univariate and multivariate Cox proportional hazard models. Results. Data from 65 eligible patients were analyzed. The rate of PSA response was 73.8%, median PSA PFS was 10.5 months (95% CI: 7.4–13.6), median TTF was 15 months (95% CI: 11.1–18.9), and median OS was 24.9 months (95% CI: 18.9–30.9). Shorter OS was significantly associated with a higher Gleason score (≥8), shorter time from ADT start to mCRPC (<12 months), visceral metastases, and <50% PSA decline (p<0.05). Conclusion. Abiraterone acetate plus prednisone is well tolerated and effective for chemotherapy-naive mCRPC patients in clinical practice. Moreover, Gleason score, visceral metastasis, time from ADT start to mCRPC, and PSA response are the independent indicators for predicting the OS of mCRPC patientsin both univariate and multivariate analyses.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting.

Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. https://clinicaltrials.gov, identifier NCT01933958.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC

ObjectivesFirst-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure. Materials and methodsPatients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018–30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS). ResultsA total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0–652) after progression on osimertinib.Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65).TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis. ConclusionsOur real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.

Characterization of molecular response and progression in patients with metastatic HR+/HER2- breast cancer receiving endocrine therapy and CDK4/6 inhibitors using a high-sensitivity tumor-informed assay.

3052 Background: Tumor-informed circulating tumor DNA (ctDNA) assays, designed to track patient (pt) specific variants identified by tumor sequencing, offer enhanced sensitivity compared to traditional assays focused on driver genes. This approach enables precise ctDNA quantification, facilitating early detection of molecular progression and innovative strategies in metastatic breast cancer (mBC). Methods: HR+/HER2- mBC pts receiving standard endocrine therapy + CDK4/6 inhibitors (CDKi) were enrolled in a prospective observational cohort (2018–2023). Plasma samples were collected at baseline (BL), within 30 days (d) and ~q3 months with restaging scans. Archival tumor WES was used to design personalized panels for ctDNA monitoring. The primary endpoint was time to treatment failure (TTF). Results: Of 51 pts analyzed (median age 60 years [range 38-88], 1/2L [75/20%], visceral disease 63%, palbo-/ribo-/abemaciclib 76/22/2%), tumor-informed panels were successfully designed for 43 (1 failed WES, 7 failed QC), detecting BL ctDNA in 39 (91%). The median BL estimated variant allele fraction (eVAF) was 0.5% (0.006–17.9) and was associated with liver metastases but no other covariates (e.g. bone-only disease, history of 1ry endocrine resistance [ER]). Higher BL eVAF predicted shorter TTF (HR 1.14 CI 95% 1.05–1.23, p<0.01). Most pts had eVAF decreases below BL in the first 30 d (78%) and before the first scan (89%; median 90 d, 23–158). Early increases above BL did not significantly predict TTF, with 3/8 cases showing prolonged responses. ctDNA clearance was observed in 11/39 (28%) pts at a median of 172 d (14–410) and predicted longer TTF (HR 0.06, CI 95% 0.01–0.45, p<0.01; median TTF not reached vs 14.5 mo for pts with and without clearance), with treatment failure (TF) rates of 0% vs 40%, and 8% vs 80%, at the 1- and 2-year landmarks, respectively. Clearance was not associated with any clinical covariate (i.e. disease sites, therapy line, CDKi, history of 1ry ER). For any sample irrespective of the trajectory, higher eVAF ratios to BL predicted shorter lead times to TF, though with poor correlation (r2 0.08, p=0.01). eVAF ratios to BL >1, >0.5 and <0.5 at any timepoint had median lead times to TF of 76 d (Q1–Q3 25–135), 133 d (41–360), and 326 d (174–471). A complete analysis of ctDNA dynamics and operating parameters will be presented along with RECIST 1.1 evaluation and WES-based genomic subgroups. Conclusions: ctDNA levels and changes on therapy are prognostic and high sensitivity tumor-informed assays expand the proportion of pts who can be monitored. ctDNA clearance identified pts with better outcome and might inform pt follow up and interventional strategies. Reappraisal of existing early response cutoffs, with limited precision for individual decision making, may be necessary with more sensitive assays.

Everolimus for advanced breast cancer: Is the histological subtype important?

e13165 Background: Invasive lobular (L) breast carcinomas (BC), which account for up to 15% of all BC, had particularly histopathological characteristics: tends to be estrogen/progesterone receptor positive and HER2-neu negative and as such are treated with endocrine therapy (ET). It had been demonstrated a frequent activation of PI3K–AKT–mTOR signaling in LBCs, suggesting this pathway to be a promising therapeutic target for LBC. Interestingly, in some of these patients, the subsequent use of a mTOR inhibitor (everolimus) combined with an ET produced greater clinical benefits. Our aim is to evaluate the efficacy of everolimus in advanced BC (ABC) in the usual clinical practice, focusing on LBC. Methods: We retrospectively analyzed 147 women with ABC from four Spanish hospitals who were treated with everolimus (Ev) in second or successive lines of treatment between 2014-2023. We performed a descriptive statistical analysis of the clinicopathological variables and calculated the investigator-assessed time to treatment failure (TTF), defined as the interval from initiation of treatment to its premature discontinuation (because of progression disease (PD) or toxicity), as well as its association using Kaplan-Meier test. Survival curves were analyzed using long-rank test. Finally, we analyzed the subgroup of those with everolimus TTF (TTF2) longer than previous line TTF (TTF1) by Xi2 test. Results: With a median (m) age of 59, 21 (14%) patients (pts) were diagnosed with advanced LBC. The histopathological characteristics of the pts are shown (Table). Treatment had to be stopped in 24 pts due to toxicity (oral mucositis 21%), and the rest was due to PD or exitus. The response rate (stabilization, partial and complete response (CR)) was 49% with 4% of CR. The overall m of TTF2 was 9,1 months, while the TTF1 m was 9,5 months. Analyzing by histology, TTF2 m was 18.16 months in LBC vs 7.85 in ductal BC (p=0.01). Contrary to expectations, 40 pts (27,2%) had a longer TTF2 compared with TTF1 (p>0.001). When analyzing this subgroup we found 9 pts with LBC and 27 DBC (p>0,05). 26 pts (65%) had not received previous line with HT (p=0.005). On the other hand, when analyzing the subgroup of pts with LBC, up to 47.36% of pts had TTF2>TTF1. Conclusions: The use of everolimus in pts with LBC appears to be more effective than in DBC according to the results reported in our series and its use in initial hormonal lines may be reconsidered. However, we need more prospective studies differentiating histologies to demonstrate our results for others Pi3k inhibitors. [Table: see text]

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step 40 Gy with 56 Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck: A phase III trial (JCOG1912, NEW BRIDGE).

TPS6121 Background: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. Methods: This study is a multicenter, two-arm, open-label, randomized phase III trial. The main inclusion criteria are as follows: (i) Primary lesions are located in the oropharynx, hypopharynx, or larynx. (ii) Histologically proven SCC on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer. (iii) Clinical stage of III, IVA, or IVB (excluding N3a) based on the 8th UICC-TNM classification. Patients are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.Patient accrual was started in May 2021 and the study is now open for accrual. A total of 186 patients have been enrolled as of January 2024. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100. Clinical trial information: jRCTs031210100 .

Efficacy of post-lenvatinib treatments in patients (pts) with advanced renal cell carcinoma (aRCC).

4538 Background: Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of post-lenvatinib therapies in pts with aRCC. Methods: We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Pts having received treatment post lenvatinib exposure were eligible and divided into two cohort: pts post-1st line lenvatinib (2nd line cohort) and pts post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results: Overall, 84 pts received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. All pts received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 9.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most pts were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed pts (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. Most pts received 2nd line everolimus + lenvatinib (97%) (ORR 39%, median TTF 5.9 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most pts were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions: In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for pts progressing on lenvatinib-based therapies.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

e20531 Background: First-line pemetrexed-platinum chemotherapy + osimertinib (Pem-Plat-Osi) improves progression free survival as compared to osimertinib (Osi) alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe the outcomes of patients who receive Pem-Plat-Osi after progression on first-line Osi in 2 tertiary cancer centres. Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line Osi at National Cancer Centre Singapore and Chinese University of Hong Kong were identified. Primary endpoints were time to treatment failure (TTF) and overall survival (OS) by Kaplan-Meier. Results: A total of 60 patients were included. Median age at diagnosis was 62, 53% (32/60) were male and 77% (46/60) were never smokers. Ex19del comprised 57% (34/60) and L858R 43% (26/60). Baseline central nervous system (CNS) metastases were present in 67% (40/60). Median TTF1 on Osi was 12 months (m) and median time to initiation of Pem-Plat-Osi was 41 days (d) (range 0-652) after progression on Osi. CNS failure occurred in 10 patients (16.7%). Partial response (PR) to Pem-Plat-Osi was achieved as best response in 45% (27/60), stable disease in 37% (22/60) and progressive disease in 18% (11/60). Three of 4 patients with CNS PD on Osi who did not undergo brain radiotherapy achieved PR/SD to Pem-Plat-Osi. At median follow up of 31m, median TTF2 on Pem-Plat-Osi was 6m, median TTF1+TTF2 was 20m and median OS was 34m. Comparing ex19del and L858R, there was no significant difference in median TTF1 (10m vs 12m, p=0.63), TTF1+TTF2 (19m vs 21m, p=0.50) and OS (34m vs 36m, p=0.40). Median TTF1+TTF2 (19m vs 20m, p=0.84) and OS (31m vs 36m, p=0.68) were similar in patients with or without baseline CNS metastases. There was no significant difference in TTF2 comparing patients who had TTF1<12m versus TTF1≥12m (both median 6m, p=0.56). Patients who started Pem-Plat-Osi within 20d of progression on Osi had significantly longer TTF2 as compared to patients who started after 20d (median 8m versus 5 months, hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.23-0.89, p=0.016) although there was no significant difference in OS (median 31m versus 34 months, p=0.35). Achieving PR was predictive of superior TTF2 (median 8m vs 5m, HR 0.46, 95% CI 0.26-0.84, p=0.005) but not OS (median 36m vs 32m, p=0.45). Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first line Osi, including among L858R subtype and patients with baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression and achieving PR were significantly associated with superior TTF2. Sequential approach of adding chemotherapy upon osimertinib failure is a plausible treatment option.

Prognostication of ß-catenin (CTNNB1) in patients with HCC treated with first line immunotherapy.

e15146 Background: Wnt/ß-catenin signaling dysregulation is found in approximately 25% of hepatocellular carcinoma (HCC) patients. The impact of B-catenin activation on HCC overall survival has remained controversial. Prior studies suggest activating CTNNB1 mutations may predict for immunotherapy (IO) resistance while others did not corroborate this finding. Here we describe the clinical outcomes of advanced HCC patients (pts) with CTNNB1 (+) and without CTNNB1 (-) mutations treated with novel first line IO/anti-VEGF therapies. Methods: We conducted a multicenter, retrospective analysis of pts with HCC who had molecular analysis performed between 2019 and 2023 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the IRB. Clinical and molecular features were compared descriptively. The primary outcomes were time to treatment failure (TTF), defined as time from first-line treatment initiation to off treatment or death, and overall survival (OS), defined as time from first-line treatment initiation to death, compared between the two cohorts using the Kaplan-Meier method. Results: We identified 29 CTNNB1+ and 62 CTNNB1- (wt) pts with HCC. Median age at diagnosis was 66 (range 30-86), 80 (88%) were Caucasian, 68 (75%) were male gender, and 22 (24%) had etiology as hepatitis B/hepatitis C, 82 (90%) were Child-Pugh A and 77 (85%) were Barcelona Clinic Liver Clinic (BCLC)=C at diagnosis. Eighteen (90%, n=20) CTNNB 1+ pts received first-line IO (Atezolizumab/bevacizumab [AB]) vs 39 (72%, n=54) in CTNNB1- pts. All pts were microsatellite stable (MSS). CTNNB1+ had a similar median tumor mutational burden (TMB), higher rate of TERT co-mutation, and lower rate of TP53 co-mutation (table) compared to CTNNB-. Of 57 AB pts, 5 (27%) of CTNNB1 + had an objective response, compared to 6 (16.7%) CTNNB1- pts. Time to treatment failure with first-line AB and overall survival were similar between the two cohorts (Table). Conclusions: Our study suggests CTNNB1 status is not prognostic in HCC pts receiving IO based therapy. Prospective study is warranted to further investigate predictive biomarkers for HCC sensitivity to immune checkpoint inhibitors and VEGF-targeted therapy. [Table: see text]

Standardizing radiologic reporting of response to improve the patient experience: Comparing response categories of RECIST 1.1 and a novel, real-world, standardized, oncologic response lexicon derived from clinical radiology reports.

e13810 Background: With the 21st Century Cures Act of 2016, rapid and complete access to medical records including radiology reports is mandated. Patients have expressed that an unmet need is improving clarity in radiology results with more structured information that avoids technical jargon. RECIST is routinely applied in clinical trials to assess treatment response but is challenging to apply in routine practice. A standardized Oncologic Response (OR) lexicon was developed to categorize response and progression directly from clinical reports, using an ordinal scale. This study aims to compare the rates of response from OR categories to RECIST categories in the setting of three phase 2 trials. Methods: Patients from three phase 2 trials were retrospectively reviewed for real world response using OR categories by a radiologist blinded to RECIST data. Clinical radiology reports generated during the trial period were reviewed and response was categorized from the report impression text according to OR categories (OR-0: no evidence of disease, OR-1: unequivocal decrease, OR-2: slight decrease, OR-3: unchanged, OR-4: slight increase, and OR-5: unequivocal increase). Best RECIST response categories of complete response (CR) or partial response (PR), stable disease (SD), and progression of disease (PD) were compared to best OR response categories (OR-0/1, OR-2/3/4, and OR-5, respectively). Time to treatment failure (TTF) and overall survival (OS) for each category was calculated using Kaplan-Meier methodology. Results: Ninety-one patients were reviewed. Best response based on RECIST v1.1 was CR for 4 patients (4%), PR for 38 patients (42%), SD for 44 patients (48%), and PD for 5 patients (6%). Using OR-categories, 1 patient (1%) was categorized as OR-0, 46 (51%) as OR-1, 34 (37%) OR-2/3/4, and 10 (11%) OR-5. Concordance between the three response categories across RECIST (CR or PR; SD; PD) and OR-RADS (0-1; 2/3/4; 5) was 73.6%. The majority of discordant cases (50%, n=12/24) were patients with SD by RECIST but OR-1 using OR categories. Median TTF was similar between RECIST and OR categories: RECIST CR/PR: 21.8, SD: 6.9, and PD: 1.0 months (p<0.0001) and OR-0/1: 21.5, OR-2/3/4: 7.0, and OR-5 1.1 (p<0.0001). Median OS was similar between RECIST and OR-categories: RECIST CR/PR: 42.6, SD: 9.9, and PD: 8.2 months (p=0.005) and OR-0/1: 42.6, OR-2/3/4: 13.6, and OR-5 7.1 (p<0.0001). Conclusions: There was high concordance between RECIST and OR-categories. This study provides preliminary evidence for the use of standardized OR categories to identify real world responses, with outcomes similar to RECIST response categories. Use of OR can improve communication with patients and oncologists and allow for standardized data extraction of radiologic response for real-world studies.