This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated, advanced TNBC. A single-agent phase II study examining a 200-mg dose given once every 3 weeks (ClinicalTrials.gov identifier: NCT02447003) is ongoing.

BackgroundIndoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod.MethodsDocetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured.ResultsTwenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted.ConclusionsDocetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.

Background Inhibition of PD-L1 with atezolizumab combined with chemotherapy has shown acceptable safety and improved survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Patients with TNBC who do not achieve a pathological complete response (pCR) to neoadjuvant chemotherapy have a high risk of disease recurrence and death. This randomized, open-label, phase 2 trial evaluates neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with previously untreated clinical stages II and III TNBC. Methods Women aged ≥18 years with clinical stage T2-T4c, any N, M0 primary tumor by AJCC 7th edition staging TNBC; ECOG PS 0-2; and no prior systemic therapy for the indexed breast cancer were eligible. Patients were randomized in a 1:2 ratio to carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 (Arm A), or carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 + atezolizumab 1200 mg q3 weeks x 4 (Arm B). Surgery was 3-6 weeks following neoadjuvant chemotherapy. Adjuvant dose-dense doxorubicin and cyclophosphamide was administered q2 weeks with growth factor support to all patients as per routine care. pCR and tumor infiltrating lymphocyte (TIL) percentages are the co-primary endpoints. pCR-evaluable population includes all eligible women who have been randomized and received at least one dose of combination therapy, while the TIL-evaluable population includes all eligible women who have evaluable TIL percentage after one cycle of therapy. A sample size of 67 (22 in Arm A, and 45 in Arm B) provided 80% power at 1-sided alpha = 0.10 to detect a minimum of 15% difference in TIL and 29% improvement (40% vs. 69%) in pCR, respectively. Herein, we report pCR results in the per protocol modified intent-to-treat population (mITT), which includes all eligible patients who were randomized and received at least one dose of combination therapy. Results Sixty-seven patients were randomized between 8/2017 and 9/2019. Six patients randomized to Arm A withdrew consent; 2 of these received protocol therapy but are excluded from the mITT analyses as they are not evaluable because definitive pathology reports are not available. Median follow up is 6 months (range 0.3 - 12.6 months). Median age is 52 years (range 25 - 78). Forty-three (64.2%) were Caucasian and thirteen (19.4%) were African American. Twenty-five (37.3%) were pre-menopausal. 67.2% and 32.8% had stages II and III disease respectively. Nine (13.4%) had a germline mutation in either BRCA1 or BRCA2. In the mITT population, 3 of 16 patients achieved pCR in Arm A - 18.8% (95% CI 4.0%- 45.6%), versus 25 of 45 patients in Arm B - 55.6% (95% CI 40.0%-70.4%); p value 0.018. pCR in those with BRCA mutations was 50% and 80% in Arm A and Arm B, respectively. Treatment delays were observed in 9 patients (40.9%) in Arm A, and 20 (44.4%) in Arm B; dose reductions occurred in 4 patients (18.1%) in Arm A, and in 6 (13.3%) in Arm B. There were 4 SAEs in Arm A and 10 in Arm B. One patient in Arm B had grade 3 adrenal insufficiency. One patient in Arm B died from recurrent disease during the follow-up period. Conclusions: The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in an increased pCR rate in patients with clinical stages II and III TNBC. However, the pCR in the control Arm A was lower than expected, possibly due to the absence of neoadjuvant anthracyclines. The high pCR rate observed in the experimental arm of this study is similar to that observed in other neoadjuvant trials utilizing anthracyclines, taxanes, and carboplatin in TNBC. Clinical trial information: NCT02883062. Citation Format: Foluso O Ademuyiwa, Feng Gao, Ina Chen, Donald W Northfelt, Robert Wesolowski, Mili Arora, Adam Brufsky, Claire Dees, Cesar A Santa-Maria, Roisin M Connolly, Jeremy Force, Alvaro Moreno-Aspitia, Sarah Larson, Elad Sharon, William Gillanders. Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-09.

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Background: Preclinical data demonstrates that activation of RAS/MEK/ERK pathway in basal-like breast cancer (BLBC) leads to resistance to chemotherapy. Inhibiting MEK pathway was highly effective in BLBC models with intact PTEN. Conversely activated PI3K/AKT pathway (loss of PTEN which occurs in ∼ 30% of TNBC) led to resistance to MEK inhibition. We proposed to test the hypothesis that single agent trametinib (T) will demonstrate efficacy in a subset of TNBC and that addition of AKTi, GSK2141795 (G) will overcome resistance to T. Methods: This is a single arm, multicenter study through the ETCTN. Eligible patients (pts) with advanced TNBC, measurable disease with 1-3 prior chemotherapies received mandatory research biopsy and entered Part I of the study with T alone (2 mg Q day-28 days). At the point of progression pts received a mandatory second biopsy and moved to PART II of study with 1.5 mg of T + 50 mg of G. Optional research biopsy was performed at the point of progression on the combination. Restaging scans were done every 2 cycles. Blood samples were collected at baseline, cycle 2 and at progression. Results: 33 pts with median age 55 (35-71) from six cancer centers were enrolled to Part I (T alone) and 17 pts entered part II (T +G). Most common toxicities for pts on T alone included Gr1: diarrhea, rash, transaminitis, Gr 2: fatigue; Gr 3: thromboembolism. Of 31 evaluable pts on T alone, two pts (1 still on study after 8 cycles) had a partial response (PR) and one pt has stable disease after 8 cycles and remains on study. Of the sixteen evaluable patients on part II (T+G) one patient has an unconfirmed PR (34% reduction on RECIST). Common toxicities for the combination include: Gr1: diarrhea, nausea, vomiting, myelosuppression, rash, hypertension, transaminitis, Gr2: Rash, fatigue, mucositis, diarrhea, Gr 3: diarrhea. Eleven patients died on study (10-progression, 1-adverse event). Blood and tissue samples are being analyzed for whole genome sequencing, IHC for PTEN, Quantitative targeted absolute proteomics (QTAP) for kinome assay and RPPA for PTEN, PI3KCA, AKT, ERK and MEK. This study is currently closed to accrual for interim analysis for efficacy on part II. Conclusion: Trametinib alone and in combination with AKTi, GSK2141795 has limited efficacy in TNBC. Proposed correlatives in serial biopsies may identify biomarkers in the few responders and help identify other novel targets. Citation Format: Bhuvaneswari Ramaswamy, Ewa Mrozek, Maryam Lustberg, Robert Wesolowski, Rachel Layman, Mahmoud Abdel-Rasoul, Cynthia Timmers, Robyn Patrick, Jennifer Sexton, Erin Macrae, Charles Shapiro, Thomas Budd, Lyndsay Harris, Claudine Isaacs, Roohi Ismail-Khan, Claire Dees, Andrew Poklepovic, Micheal Grever, Helen Chen, Miguel Villalona, William Carson. NCI 9455: Phase II study of trametinib followed by trametinib plus AKT inhibitor,GSK2141795 in patients with advanced triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-216.

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Background: In the multicenter, nonrandomized phase Ib KEYNOTE-012 trial (NCT01848834), the anti–PD-1 antibody pembrolizumab demonstrated promising antitumor activity (18.5% ORR in patients [pts] with measurable disease at baseline as assessed by RECIST v1.1 and central radiology review; 6-mo PFS rate, 24%; 12-mo OS rate, 43.1%; data cutoff date, March 23, 2015) and a manageable toxicity profile as later-line of therapy for previously treated, PD-L1+ mTNBC. Here we present updated data for the mTNBC cohort of KEYNOTE-012. Methods: Key enrollment criteria were: age ≥18 yr; ER-negative, PR-negative, HER2-negative, recurrent or metastatic breast cancer; measurable disease based on RECIST v1.1; ECOG PS 0-1; any number of prior systemic treatments in the metastatic setting; and PD-L1+ tumors (expression in stroma or ≥1% of tumor cells by IHC using the 22C3 antibody). Pts received pembrolizumab 10 mg/kg Q2W for 24 mo or until disease progression or unacceptable toxicity. Clinically stable pts with initial evidence of radiographic progression could remain on pembrolizumab until progression was confirmed. Response was assessed every 8 wk by central radiology review based on RECIST v1.1. After pembrolizumab discontinuation, pts were followed every 3 mo until death or withdrawal of consent. OS was estimated using the Kaplan-Meier method. Results: Thirty two female pts were enrolled. Median age was 50.5 yr (range, 29-72); 46.9% had received ≥3 lines of therapy and 25.0% had received ≥5 lines of therapy for metastatic disease. As of the data cutoff date of April 26, 2016, median follow-up duration was 10.7 mo (range, 0.4-32.7). Median OS was 10.2 mo (95% CI, 5.3-17.5) and 12-mo OS rate was 41.1%; 25 (78.1%) pts had died. Median PFS was 1.9 mo (95% CI, 1.3-4.3) and 12-mo PFS rate was 15.0%. Of the 5 responders (including 1 complete response [CR] and 4 partial responses [PR]), 3 have had long-lasting benefit from pembrolizumab. The pt with CR discontinued study medication 11 mo after achieving CR and has remained in CR for approximately 15 mo without receiving any additional anticancer treatment. Two pts with PR discontinued pembrolizumab after completing 2 yr of treatment. The first pt has maintained response for 22.7 mo; the second pt had disease progression after 7.7 mo of response and recently restarted pembrolizumab as allowed by protocol. Median duration of response has not been reached (range, 15-58+ wk). Thirty (93.8%) pts discontinued pembrolizumab (27 [84.4%] with progressive disease and 3 [9.4%] for AEs) before reaching 2 yr of treatment. Six (18.8%) pts experienced grade 3-5 treatment-related AEs; there was 1 treatment-related death (disseminated intravascular coagulation with decreased blood fibrinogen). Conclusions: Pembrolizumab provides long-lasting responses in heavily pretreated pts with mTNBC. Further development of pembrolizumab for treatment of this poor-prognosis pt population is warranted, and a phase II study evaluating efficacy and safety of single-agent pembrolizumab as later line of treatment for mTNBC is ongoing (KEYNOTE-086, NCT02447003). Citation Format: Nanda R, Specht J, Dees C, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Ray A, Karantza V, Buisseret L. KEYNOTE-012: Long-lasting responses in a phase Ib study of pembrolizumab for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-10-03.