A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non–small cell lung cancer: Hoosier Cancer Research Network LUN 14-179

Background Five-year overall survival (OS) for patients with unresectable stage III non–small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti–programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. Methods Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. Results The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1-, 2-, and 3-year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). Conclusions Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone

Testing the optimal defence hypothesis for two indirect defences: extrafloral nectar and volatile organic compounds

Many plants respond to herbivory with an increased production of extrafloral nectar (EFN) and/or volatile organic compounds (VOCs) to attract predatory arthropods as an indirect defensive strategy. In this study, we tested whether these two indirect defences fit the optimal defence hypothesis (ODH), which predicts the within-plant allocation of anti-herbivore defences according to trade-offs between growth and defence. Using jasmonic acid-induced plants of Phaseolus lunatus and Ricinus communis, we tested whether the within-plant distribution pattern of these two indirect defences reflects the fitness value of the respective plant parts. Furthermore, we quantified photosynthetic rates and followed the within-plant transport of assimilates with 13C labelling experiments. EFN secretion and VOC emission were highest in younger leaves. Moreover, the photosynthetic rate increased with leaf age, and pulse-labelling experiments suggested transport of carbon to younger leaves. Our results demonstrate that the ODH can explain the within-plant allocation pattern of both indirect defences studied

Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer

Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival.12 month embargo; first published online 9 April 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Abstract GS5-02: Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158

Abstract Background: A significant proportion of patients with early-stage TNBC are treated with neoadjuvant chemotherapy (NAC). Sequencing of ctDNA after surgery can be used to detect minimal residual disease and predict which patients may experience clinical recurrence. Methods: BRE12-158 is a recently completed Phase II clinical trial which randomized early-stage TNBC patients with residual disease after NAC to post-neoadjuvant genomically-directed therapy vs treatment of physician choice. 151 patients had a plasma sample collected at the time of treatment assignment (after surgery and radiation). ctDNA was successfully sequenced in 150 patients. 148 of the 150 sequenced patients had clinical follow-up. Sequencing was performed by Foundation Medicine using the FoundationOne Liquid assay which profiles for 70 commonly mutated oncogenes. Presence of mutated ctDNA was associated with distant disease free survival (DDFS) and overall survival (OS) in univariate analysis using the Log-Rank test, and in multi-variate analysis using Cox proportional hazards model. Results: Mutated ctDNA was detected in 94 of 148 sequenced patients (64%). TP53 was the most commonly mutated gene consistent with prior genomic studies of TNBC. At 16.7 months of median follow-up, detection of ctDNA was significantly associated with an inferior DDFS (median DDFS 32.5 months vs. Not Reached, p=0.0030). At 24 months, the DDFS probability was 53% in ctDNA-positive patients as compared to 81% in ctDNA-negative patients. In multi-variate analysis, when considering significant covariates, including: residual cancer burden (RCB); number of positive lymph nodes; tumor size; stage; grade; age; and race; detection of ctDNA remained independently associated with inferior DDFS (HR=3.1, CI: 1.4-6.8, p=0.0048). Similarly, detection of ctDNA was associated with inferior OS in univariate (p=0.021) and multi-variate analysis (HR=2.7, CI:1.1-6.2, p=0.022). Lastly, we observed a correlation between higher maximum somatic allele frequency and a shorter DDFS interval in multivariate analysis (HR=4.7, CI: 1.04-21.1, p=0.044) and shorter OS (HR=4.9, CI:1.06-22.4, p=0.041), suggesting that the quantitative degree of ctDNA burden is associated with clinical outcome. Conclusions: Detection of ctDNA in early-stage TNBC after neoadjuvant chemotherapy is an independent predictor of disease recurrence, and represents an important novel stratification factor for future post-neoadjuvant trials. Citation Format: Milan Radovich, Guanglong Jiang, Christopher Chitambar, Rita Nanda, Carla Falkson, Filipa C. Lynce, Christopher Gallagher, Claudine Isaacs, Marcelo Blaya, Elisavet Paplomata, Radhika Walling, Karen Daily, Reshma Mahtani, Michael A. Thompson, Robert Graham, Maureen E. Cooper, Dean C. Pavlick, Lee Albacker, Jeff Gregg, Casey L. Bales, Bradley A. Hancock, Erica Cantor, Fei Shen, Anna Maria V. Storniolo, Sunil Badve, Tarah Ballinger, Kathy D. Miller, Bryan P. Schneider. Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-02

Abstract PD9-10: BRE12-158: A post-neoadjuvant, randomized phase 2 trial of personalized therapy vs. treatment of physician’s choice for patients with residual triple negative breast cancer

Abstract Purpose: Patients with triple negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase 2, multicenter trial that randomized TNBC patients with residual disease after NAC to genomically-directed therapy vs. treatment of physician choice (TPC). Patients and Methods: From March 2014 to December 2018, 197 patients were enrolled. Residual tumors were sequenced using a next generation sequencing (NGS) test. A molecular tumor board adjudicated all results. Patients were randomized to 4 cycles of genomically-directed therapy (arm A) vs. TPC (arm B). Patients without a target were assigned to arm B. Primary endpoint was 2-year disease free survival (DFS) among randomized patients. Secondary/exploratory endpoints included: distant disease free survival (DDFS), overall survival (OS), toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. Results: 193 patients were randomized or were assigned to arm B. The estimated 2-year DFS was 56.6% (95%CI:0.45-0.70) for arm A vs. 62.4% (95%CI:0.52-0.75) for randomized arm B. No difference was seen in DFS, DDFS, or OS for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomized later had less distant recurrences. ctDNA status remained a significant predictor of outcome with some patients demonstrating clearance with post-neoadjuvant therapy. Conclusion: Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes for this high-risk population. ctDNA should be considered a standard covariate for trials in this setting. Citation Format: Bryan P Schneider, Guanglong Jiang, Tarah J Ballinger, Fei Shen, Christopher Chitambar, Rita Nanda, Carla Falkson, Filipa C Lynce, Christopher Gallagher, Claudine Isaacs, Marcelo Blaya, Elisavet Paplomata, Radhika Walling, Karen Daily, Reshma Mahtani, Michael A Thompson, Robert Graham, Maureen E Cooper, Dean C Pavlick, Lee A Albacker, Jeffery Gregg, Jeffery P Solzak, Yu-Hsiang Chen, Casey L Bales, Erica Cantor, Bradley A Hancock, Nawal Kassem, Paul Helft, Bert O'Neil, Anna Maria Storniolo, Sunil Badve, Kathy D Miller, Milan Radovich. BRE12-158: A post-neoadjuvant, randomized phase 2 trial of personalized therapy vs. treatment of physician’s choice for patients with residual triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-10

BRE12-158: A postneoadjuvant, randomized phase II trial of personalized therapy versus treatment of physician\u27s choice for patients with residual triple-negative breast cancer

Purpose: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). Patients and methods: From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. Results: One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. Conclusion: Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting

Association of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy with disease recurrence in patients with triple-negative breast cancer: Preplanned secondary analysis of the BRE12-158 randomized clinical trial

Importance: A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence. Objective: To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes. Design, Setting, and Participants: A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months). Interventions: Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device. Main Outcomes and Measures: Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Results: Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007). Conclusions and Relevance: In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02101385