1L Therapy Research Articles

Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting

BackgroundKRAS mutations occur frequently in advanced non-small cell lung cancer (aNSCLC); the G12C mutation is the most prevalent. Alterations in STK11 or KEAP1 commonly co-occur with KRAS mutations in aNSCLC. Using real-world data, we assessed the effect of KRAS G12C mutation with or without STK11 and/or KEAP1 mutations on overall survival (OS) in patients with aNSCLC receiving cancer immunotherapy (CIT), chemotherapy, or both in first line (1L) and second line (2L).MethodsPatients diagnosed with aNSCLC between January 2011 and March 2020 in a clinico-genomic database were included. Cox proportional hazards models adjusted for left truncation, baseline demographics and clinical characteristics were used to analyze the effect of STK11 and/or KEAP1 co-mutational status on OS in patients with KRAS wild-type (WT) or G12C mutation.ResultsOf 2715 patients with aNSCLC without other actionable driver mutations, 1344 (49.5%) had KRAS WT cancer, and 454 (16.7%) had KRAS G12C–positive cancer. At 1L treatment start, significantly more patients with KRAS G12C–positive cancer were female, smokers, and had non-squamous histology, a higher prevalence of metastasis and programmed death-ligand 1 positivity than those with KRAS WT cancer. Median OS was comparable between patients with KRAS G12C–positive and KRAS WT cancer when receiving chemotherapy or combination CIT and chemotherapy in the 1L or 2L. Median OS was numerically longer in patients with KRAS G12C vs KRAS WT cancer treated with 1L CIT (30.2 vs 10.6 months, respectively) or 2L CIT (11.3 vs 7.6 months, respectively). Co-mutation of STK11 and KEAP1 was associated with significantly shorter OS in patients receiving any type of 1L therapy, regardless of KRAS G12C mutational status.ConclusionsThis real-world study showed that patients with KRAS G12C–positive or KRAS WT cancer have similar OS in the 1L or 2L when treated with chemotherapy or combination CIT and chemotherapy. In contrast to aNSCLC patients with EGFR or ALK driver mutations, patients with KRAS G12C–positive cancer may benefit from CIT monotherapy. Co-mutation of STK11 and KEAP1 was associated with significantly shorter survival, independent of KRAS G12C mutational status, reflecting the poor prognosis and high unmet need in this patient population.

Abstract CT219: Efficacy and safety of Low dose radiotherapy (LDRT) concurrent Atezolizumab (Atezo) plus chemotherapy as first line (1L) therapy for ES-SCLC: Primary analysis of Phase II MATCH study

Abstract Background: The IMpower133 represented the current standard of care in the 1L setting for patients (pts) with ES-SCLC (extensive-stage small cell lung cancer). However, there are still unmet needs for ES-SCLC treatment. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. The interim analysis of MATCH study after stage I showed promising benefit and tolerability of combination of Atezo + chemotherapy + LDRT in pts with ES-SCLC. Here we report the primary efficacy and safety results of this study. Methods: The MATCH study was a single-arm phase II trial conducted in 8 centers across China. Previously untreated ES-SCLC pts with measureable disease per RECIST v1.1 at baseline, age≥18, ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with a complete response or partial response on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. A Simon’s minimax 2-stage design was adopted. Results: As the cutoff date of 30th Nov. 2022, 56 pts have been enrolled. 49 (87.5%) were males; mean age was 58.9 years with 78.6% pts had ECOG PS of 1. 80.4% pts had smoking history. Most pts were staged T4 (n = 33, 58.9%), N3 (n = 37, 66.1%) and M1(n = 40, 71.4%). Median follow-up was 14.8 months (range: 11.6-17.8 m). The confirmed ORR was 87.5% (95% CI: 75.9%-94.8%), all partial response. DCR was 94.6% (95% CI: 85.1%-98.9%). Median PFS was 6.9 m (95% CI: 5.4-9.3 m). The 6-month and 12-month PFS rate were 56.5% and 27.7%. Median OS was not reached (NR, 95% CI: 13.3m, NR). The 12-month OS rate was 71.9%. The safety profile, analyzed in all 56 pts, was consistent with the previous reports. Neutrophil count decreased (60.7%), white blood cell count decreased (58.9%) and platelet count decreased (23.2%) were the most common grade (G) 3-4 adverse events (AE). G5 AE occurred in 1 pt (pneumonia and pulmonary embolism). 4 pts experienced AEs leading to treatment discontinuation. IrAEs were reported in 21 (37.5%) pts, most common irAEs were hyperthyroidism (5.4%) and rash (5.4%). Radiation pneumonitis (G1) was observed in 1 pt. Conclusions: Adding LDRT to Atezo + chemotherapy shows impressive antitumor activity, potential survival benefit and well tolerability in 1L treatment of ES-SCLC. Clinical registration: NCT04622228. Citation Format: Lin Zhou, Jianguo Sun, Conghua Xie, Youling Gong, Meijuan Huang, Zhiyong Yuan, Lin Wu, Hui Wang, Nan Bi, Yaping Xu, Jiang Zhu, Yongmei Liu, Yan Zhang, Min Fan, Bingwen Zou, Min Yu, Yanying Li, Feifei Na, Weigang Xiu, Yong Xu, Jin Wang, Xuanwei Zhang, Jianxin Xue, You Lu. Efficacy and safety of Low dose radiotherapy (LDRT) concurrent Atezolizumab (Atezo) plus chemotherapy as first line (1L) therapy for ES-SCLC: Primary analysis of Phase II MATCH study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT219.

Abstract CT077: Association of tumor mutational burden (TMB) and clinical outcomes with tislelizumab versus chemotherapy in esophageal cell carcinoma (ESCC) from RATIONALE-302

Abstract Background: Programmed cell death protein 1 (PD-1) inhibitors are approved as second-line (2L) therapy for patients (pts) with ESCC. TMB is a predictive biomarker of response to immune checkpoint blockade in multiple cancers, but its role in ESCC is unclear. Here, we retrospectively investigated the association between TMB and clinical outcomes in the phase 3 RATIONALE-302 study of anti-PD-1 antibody tislelizumab (TIS) vs investigator-chosen chemotherapy (ICC) as 2L treatment for advanced unresectable/metastatic ESCC (NCT03430843). Methods: Genomic profiling was assessed on tumor tissues collected at baseline using BurningRock OncoScreen Plus 520 NGS panel to determine TMB status. Median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Objective response rate (ORR) was calculated using the binomial exact method. Cox model was applied to assess the effect of TMB on survival outcomes. Hazard ratio (HR) and 95% confidence interval (CI) for OS and PFS in TMB subgroups were estimated. Results: Of 512 pts enrolled, 209 had evaluable tumor samples (TIS, n=105; ICC, n=104). Using the widely used cutoff of 10 mutations per megabase (mut/Mb), numerically higher ORR and survival benefit with TIS over ICC were observed in the high TMB (TMB-H) vs the low TMB (TMB-L) subgroup (Table). The predictive effect of TMB on survival outcomes was not significant (interaction p-value = 0.0537 for PFS, 0.5374 for OS); however, the effect became significant using the increased cutoff of 12 mut/Mb (TMB-H prevalence = 16.7%; interaction p-value = 0.0267 for PFS, 0.0175 for OS). Conclusions: TMB status may play a role in predicting clinical outcomes in pts with advanced ESCC treated with TIS versus ICC, especially when a higher TMB cutoff is chosen. These findings need further prospective validation. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Table. Clinical outcomes by TMB status (cutoff 10 mut/Mb) TMB status TMB-H TMB-L Treatment TIS ICC TIS ICC n (% in TMB BEP, N=209) 27 (12.9) 31 (14.8) 78 (37.3) 73 (34.9) ORR, % (95% CI) 33.3 (16.5, 54.0) 6.5 (0.8, 21.4) 16.7 (9.2, 26.8) 17.8 (9.8, 28.5) Median PFS, months (95% CI) 2.4 (1.4, 5.5) 2.3 (1.3, 2.9) 1.4 (1.3, 2.7) 2.7 (1.5, 3.3) PFS HR (95% CI) 0.52 (0.28, 0.97) 1.06 (0.73, 1.53) Interaction p-value 0.0537 Median OS, months (95% CI) 6.1 (4.2, 18.6) 4.7 (3.4, 7.0) 8.6 (4.6, 11.8) 7.0 (4.6, 8.6) OS HR (95% CI) 0.58 (0.32, 1.04) 0.72 (0.50, 1.03) Interaction p-value 0.5374 TMB-adjusted OS HR (95% CI) 0.68 (0.5, 0.92) BEP, biomarker evaluable population; CI, confidence interval; HR, hazard ratio; ICC, investigator chosen chemotherapy; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; TIS, tislelizumab; TMB-H, high tumor mutational burden; TMB-L, low tumor mutational burden; TMB-adjusted OS HR, overall HR adjusted for the impact of TMB on OS Citation Format: Lin Shen, Yongqian Shu, Kuaile Zhao, Taroh Satoh, Zhendong Chen, Eric Van Cutsem, Guohua Yu, Jun Wu, Chih-Hung Hsu, Sung Bae Kim, Wenting Du, Yang Shi, Ruiqi Huang, Qiao Li, Jingwen Shi, Yun Zhang, Kato Ken. Association of tumor mutational burden (TMB) and clinical outcomes with tislelizumab versus chemotherapy in esophageal cell carcinoma (ESCC) from RATIONALE-302 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT077.

Abstract CT057: Phase 2, multicenter open-label basket trial of nab-sirolimus for patients with inactivating alterations in TSC1 or TSC2 (PRECISION I)

Abstract nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC1 and TSC2, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with long-term treatment of nab-sirolimus. PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 years old and mTORi-naïve, possess malignant solid tumors with TSC1 or TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, as determined by the investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1 or TSC2 mutations; study access will be facilitated through a “just-in-time” approach to trial location activation. Based on the prevalence of TSC1 or TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Est incidence of patients with TSC1 or TSC2 alterations available for 1L therapy in 2030 Tumor Type TSC1 Mutations, %a TSC2 Mutations, %a Eligible TSC1 or TSC2 Combined, % Bladder 6.33 1.70 8.03 Hepatobiliary 1.27 3.31 4.58 Endometrial 2.10 1.22 3.32 Soft tissue sarcoma 1.28 1.71 2.99 Ovarian 1.85 0.92 2.77 Esophagogastric 0.65 1.46 2.11 Colorectal carcinoma 0.99 0.39 1.38 Pancreatic 0.57 — 0.57 Note: Estimated incidence of patients in the United States with definite impact TSC1 or TSC2 alterations available for 1L therapy in 2030. All gastrointestinal tumors (bolded) with known incidence of TSC1 or TSC2 and tumor types with combined incidence of TSC1 or TSC2 alterations of >2% are listed. aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) was derived from the NIH NCI Genomic Data Commons Data Portal (NIH NCI Genomic Data Commons). 1L, first-line. Citation Format: Jordi Rodon Ahnert, Brian Schulte, Michael J. Demeure, Dustin Deming, Noah Federman, Meredith A. McKean, Elizabeth Lee, Alexander Spira, David J. Kwiatkowski, Maen Hussein, Erlinda Gordon, David Crockett, Kristen Ganjoo, Lee D. Cranmer, Anita N. Schmid, Willis H. Navarro, Loretta M. Itri, Gopa Iyer. Phase 2, multicenter open-label basket trial of nab-sirolimus for patients with inactivating alterations in TSC1 or TSC2 (PRECISION I) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT057.

Real-World Outcomes Following First-Line Treatment in Patients with Advanced Ovarian Cancer with Multiple Risk Factors for Disease Progression who Received Maintenance Therapy or Active Surveillance.

We evaluated real-world outcomes in patients with advanced ovarian cancer (AOC) based on their cumulative risk profile and maintenance therapy (MT) status following first-line (1L) treatment. This retrospective observational study of a nationwide electronic health record-derived de-identified database included adult patients diagnosed with stageIII/IV OC from January1, 2011 to February28, 2021, who received 1L therapy and had ≥ 12weeks of follow-up after the index date (end of 1L therapy). Patients were grouped according to whether they received MT or active surveillance (AS) following 1L treatment and by the cumulative number of risk factors (RF) present (stageIV disease; no surgery/treated with neoadjuvant therapy and interval debulking surgery; had postoperative visible residual disease; and had BRCA wild-type disease/unknown BRCA status). Time to next treatment (TTNT) and overall survival (OS) were assessed with a cloning and inverse probability of censoring (IPC)-weighted Kaplan-Meier method. Among 1920 patients, 22.2% received MT and 77.8% received AS. Median IPC-weighted TTNT and OS were 13.3months (95%CI 11.7-15.8) and 39.1months (95%CI 32.5-48.6) in the MT cohort, respectively, and 8.6months (95%CI 8.0-9.5) and 38.4months (95%CI 36.4-41.0) in the AS cohort, respectively. Almost all patients had ≥ 1 RF (MT 95.3%; AS 96.7%). Median IPC-weighted TTNT was shorter among patients with more RF in both cohorts (MT: 1RF, 19.3months, 95%CI 13.5-37.8; 2RF, 17.2months, 95%CI 12.8-20.2; 3RF, 11.0months, 95%CI 8.2-13.8; 4RF, 7.0months, 95%CI 6.2-8.8; AS: 1RF, 17.7months, 95%CI 13.5-22.3; 2RF, 10.2months, 95%CI 9.1-11.5; 3RF, 6.5months, 95%CI 5.8-7.4; 4RF, 4.1months, 95%CI 3.5-4.5). Regardless of RF number, MT was associated with longer TTNT in real-world patients with AOC.

Abstract 933: Real world treatment patterns and outcomes in patients with advanced non-small cell lung cancer (aNSCLC) post-EGFR tyrosine kinase inhibitor (TKI) therapy

Abstract Background:Third generation EGFR TKIs have emerged as a first line treatment of choice for aNSCLC patients with qualifying EGFR mutations due to high and durable response rates; however most patients will progress on therapy and may receive further treatment. Second line (2L) options include other EGFR TKIs, chemotherapy (C) and chemoimmunotherapy (C-IO). An optimal treatment strategy and utility of biomarkers in this 2L setting remain uncharacterized. In this study, we aim to describe the real-world treatment patterns and outcomes of patients with aNSCLC after treatment with first line (1L) EGFR TKIs to elucidate the potential for biomarker-guided approaches. Methods:We selected patients with non-squamous aNSCLC treated with 1L EGFR TKIs on or after April 1, 2018 (based on 1L approval of osimertinib) within the US-based de-identified Flatiron Health-Foundation Medicine (FMI) real world clinico-genomic database. Real world overall survival (rwOS) and progression free survival (rwPFS) curves and estimates of median survival time were generated using the Kaplan-Meier method. PD-L1 and tumor mutational burden (TMB) were summarized overall and by 2L treatment regimen. Results:Among 428 patients who received 1L EGFR TKI treatment, 386 (90%) received osimertinib, 30 (7%) received afatinib and 11 (3%) received erlotinib. For patients with known 2L treatment information (n=139, 32%) most received EGFR TKI alone (n=43, 31%), followed by C-IO (n=38, 27%), and C alone (n=14, 10%). Median rwOS following 2L treatment with EGFR TKI, C-IO, and C was 21.0 (95% CI 17.4-28.7) months, 9.9 (95% CI 7.7-19.8) months, and 17.4 (95% CI 4.3-NA) months respectively. Median rwPFS for the EGFR-TKI, C-IO, and C cohorts was 5.1 (95% CI 3.4-12.5) months, 5.5 (95% CI 3.3-7.0) months, and 3.5 (95% CI 1.9-NA) months. 416 (97%) of 428 patients harbored an EGFR mutation detected by FoundationOne®CDx, including 361 (84%) patients with at least one EGFR mutation in NCCN Guidelines. Among patients with available PD-L1 status (n=254, 59%), PD-L1 positivity (≥1% tumor proportion score) was more common among patients who received 2L C-IO (88%) compared to patients overall (59%). 30 (7%) of 428 patients had high TMB (≥10 mut/Mb); prevalence of high TMB was similar regardless of 2L therapy choice. Conclusions:This real-world data analysis confirmed that among patients with aNSCLC treated with EGFR TKIs, the vast majority received 1L osimertinib. Among 2L treatment options, additional EGFR TKI use was the most common and patients in this cohort had robust outcomes, with a median rwOS of 21 mos. Further analyses will describe the clinical characteristics of patients receiving different 2L treatment strategies and evaluate the association of PD-L1 status and select EGFR mutations with outcomes across therapeutic classes. Citation Format: Ericka Ebot, Jie He, David Fabrizio, Ivy Altomare, Neha Jain, Davey Daniel, Thomas Stricker, Edward Arrowsmith. Real world treatment patterns and outcomes in patients with advanced non-small cell lung cancer (aNSCLC) post-EGFR tyrosine kinase inhibitor (TKI) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 933.

Real-world outcomes in metastatic HR+/HER2-, HER2+ and triple negative breast cancer after start of first-line therapy.

Aim: We evaluated outcomes of first-line (1L) treatment of metastatic breast cancer by biomarker subtype in the community setting over the last decade. Methods: Eligible patients (n=1518) were female, ≥18years, diagnosed with metastatic breast cancer 2010 or later, had documented HR+/HER2-, HER2+, or triple negative breast cancer (TNBC); and initiated 1L therapy. Kaplan-Meier and Cox methods were used to evaluate 1L real-world progression-free survival and overall survival from start of 1L. Results: TNBC was diagnosed at an earlier stage and had higher tumor grade at initial diagnosis. 1L real-world progression-free survival and overall survival from start of 1L were shorter for TNBC than HR+/HER2- or HER2+. Conclusion: Overall prognosis for patients with metastatic TNBC remains poor, and new therapies are needed to improve clinical outcomes.

Cost-Effectiveness Analysis of Tofacitinib Compared with Biologics in Biologic-Naïve Patients with Moderate-to-Severe Ulcerative Colitis in Japan.

Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). The objective of this study was to evaluate the long-term cost-effectiveness of tofacitinib versus current biologics, considering combinations of first-line (1L) and second-line (2L) therapies, from a Japanese payer's perspective in patients with moderate-to-severe active UC following an inadequate response to conventional therapy and in those who were naïve to biologics. A cost-effectiveness analysis was conducted during the time horizon specified in the Markov model, which considers a patient's lifetimeas 60 years and an annual discount rate of 2% on costs and effects. The model compared tofacitinib with vedolizumab, infliximab, adalimumab, golimumab, and ustekinumab. The time of active treatment was divided into induction and maintenance phases. Patients not responding to their biologic treatment after induction or during the maintenance phase were switched to a subsequent line of therapy. Treatment response and remission probabilities (for induction and maintenance phases) were obtained through a systematic literature review and a network meta-analysis that employed a multinomial analysis with fixed effects. Patient characteristics were sourced from the OCTAVE Induction trials. Mean utilities associated with UC health states and adverse events (AEs) were obtained from published sources. Direct medical costs related to drug acquisition, administration, surgery, patient management, and AEs were derived from the JMDC database analysis, which corresponded with the medical procedure fees from 2021. The drug prices were adjusted to April 2021. Further validation through all processes by clinical experts in Japan was conducted to fit the costs to real-world practices. Scenario and sensitivity analyses were also performed to confirm the accuracy and robustness of the base-case results. In the base-case, the treatment pattern including 1L tofacitinib was more cost-effective than vedolizumab, infliximab, golimumab, and ustekinumab for 1L therapies in terms of cost per quality-adjusted life year (QALY) gained (based on the Japanese threshold of 5,000,000 yen/QALY [38,023 United States dollars {USD}/QALY]). The base-case results demonstrated that the incremental costs would be reduced for all biologics, and decreases in incremental QALYs were observed for all biologics other than adalimumab. The incremental cost-effectiveness ratio (ICER) was found to be dominant for adalimumab; for the other biologics, it was found to be less costly and less efficacious. The efficiency frontier on the cost-effectiveness plane indicated that tofacitinib-infliximab and infliximab-tofacitinib were more cost-effective than the other treatment patterns. When infliximab-tofacitinib was compared with tofacitinib-infliximab, the ICER was 282,609,856 yen/QALY (2,149,157 USD/QALY) and the net monetary benefit (NMB) was -12,741,342 yen (-96,894 USD) with a threshold of 5,000,000 yen (38,023 USD) in Japan. Therefore, infliximab-tofacitinib was not acceptable by this threshold, and tofacitinib-infliximab was the cost-effective treatment pattern. The current analysis suggests that the treatment pattern including 1L tofacitinib is a cost-effective alternative to the biologics for patients with moderate-to-severe UC from a Japanese payer's perspective.

Abstract P1-11-19: A real-world evidence study of treatment patterns in patients with HER2-positive metastatic breast cancer who have received at least 2-lines of therapy

Abstract Background. Standard-of-care treatment for HER2-positive metastatic breast cancer (HER2+ mBC) patients has traditionally included targeted therapies such as trastuzumab and/or pertuzumab in first line (1L) and ado-trastuzumab emtansine (T-DM1) in the second line (2L). In 2021, fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu®) was approved following DESTINY-Breast 03 trial results, demonstrating a significant reduction in the risk of progression compared to T-DM1 in 2L. Contemporary data on treatment patterns and clinical outcomes for HER2+ mBC patients after their 1L therapy in a real-world setting is limited and would help understand whether all eligible patients receive optimal and timely targeted therapies. This study aimed to report 2L treatment patterns and outcomes among HER2+ mBC patients in the United States (US). Methods. Adult HER2+ mBC patients with ≥2 lines of therapy were identified from the Syapse Learning Health Network (LHN) database; a longitudinal US oncology database integrating data from community health systems, labs and other external sources. Included patients initiated 2L treatment for metastatic disease between January 2014-February 2021 (index date), allowing for 12-months of follow-up. Descriptive statistics for patient characteristics, treatment patterns including prior metastatic treatments, time to treatment discontinuation (TTD), and reasons for 2L discontinuation were reported. Results. Of the 15,241 breast cancer patients in the LHN with abstracted data, 312 HER2+ mBC patients received ≥2L treatment. The patients were mostly White (69%) or African American (21%), median age of 59 years (interquartile range [IQR], 50-66) at start of 2L. The African American population was typically diagnosed young (median age 50 [IQR, 44-61] vs. 54 [IQR, 46-62] years) with stage IV disease at initial diagnosis (69% vs 62%) versus Whites. Majority of the 312 patients had stage IV disease at initial diagnosis (62%); most common sites of metastasis at mBC diagnosis were bone (52%), distant lymph node(s) (38%), liver (36%) and brain (10%). The median length of follow-up was 22 months (IQR, 13-37), 54% had initiated their 2L therapy since 2018. Majority of the 312 patients had received a trastuzumab-based (T-based) regimen in 1L (78%). Among the 312 patients, 37% had received only 2 lines of therapy in the metastatic setting, 28% received 3 and 35% received ≥4 lines of therapy. In 2L, 89% of the 312 patients received a HER2-targeted treatment (monotherapy or combination); the most frequent 2L regimens included T-DM1 monotherapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Subsequently, 197 of the 312 patients (63%) received 3L therapy. Among these 197 patients, T-DM1 monotherapy (19%), T-DXd monotherapy (10%) and capecitabine/lapatinib (8%) were the most frequently reported 3L regimens. Around 88% (n=274) of the 312 patients discontinued their 2L therapy. Median TTD of 2L from index date was 7.2 months (95% CI, 6.5-8.9); median TTD was 10.6 months (95% CI, 7.4-14.0) among a sub-group of patients who received a T-based regimen in their 2L (N=116). Approximately 47% of patients discontinued their 2L regimen due to progression/worsening of cancer, 17% discontinued from intolerance/toxicity in the absence of progression. Conclusions. This study suggests the treatment trajectory of US HER2+ mBC patients is variable in the real world clinical practice. Approximately two-thirds of the 2L patients had to receive a subsequent therapy and disease progression was the most common reason for 2L treatment discontinuation, reflecting a remaining need to improve outcomes for patients in 2L HER2+ disease. Citation Format: Della Varghese, Giovanna I. Cruz, Colden Johanson, Liz Toland, Miguel Miranda, Eleanor C. Faherty, David Harland, Henry G. Kaplan. A real-world evidence study of treatment patterns in patients with HER2-positive metastatic breast cancer who have received at least 2-lines of therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-19.

Abstract PD13-09: PD13-09 Clinical outcomes of patients with HR+ HER2- advanced breast cancer with early progression on CDK4/6 inhibitors

Abstract Background: CDK4/6 inhibitors (CDK4/6i) paired with endocrine therapy (ET) are considered first-line (1L) therapy for patients (pts) with HR+ HER2- advanced breast cancer (aBC). A minority of pts will demonstrate primary resistance to CDK4/6i, as characterized by early progression. Thymidine kinase 1 (TK1) is a cell-cycle regulated enzyme downstream of CDK4/6 and involved in nucleotide metabolism during DNA synthesis. Prior studies have shown TK1 may serve as a biomarker of response to CDK4/6i, with early TK1 activity (TK1a) suppression after initiation of CDK 4/6i therapy associated with improved PFS. Lack of TK1a suppression may be associated with primary resistance to CDK4/6i. In this study, we aim to analyze response to subsequent lines of therapy and overall survival (OS) of pts with early progression on 1L CDK4/6i. Methods: Pts with HR+ HER2- aBC from a phase II trial of an alternative schedule of palbociclib (palbo alt dosing trial NCT 3007979) and from a retrospective palbociclib study were included in this analysis. Pts in the palbo alt dosing trial underwent baseline and C1D15 TK1a analysis after initiation on CDK4/6i. C1D15 TK1a suppression was defined at TK1a < 30 Du/L. Pts in the retrospective palbociclib study included pts receiving palbo as part of their standard of care 1L therapy for HR+ HER2- aBC at Washington University in Saint Louis from 2016 to 2021. Clinical information, including treatment start and stop dates on each of the next-line therapies, were collected from the electronic medical record. PFS was estimated by the treatment duration on a specified treatment regimen. Early progression on CDK4/6i was defined as PFS < 6 mo. Best response was defined as next line of therapy with the numerically longest PFS. OS was defined as time to death from the initiation of CDK4/6i. Results: Of the 54 pts enrolled on the palbo alt dosing trial, 51 pts were evaluable for clinical benefit and 46 pts were evaluable for TK1a suppression rate at C1D15. 7 pts (15.2%) were found without TK1a suppression at C1D15. This lack of TK1a suppression on palbo was associated with a significantly shorter PFS (median PFS=3.1 mo) compared to not reached in pts with TK1a suppression at C1D15. We conducted clinical analysis on N=26 pts who exhibited early progression on CDK4/6i which included 10 pts from the palbo alt dosing trial and 16 from the retrospective study. The average subsequent line of therapies in this cohort was 3, with the most common second line (2L) therapy being chemotherapy (N=17, 65.4%) and ET (N=8, 30.8%). The median PFS for pts receiving 2L chemotherapy and ET was 4.09 mo and 3.64 mo, respectively. 10 pts received both chemotherapy and ET with 7 (70.0%) achieving best response with chemotherapy compared to 3 pts (30.0%) who achieved best response with ET. The median OS for the cohort was 14.6 mo. Conclusions: Early progression on CDK4/6i is associated with a particularly poor prognosis. In our cohort, the median OS was far below the expected median OS for pts receiving 1L palbo as reported in the PALOMA-2 trial (14.6 mo vs 53.9 mo). Early progression on CDK4/6i is associated with more aggressive disease which may respond more favorably to chemotherapy, as demonstrated by best response to therapy. Further prospective studies are warranted to explore this treatment approach. Citation Format: Katherine K. Clifton, Shana N. Thomas, Jingqin Luo, Jing Xi, Nusayba A. Bagegni, Foluso O. Ademuyiwa, Rama Suresh, Ashley Frith, Andrew A. Davis, Ron Bose, Katherine Weilbaecher, Whitney L. Hensing, Timothy Pluard, Massimo Cristofanilli, Hyo S. Han, Adam M. Brufsky, Kevin Kalinsky, Shom Goel, Seth A. Wander, Lindsay L. Peterson, Cynthia Ma. PD13-09 Clinical outcomes of patients with HR+ HER2- advanced breast cancer with early progression on CDK4/6 inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-09.

Abstract P4-01-03: Progression-free survival and patient-reported outcomes in HR+, HER2– ABC patients treated with first-line ribociclib + endocrine therapy (ET) or ET monotherapy or chemotherapy in real world setting: 5th interim analysis of RIBANNA

Abstract Background: Ribociclib in combination with endocrine therapy (ET) has demonstrated survival benefits in a broad patient population with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). RIBANNA (CLEE011ADE03) is an ongoing, prospective, noninterventional study assessing the efficacy and safety of first-line (1L) ribociclib in combination with ET in routine clinical practice in women with HR+, HER2– ABC. This study will provide insights into the use of ribociclib in combination with ET with regard to effectiveness and patient-reported outcomes (PRO) in the real-world setting in a large patient population. Methods: Patients with HR+, HER2– ABC starting their 1L treatment with ribociclib + ET, or ET monotherapy, or chemotherapy (CT) were included. Data after disease progression to second-line (2L) and further lines of therapy are being collected too. The progression-free survival (PFS) in 1L, 2L and PFS2 (time from inclusion into the trial in the 1L setting until progression from 2L to third-line therapy) for individual treatment sequences will be analyzed using the Kaplan–Meier method. PRO for all the patients in the 1L and 2L treatment cohorts are being evaluated using the Morisky Medication Adherence Scale (MMAS-8), questionnaires related to quality-of-life (EORTC QLQ-C30) and its breast cancer–specific module (EORTC QLQ-BR23) as well as the Hospital Anxiety and Depression Scale (HADS). Data were collected at baseline and at every 3 months until the end of treatment. Results: By the cutoff date (October 11, 2021) of the fourth interim analysis, data were available for 2187 patients (Table 1). Overall, 633 patients progressed after 1L therapy, including 27.6%, 30.6%, and 43.4% of patients from the 1L ribociclib + ET, ET monotherapy, and CT cohorts, respectively. A total of 286 patients received CDK4/6 inhibitors in 2L, which represents 48.3%, 37.3%, and 27.0% of patients from the 1L ribociclib + ET, ET monotherapy, and CT cohorts, respectively. The PFS in 1L, 2L and PFS2 results for individual treatment sequences will be presented at SABCS 2022. PRO compliance rates at baseline were 88.2%, 89.8%, and 89.4% for EORTC QLQ-C30 global health status, QLQ-BR23, and HADS-D/A, respectively, in the overall population, and 84.5% for MMAS-8 in the 1L ribociclib + ET cohort. Data for patient-reported adherence to 1L ribociclib + ET and for questionnaires related to global health-related quality of life, functioning, and symptoms from patients receiving treatment in 1L and 2L settings will be analyzed and presented at SABCS 2022. Conclusion: The RIBANNA study has shown diverse population characteristics among patients who received ribociclib treatment in a real-world setting. The 5th interim analysis is planned in October 2022. Data on PFS, PFS2, specific therapy sequences and PRO from 1L and 2L that will provide insights on therapy sequencing strategy will be presented at SABCS 2022. Table 1. Patient disposition at the data cutoff date (October 11, 2021). Citation Format: Peter A. Fasching, Cosima Brucker, Thomas Decker, Anne Engel, Thomas Göhler, Christian Jackisch, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Marion van Mackelenbergh, Frederik Marmé, Arnd Nusch, Beate Rautenberg, Toralf Reimer, Marcus Schmidt, Rudolf Weide, Pauline Wimberger, Christian Roos, Achim Wöckel. Progression-free survival and patient-reported outcomes in HR+, HER2– ABC patients treated with first-line ribociclib + endocrine therapy (ET) or ET monotherapy or chemotherapy in real world setting: 5th interim analysis of RIBANNA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-03.

Abstract P4-01-18: Real-world second-line treatment patterns and associated clinical outcomes for 2795 patients with advanced HR+ HER2- breast cancer treated with first-line CDK4/6 inhibitors

Abstract Background: CDK4/6 inhibitors (CDK4/6i) are standard first-line (1L) regimens for HR+/HER2- advanced breast cancer (aBC). Recent data from the randomized phase II MAINTAIN trial reported a PFS benefit for patients (pts) who received a new endocrine therapy plus ribociclib (ribo) versus new endocrine therapy alone) following progression on CDK4/6i as compared to pts who received endocrine therapy alone. However, second-line (2L) treatment patterns and patient outcomes following 1L CDK4/6i are relatively undescribed. Here we describe real-world 2L treatment patterns following 1L CDK4/6i and associated clinical outcomes from a large clinical genomics database. Methods: Real-world evidence (RWE) was sourced from the GuardantINFORM (Guardant Health) database which comprises aggregated commercial payer health claims and de-identified records from over 207,000 pts with comprehensive circulating tumor DNA (ctDNA) results via Guardant360 (G360) from 2014 to 2021. Pts with HR+/HER2- aBC with >1 claim of CDK4/6i and >1 claim for treatment after the index G360 test were included. Real-world time to treatment discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were assessed in months as proxies for progression-free survival. Real-world overall survival (rwOS) was also reported in months. Results: 2,795 pts met criteria for inclusion; 2,361 (84.5%) were treated with 1L palbociclib (palbo), 271 (9.7%) with 1L abemaciclib (abema) and 163 (5.8%) with 1L ribo. Chemotherapy (chemo,35.5%) and endocrine-only therapy (32.8%) were the most common 2L therapy regardless of the 1L CDK4/6i agent (Table 1). Other 2L agents included endocrine backbone change (14.7%) or CDK4/6i change (7.7%). Endocrine backbone changes were observed more frequently (15.6%) in pts receiving 1L palbo while CDK4/6i changes were more frequent in pts receiving abema (14.0%) or ribo (22.0%). Pts treated with 2L CDK4/6i had improved rwTTNT, rwTTD and rwOS compared to 2L chemo regardless of 1L agent [rwTTNT: 10.2 (95% CI: 7.2-11.7) vs. 7.2 (6.5-8.1); rwTTD: 6.8 (95% CI: 5.8-8.5) vs. 4.3 (95% CI:3.9-4.7); rwOS: NR (95% CI: 40.0-NR) vs. 34.8 (95% CI: 31.3-37.2)]; improvement in rwTTNT, rwTTD and rwOS were also observed for pts with 2L endocrine backbone changes compared to chemo [rwTTNT: 8.5 (95% CI: 7.2-9.6) vs. 7.2 (6.5-8.1); rwTTD: 6.9 (95% CI: 5.8-7.9) vs. 4.3 (95% CI:3.9-4.7); rwOS: 63.4 (95% CI: 51.2-NR) vs. 34.8 (95% CI: 31.3-37.2)]. Pts treated with 2L alpelisib had the shortest rwOS regardless of 1L CDK4/6i agent used [any 1L: NR (95% CI: 23.6-NR)]. Conclusions: A variety of 2L regimens following 1L CDK4/6i were observed, with an improvement in rwTTNT, rwTTD and rwOS in pts receiving 2L CDK4/6i or 2L endocrine backbone change only relative to 2L chemo. These data are hypothesis generating, and the observed improvement may be secondary to therapy choice versus pts who received 2L chemo having more aggressive disease. Larger randomized trials are ongoing to study sequencing and efficacy of 2L treatments following 1L CDK4/6i. Table 1. Distribution of 2L therapies by 1L CDK4/6i agent. Citation Format: Katherine K. Clifton, Seth A. Wander, Cynthia Ma, Andrew A. Davis, Caroline Weipert, Nicole Zhang, Leslie Bucheit. Real-world second-line treatment patterns and associated clinical outcomes for 2795 patients with advanced HR+ HER2- breast cancer treated with first-line CDK4/6 inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-18.

Abstract P4-01-42: Pooled analysis of post-progression treatments after first-line ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer in the MONALEESA-2, -3, and -7 studies

Abstract Background: The MONALEESA (ML) studies showed significant PFS & OS benefits for 1L ribociclib (RIB) + endocrine therapy (ET) in patients (pts) with pre/peri & postmenopausal advanced breast cancer. The benefit of RIB beyond study treatment (tx) was also observed, with improvements in PFS2 & delays in time to 1st subsequent chemotherapy (CT). While there is currently no preferred tx for the next line post-progression on a CDK4/6 inhibitor (CDK4/6i), except alpelisib in pts with a PIK3CA mutation, guidelines encourage multiple lines of ET or ET-based therapies before switching to CT (except for visceral crisis). This pooled exploratory analysis of the ML studies examined outcomes of various tx strategies post progression on RIB + ET. Methods: Data from pts receiving 1L therapy in ML-2, -3, & -7 (NSAI cohort only & excluding pts with early relapse [≤ 12 mo after end of (neo)adjuvant ET] whose prognosis is closer to that of 2L pts) were pooled & pts receiving 1st subsequent therapies after progression were analyzed. Three groups of subsequent therapies were assessed: ET only, CT, & targeted therapy. Subsequent CT comprises CT +/- any other therapy; targeted therapy includes CDK4/6i, mTORi, PI3Ki, AKTi, etc, +/- ET. Subsequent CT & targeted therapy groups are mutually exclusive. Median duration of study tx, 1st subsequent therapy, & OS (from randomization to death) were analyzed by KM methods. Weighted Cox regressions were performed using inversed propensity scoring matching method (inverse probability tx weighting [IPTW]) to ensure compatible pt characteristics between tx arms. These are not randomized comparisons; only baseline characteristics were used for the estimation of propensity scores in the IPTW, imbalance of prognostic factors at progression may exist. Results: Median follow-up time was 74 mo. 461 pts treated with RIB (81%) & 440 (86%) with PBO discontinued study tx & received a subsequent therapy. In the RIB arms, the most common 1st subsequent therapies were ET only (40%), CT (29%), combination with targeted therapy (28%), & other (4%); for the PBO arms, 34% received CT as a 1st subsequent therapy & 31% each received ET only or combination with targeted therapy (5% received other). In 14% & 20% of pts in the RIB & PBO arms, the 1st subsequent therapy was a CDK4/6i, of these 31% & 12% were RIB. In general, regardless of type of 1st subsequent therapy, the duration of both the study tx & the 1st subsequent therapy was longer for pts treated with RIB vs PBO (Table). In both RIB & PBO arms, pts who received subsequent CT had the shortest duration on study tx, whereas those who received subsequent targeted therapy combination had the longest. Among pts on 1L RIB + ET, after matching pre-randomization baseline characteristics, subsequent CDK4/6i use was associated with the longest mOS (84 [84-NE] mo), followed by ET only (60 [51-68] mo), then a non-CDK4/6i targeted therapy (52 [43-72] mo); post-progression CT was associated with the shortest mOS (37 [32-48] mo). Conclusions: This large, pooled analysis of the ML studies shows that, in general, duration of any subsequent therapy was numerically longer post-1L RIB + ET vs PBO + ET, & subsequent CT was used less frequently for pts on RIB vs PBO. Both findings confirm that upfront tx with RIB does not worsen pt outcomes. This trend in enhancement of outcomes of subsequent therapies seen with 1L RIB suggests a post-tx effect that merits further exploration. Citation Format: Erika Hamilton, Laura M. Spring, Peter A. Fasching, Sandra Franco, Richard H DeBoer, Javier Cortés, Kevin Kalinsky, Dejan Juric, Aditya Bardia, Sina Haftchenary, Agnes Lteif, Juan Pablo Zarate, Liyi Cen, Patrick Neven. Pooled analysis of post-progression treatments after first-line ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer in the MONALEESA-2, -3, and -7 studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-42.

Abstract P4-03-34: Treatment Patterns and Associated Outcomes Among Patients with HER2+ Metastatic Breast Cancer in the United States

Abstract Background Historically, standard-of-care treatments for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) have been pertuzumab and trastuzumab combined with a chemotherapeutic agent in first line (1L), and trastuzumab emtansine (T-DM1) in the second line (2L). However, two new treatments have recently been approved for patients who previously received HER2-targeted therapy; fam-trastuzumab deruxtecan-nxki [Enhertu®] and tucatinib [Tukysa] (in triplet combination) in 2019 and 2020, respectively. The goal of this study was to characterize treatment patterns of patients with HER2+ mBC from receipt of first line therapy and subsequent treatments received in real world community oncology practices. Methods Adults diagnosed with HER2+ mBC from January 2013 – January 2021 were selected from the Flatiron Health electronic health record–derived database; a US-wide database curated from community clinics that comprises de-identified patient-level structured and unstructured data. Patients were followed from index date (start of 1L therapy) to death or last activity date. Descriptive statistics reported baseline patient characteristics and treatment patterns. Time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS) were estimated using the Kaplan-Meier method. Results A total of 2,074 mBC HER2+ patients with at least 1 line of therapy were included during the study time period. Median follow-up time was 26.0 months (Interquartile range [IQR]: 12.6-44.7). Patients were mostly white (62.7%), median age 61 years (IQR:24-84), 43.0% were stage IV at initial breast cancer diagnosis, and 62.8% had positive hormone receptor (HR) status. Of the 2,074 patients in our study population, 1,159 (55.8%) received 2L therapy, and 584 (28.2%) received a 3L therapy. In terms of 1L therapy, 1,607 (77.5%) received a trastuzumab-based (T-based) regimen, 205 (9.9%) received chemotherapy only, and 153 (7.4%) received a T-DM1 based therapy. The most common regimens across 1L included pertuzumab+trastuzumab+taxane (THP) (38.9%), THP + a platinum agent (7.5%), and T-DM1 (6.1%). From start of 1L, overall median TTD was 10.8 months (95% confidence interval [CI]: 10.1-11.5), median rwPFS was 11.5 months (95% CI: 10.8-12.3), and median rwOS was 40.3 months (95% CI: 37.8-43.4). Among the 1,607 patients who received any T-based regimen in 1L, 496 (30.9%) received T-DM1, 175 (10.9%) received a T-based regimen again, 78 (4.9%) received any other HER2-based regimen, 59 (3.7%) received hormonal therapy alone and 33 (2.1%) received chemotherapy. The most common regimens across 2L (n=1,159) were T-DM1 monotherapy (35.7%), THP (11.2%), and T-DM1+hormone therapy (8.0%). From start of 2L, overall median TTD was 8.3 months (95% CI: 7.6-9.0), median rwPFS was 7.4 months (95% CI: 6.8-8.1), and median rwOS was 27 months (95% CI: 25.9-30.0). Conclusions Variability, which may impact outcomes, is observed in treatment approaches for HER2+ mBC. Additionally, more than half the patients on 1L treatment progressed within a year of initiating treatment, highlighting a remaining need for effective therapies that limit progression and maintain clinical benefit in 1L. Citation Format: Clara Lam, Della Varghese, Beth L. Nordstrom, Brian Murphy, Jenna Collins, Sandhya Mehta. Treatment Patterns and Associated Outcomes Among Patients with HER2+ Metastatic Breast Cancer in the United States [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-34.

Abstract P4-01-30: Real-world treatment patterns and survival among adults with metastatic breast cancer with BRCA1/2 mutations

Abstract Background: Limited information is available about real-world treatment patterns and survival among patients with metastatic breast cancer (mBC) with BRCA1/2 mutations. BRCA1/2 mutations, which are involved in the repair of DNA double-strand breaks, are rare. Since 2018, PARP inhibitors (olaparib and talazoparib) have been approved for the treatment of patients with germline BRCA-mutated HER2-negative locally advanced and/or mBC. Methods: This retrospective chart review study included adults diagnosed with mBC with ≥1 oncogenic somatic BRCA1/2 mutation detected by tumor comprehensive genomic profiling who began a line of therapy on or after July 1, 2014, at 3 oncology centers in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) consortium. The index date was the first initiation of a new therapy for mBC in this period (which could be first-line [1L] or subsequent line of therapy). Data on all available lines of therapy post-index were collected. Treatments received in different lines of therapy for mBC and overall survival (OS) were described separately for patients with HR-positive/HER2-negative (HR+/HER2-) mBC, triple negative mBC (TNBC), and HER2-positive (HER2+) mBC. OS from the start of each line of therapy was assessed using Kaplan-Meier analysis. Results: A total of 48 women with mBC met the inclusion criteria. The mean age at index was 58 years; 73% of women were White. Common sites of metastases included lymph nodes (56%), bone (52%), and lungs (31%). Somatic BRCA1 mutation was detected in 48% and BRCA2 mutation was detected in 54% of women. Assessment of germline BRCA mutations was conducted in 25 (52%) women; 2 (8%) of assessed women tested positive for germline BRCA mutations. 29 (60%) of women had HR+/HER2- mBC, 9 (19%) had TNBC, 9 (19%) had HER2+ mBC, and 1 woman had unknown HER2 status. Treatments received in different lines of therapy for mBC and OS from start of each line of therapy by HR and HER2 status are reported in Table 1. Common treatments for women with HR+/HER2- mBC included endocrine-based therapy, and chemotherapy. Women with TNBC were most often treated with chemotherapy. Women with HER2+ mBC most often received endocrine-based therapy in 1L; chemotherapy or HER2-targeted combination therapy in second-line (2L); and chemotherapy or HER2-targeted monotherapy in third-line (3L). Median OS from the start of 1L therapy was 37.5 months among women with HR+/HER2- disease; 20.0 months for women with TNBC; and 51.7 months for women with HER2+ disease. Conclusions: These findings provide real-world insights about treatment patterns and survival among women with mBC and BRCA1/2 mutations. Further studies with larger sample sizes are needed to confirm these findings. Table 1. Treatment patterns and survival by line of therapy, HR, and HER2 status among patients with BRCA1/2 mutated mBC Citation Format: Priyanka Bobbili, Jasmina Ivanova, David B. Solit, Niharika Mettu, Shannon McCall, Mallika Dhawan, Maral DerSarkissian, Bhakti Arondekar, Jane Chang, Alexander Niyazov, Jocelyn Lee, Risha J. Huq, Michelle Green, Michelle Turski, Aruna Muthukumar, Mianzhao Guo, Mei Sheng Duh, William Oh. Real-world treatment patterns and survival among adults with metastatic breast cancer with BRCA1/2 mutations [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-30.

Abstract P6-10-03: Datopotamab Deruxtecan (Dato-DXd) in Advanced Triple-Negative Breast Cancer (TNBC): Updated Results From the Phase 1 TROPION-PanTumor01 Study

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 mAb covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor selective, tetrapeptide-based cleavable linker. Dato-DXd has previously shown encouraging activity in heavily pretreated patients (pts) with metastatic TNBC (Krop, SABCS 2021). Here we report updated results from the TROPION-PanTumor01 study in pts with advanced/metastatic TNBC. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part dose-escalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with advanced TNBC that relapsed/progressed on standard therapies; 2 pts received 8 mg/kg prior to selection of 6 mg/kg. The primary objectives were safety and tolerability. Tumor responses, including objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]), were assessed per RECIST v1.1 by blinded independent central review. Results: As of April 29, 2022, 44 pts received Dato-DXd (median follow-up, 16.6 mo [range, 13-22]) at the time of data cutoff. The primary cause of treatment discontinuation was disease progression (86%; PD or clinical progression), and 4 pts are still receiving therapy. Median age was 53 y (range, 32-82); 32% had de novo metastatic disease. Pts were heavily pretreated with a median of 3 (range, 1-10) prior regimens in the metastatic setting. Prior treatments included taxanes (91%), anthracyclines (75%), capecitabine (61%), platinum (52%), immunotherapy (43%), Topo I inhibitor–based ADC therapy (32%), and PARPi (18%). Treatment-emergent adverse events (TEAEs; all cause) occurred in 100% (any grade) and 50% (grade ≥3) of pts, respectively. Most common TEAEs (any grade, grade ≥3) were stomatitis (73%, 11%), nausea (66%, 2%), vomiting (39%, 5%), fatigue (34%, 7%), and alopecia (36%, 0%). One pt had grade 3 decreased neutrophil count; no cases of interstitial lung disease (ILD) or grade ≥3 diarrhea were observed. Serious TEAEs were reported in 9 pts (20%); no deaths associated with adverse events (AEs) were observed. Dose reductions occurred in 8 pts (18%) due to stomatitis (n=3), fatigue (n=2), dry eye (n=1), retinal exudates (n=1), and dysgeusia (n=1); 12 pts (27%) delayed treatment due to stomatitis (n=5), dry eye (n=1), keratitis (n=1), blurred vision (n=1), fatigue (n=1), bronchitis (n=1), skin infection (n=1), musculoskeletal chest pain (n=1), dysgeusia (n=1), chronic obstructive pulmonary disease (n=1), and dyspnea (n=1; >1 AE per pt). One pt (2%) discontinued treatment due to grade 1 pneumonitis (which was centrally adjudicated as not ILD). ORR in all pts was 32% (1 CR, 13 PRs), DCR was 80% (35/44), and clinical benefit rate (CR + PR + SD ≥6 mo) was 34% (15/44). Median duration of response was not yet reached; median progression-free survival (mPFS) was 4.3 mo (95% CI, 3.0-7.3), and median overall survival (mOS) was 12.9 mo (95% CI, 10.1-14.7). In the subset of pts without prior Topo I inhibitor–based ADC therapy and with measurable disease at baseline, ORR was 44% (12/27). Among all pts without prior Topo I inhibitor–based ADC therapy (n=30), mPFS was 7.3 mo (95% CI, 3.0-NE), and mOS was 14.3 mo (95% CI, 10.5-NE). Conclusions: Dato-DXd continues to demonstrate encouraging and durable antitumor activity, along with a manageable safety profile, in heavily pretreated pts with metastatic TNBC. Based on these findings, the phase 3 randomized TROPION-Breast02 (NCT05374512) trial comparing Dato-DXd vs chemotherapy as 1L therapy for pts with metastatic TNBC is currently underway. Citation Format: Aditya Bardia, Ian Krop, Funda Meric-Bernstam, Anthony W. Tolcher, Toru Mukohara, Aaron Lisberg, Toshio Shimizu, Erika Hamilton, Alexander I. Spira, Kyriakos P. Papadopoulos, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Hong Zebger-Gong, Yui Kawasaki, Rie Wong, Takahiro Kogawa. Datopotamab Deruxtecan (Dato-DXd) in Advanced Triple-Negative Breast Cancer (TNBC): Updated Results From the Phase 1 TROPION-PanTumor01 Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-03.

Abstract OT1-03-06: Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress)

Abstract Background Patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. Treatment combinations of anti-programmed death protein 1 (anti–PD-1) agents with chemotherapy have shown promise in mTNBC. Ladiratuzumab vedotin (LV) is an investigational antibody-drug conjugate directed to LIV-1, a protein highly expressed on breast cancer cells, via a humanized IgG1 monoclonal antibody conjugated to approximately 4 molecules of monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1–mediated delivery of MMAE disrupts microtubules and induces cell cycle arrest and apoptosis. LV has also been shown to drive immunogenic cell death (ICD) to elicit an immune response. LV + pembrolizumab may result in synergistic activity through LV-induced ICD, creating a microenvironment favorable for enhanced anti–PD-1 activity. Interim results from an ongoing, multi-part, open-label study investigating the safety and efficacy of LV in patients with metastatic breast cancer (SGNLVA-001, NCT01969643), showed weekly LV monotherapy at doses up to 1.5 mg/kg were clinically active and generally well tolerated (Tsai 2021). Based on pharmacokinetic and pharmacodynamic modeling and simulation analysis, an intermittent LV + pembrolizumab dosing regimen is being evaluated to further enhance efficacy and improve the tolerability profile. Due to an unmet medical need for patients with unresectable locally advanced (LA)/mTNBC who are programmed death ligand 1 (PD-L1) low or negative, Part D will focus on this patient population. Trial Design SGNLVA-002 (NCT03310957) is an ongoing global single-arm, open-label phase 1b/2 study of LV + pembrolizumab as 1L therapy for patients with unresectable LA/mTNBC. Part D is currently enrolling ~40 patients. Eligible patients must have advanced disease with no prior cytotoxic/anti–PD-1 treatment, PD-L1 combined positive score < 10, measurable disease per RECIST v1.1, and an ECOG performance status ≤1. Patients with Grade ≥2 pre-existing neuropathy or active central nervous system metastases are not permitted. Patients will receive LV at 1.5 mg/kg on Days 1 and 8 every 21 days plus pembrolizumab 200 mg on Day 1 q3w. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab. Secondary objectives include duration of response, disease control rate, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized with descriptive statistics. Global enrollment is ongoing in the US, EU, and Asia. Citation Format: Patrick Dillon, Reva Basho, Hyo S. Han, Hans-Christian Kolberg, Katherine Tkaczuk, George Zahrah, Maria Gion, Herman Voss, Jane Meisel, Timothy Pluard, Jenny Fox, Mafalda Oliveira, Ursa Brown-Glaberman, Erica Stringer-Reasor, Luis Manso, Sherko Küemmel, Lin Chi Chen, Sheng Wu, Brandon Croft, Valentina Boni. Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-06.

Health outcomes and healthcare resource utilization among Veterans with stage IV non-small cell lung cancer treated with second-line chemotherapy versus immunotherapy.

Until recently, multi-agent chemotherapy (CT) was the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Clinical trials have confirmed benefits in overall survival (OS) and progression-free survival with immunotherapy (IO) compared to CT. This study compares real-world treatment patterns and outcomes between CT and IO administrations in second-line (2L) settings for patients with stage IV NSCLC. This retrospective study included patients in the United States Department of Veterans Affairs healthcare system diagnosed with stage IV NSCLC during 2012-2017 and receiving IO or CT in the 2L. Patient demographics and clinical characteristics, healthcare resource utilization (HCRU), and adverse events (AEs) were compared between treatment groups. Logistic regression was used to examine differences in baseline characteristics between groups, and inverse probability weighting multivariable Cox proportional hazard regression was used to analyze OS. Among 4,609 Veterans who received first-line (1L) therapy for stage IV NSCLC, 96% received 1L CT alone. A total of 1,630 (35%) were administered 2L systemic therapy, with 695 (43%) receiving IO and 935 (57%) receiving CT. Median age was 67 years (IO group) and 65 years (CT group); most patients were male (97%) and white (76-77%). Patients administered 2L IO had a higher Charlson Comorbidity Index than those administered CT (p = 0.0002). 2L IO was associated with significantly longer OS compared with CT (hazard ratio 0.84, 95% CI 0.75-0.94). IO was more frequently prescribed during the study period (p < 0.0001). No difference in rate of hospitalizations was observed between the two groups. Overall, the proportion of advanced NSCLC patients receiving 2L systemic therapy is low. Among patients treated with 1L CT and without IO contraindications, 2L IO should be considered, as this supports potential benefit of IO for advanced NSCLC. The increasing availability and indications for IO will likely increase the administration of 2L therapy to NSCLC patients.

Evaluation of PBRM1, PD-L1, CD31, and CD4/CD8 ratio as a predictive signature of response to VEGFR-TKI–based therapy in patients with metastatic renal cell carcinoma (mRCC) with IMDC intermediate prognosis: Results from the APAChE-I Study.

714 Background: Intermediate IMDC group is the largest and most heterogeneous group of mRCC. Current first-line (1L) therapy options for these patients (pts) are based on either an anti-angiogenic agent (VEGFR-TKI) combined with immunotherapy (IO), or a combo of IO (ipilimumab+nivolumab [I/N]). No biomarkers (BM) for selecting the most effective regimen have been identified so far. Methods: Immunohistochemical expression of PBRM1, PD-L1, CD31, and CD4/CD8 ratio was evaluated on histological samples of intermediate-risk mRCC pts treated with VEGFR-TKI monotherapy, and then in pts receiving a VEGFR-TKI-based therapy or the immune doublet I/N. PBRM1 positivity score was based on the percentage of positive cells and on the intensity of nuclear expression; PD-L1 positivity was defined as CPS≥10; CD31 high-density had moderate to strong nuclear staining; and the CD4/CD8 ratio cut-off for positivity was &gt;0.2. Cox model was used to assess the correlation between BM and outcomes; PFS and OS were estimated by Kaplan-Meier method. Results: After screening of tumor tissues from 150 pts, a total of 111 were included in the final analysis (Table). In pts treated with VEGFR-TKI monotherapy, a significant correlation with PFS was observed with loss of PBRM1 expression (HR 0.58, p=0.035), PD-L1 negativity (HR 0.44, p=0.048), and high CD4/CD8 ratio (HR 0.62, p=0.073). CD31 density did not significantly correlate with PFS. A profile potentially predictive of angiogenesis (AP+) was defined based on the PBRM1 loss, PD-L1 negative, and high CD4/CD8. In pts treated with VEGFR-TKI monotherapy, tumors with the AP+ (43% of all cases) had a significantly longer median PFS (mPFS 23.8 vs. 11.8 months, p=0.003) and mOS (41.5 vs. 26.9 months, p=0.024) compared to the others. The AP+ retained its significant correlation with PFS (mPFS 23.8 vs. 11.1 months, p&lt;0.001) and OS (41.5 vs. 24.9, p=0.006) in pts receiving VEGFR-TKI-based therapies. The rate of AP+ tumors was 55.6% and 32.7% in pts with one or two IMDC risk factors, respectively (p=0.022). In the small cohort of pts treated with I/N, no differences were observed in PFS (p=0.64) and OS (p=0.75) between AP+ and AP-negative. Conclusions: The AP+ signature (loss of PBRM1, PD-L1 negative, and CD4/CD8 high ratio) was associated with improved clinical outcomes in mRCC pts at IMDC intermediate prognosis treated with VEGFR-TKI-based therapy; this correlation was significant regardless from the addition of IO to VEGFR-TKI monotherapy. Prospective validation of this signature is required for guiding the selection of the most appropriate 1L therapy. [Table: see text]

Real-world treatment patterns, survival outcomes, and health care resource utilization (HCRU) for locally advanced or metastatic urothelial carcinoma (la/mUC) in Spain.

463 Background: Real-world evidence on la/mUC management in Europe is limited. This study describes patient (pt) characteristics, treatment patterns, survival, and HCRU for pts with la/mUC in Spain. Methods: A retrospective chart review was conducted using electronic medical records from 9 university hospitals in Spain. The study population included all pts aged ≥18 y with a first diagnosis/record of la/mUC from 1/1/2015–12/31/2020 (study period). Date of first la/mUC record/diagnosis during the study period was the index date. Pts with urachus carcinoma or other nonurothelial cancers were excluded. Pt characteristics are described for the full study population. Treatment patterns, survival, and la/mUC-associated HCRU are described for the follow-up cohort: a subset of the study cohort with a first la/mUC diagnosis/record from 1/1/2015–6/30/2020 (ie, to allow for ≥6 mo follow-up). Pts were followed from index date to death, loss to follow-up, or end of study. Median overall survival (OS) and progression-free survival (PFS; evaluated in a real-world setting) were determined using Kaplan–Meier curves. Time to progression, excluding pts who died and were censored at death, was also estimated. HCRU included inpatient admissions, outpatient visits, and emergency visits. Results: Overall, 903 pts were included. Median age at la/mUC diagnosis was 70 y; 79.6% were men. Most (71.0%) had ≥1 comorbidity, most commonly cardiovascular disease (54.2%). Primary tumor sites were the bladder (83.7%), urethra (7.0%), and upper tract (6.6%). De novo la/mUC (41.9%) was the most common initial UC diagnosis. In the follow-up cohort (n = 829), median follow-up was 12.7 mo. Most (84.7% [n = 702]) pts received first-line (1L) systemic treatment; of these, 46.9% (n = 329) received second-line (2L) and 16.6% (n = 116) received third-line (3L) therapy. Chemotherapy was the most common treatment (1L: 77.8% [n = 546]; 2L: 49.8% [n = 164]; 3L: 74.1% [n = 86]), followed by PD-1/L1 inhibitors (1L: 28.3% [n = 199]; 2L: 47.7% [n = 157]; 3L: 19.0% [n = 22]). From index la/mUC diagnosis, estimated median (95% CI) OS was 18.8 (17.5–21.5), PFS was 9.9 (8.9–10.5), and time to progression was 12.7 (11.3–14.6) mo. From the start of 1L, 2L and 3L therapy, estimated median (95% CI) OS were 16.9 (14.3–18.9), 11.6 (9.6–14.3), and 9.9 (7.9–12.6) mo. For HCRU, 71.8% (n = 595) of pts had ≥1 outpatient visit (mean: 2.2/mo), 56.6% (n = 469) had ≥1 inpatient admission (0.4/mo; median duration: 8.0 d), and 56.5% (n = 468) had ≥1 emergency visit (0.4/mo). Conclusions: This retrospective study of university hospital data describes pt characteristics and real-world treatment patterns, survival, and HCRU for pts with la/mUC in Spain. Advances in immunotherapy are shifting the treatment landscape for targeted groups of pts with la/mUC, but a need remains for innovative treatments that could improve pt outcomes.