Abstract P2-09-05: LCCC 1525: A phase II study of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer (mTNBC)

Abstract

Background: While immunotherapy holds promise in the treatment of mTNBC, response rates (RR) in unselected patients (pts) are approximately 20%. Strategies to augment response to immunotherapy include depletion of regulatory T cells (Tregs). A single dose of cyclophosphamide (Cy) given prior to checkpoint inhibition achieved this goal in preclinical models of TNBC (Taylor et al., JCI, 2017). Thus, we designed a phase II study to evaluate this strategy in the clinical setting of mTNBC. Patients/Methods: In cycle 1 (C1), eligible pts with mTNBC received a single dose of Cy 300mg/m2 IV on day 1 (C1D1) followed by pembrolizumab 200mg IV on day 2 (C1D2), then every 3 weeks thereafter. The co-primary objectives were (1) progression free survival (PFS, null 1.9 mos vs. 2.9 mos, 80% power, alpha 0.05) and (2) reduction in Tregs in peripheral blood measured by flow cytometry. Secondary endpoints were response rate (RR), survival (OS), and RNA-based correlative endpoints. Results: 40 patients were evaluable for efficacy: mean age 54.5 yrs (33 – 82 yrs), 75% white, 22% black, 3% American Indian. All patients had received 1 prior line of chemotherapy in the metastatic setting; 29% received 5 or more prior lines. The most common grade 3 adverse events (AE's), all 5%, were neutropenia, anemia, elevated AST, and fatigue. Immune-related grade 3 AE's, all 3%, included colitis, dry mouth, pneumonitis. Overall RR was 21% (0 CR, 8 PR), 3 pts had stable disease. Median PFS was 1.8 months (mos) (95% CI 1.4–2.5) and OS was 6.3 mos (95% CI 2.8–8.4). There was a non-significant decrease in Tregs from C1D1 to C1D2 (-3.3%, p=0.19); but from C1D2 to C2D1, Tregs increased 21.7% (p=0.005). There was no association between changes in Tregs or number of prior lines of therapy with RR (p>0.09), while immune-related AE's were associated with response (p=0.02). Correlatives studies illustrate B cell immune gene signature expression and B cell receptor repertoire diversity were enriched in responders, while genes/pathways associated with neutrophils, anti-apoptosis, PI3K/AKT and down-regulation of MHC class 1 were associated with non-response. Conclusions: While pembroliuzumab plus Cy was well-tolerated among pts with mTNBC, efficacy was similar to historical control, likely due to minimal effect of Cy on Tregs. Correlative analyses illustrate that study of adaptive immune features, including B cell biology, is a promising strategy for understanding response to PD-1 inhibition in breast cancer. Further strategies to deplete Tregs in a more sustained manner are worthy of future exploration (NCT02768701). Citation Format: Anders CK, Moore D, Sambade M, Cuaboy L, Garrett A, Woodcock M, McKinnon K, Cowens K, Bortone D, Calhoun B, Carey L, Dees C, Jolly T, Muss H, Reeder-Hayes K, Kaltman R, Jankowitz R, Gudena V, Olajide O, Perou C, Vincent B, Serody J. LCCC 1525: A phase II study of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-05.

Efficacy and predictive factors of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis

“…Of the 27 studies, 16 were full-text articles, whereas 11 studies were abstracts. Sixteen studies used PD-1 antibody, 7,8,12,[19][20][21][22][23][24][25][26][27][28][29][30][31] eight studies used PD-L1 antibody, 6,[9][10][11][32][33][34][35] two studies used CTLA-4 antibody 36,37 and one study used both PD-1 and CTLA-4 antibody. 38 Patients with triple-negative breast cancer (TNBC), human epidermal growth factor receptor 2 (HER2) overexpression, and breast cancer with any subtypes were enrolled in 16, two, and nine studies, respectively.…”

PD-L1 expression as biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in metastatic triple negative breast cancer: A systematic review and meta-analysis

“…Title and abstract screening excluded 1765 studies for various reasons including duplicates, irrelevant, lacking data of main outcomes, and not target agent/s, etcetera. Further scrutiny for eligibility and full text reading yielded 20 studies that were included in this meta-analysis (11)(12)(13)(14)(15)(16)(17)(18)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). General characteristics of the included studies and participants are presented in Table 1.…”

“…Pembrolizumab was investigated in 12 studies; atezolizumab in 4; durvalumab in 2; and avelumab in only one study ( Figure 1C and Table 1 ). Pembrolizumab was also administered with induction chemotherapy in few trials ( 31 , 32 ) and was followed by radiotherapy in a single trial ( 33 ). Likewise, three studies had evaluated immune modulating agents along with pembrolizumab ( 34 – 36 ).…”

“…Quality assessment of the included studies based on the MINORS and QUIPS tools are detailed in Supplementary Tables 2, 3 . MINORS demonstrated that about 80% of the studies ( 11 – 18 , 30 , 32 , 33 , 36 – 41 ) had low risk of bias (score 10-15) and 20% exhibited a moderate risk of bias (score <10) ( 31 , 34 , 35 ). QUIPS tool, which assess the risk of bias in the studies involving assessment of prognostic factors, showed 66% of the studies had low risk of bias.…”

Clinical trials of immunotherapy in triple-negative breast cancer

“…However, several small studies have evaluated the use of limited low-dose chemotherapy prior to immunotherapy treatment, given the impact of chemotherapy on the tumor microenvironment [ 25 , 26 , 42 ]. A phase II trial evaluating a single priming dose of cyclophosphamide one day prior to initiation of pembrolizumab in previously treated metastatic TNBC demonstrated an ORR of 21% with a median PFS of 1.8 mos and median OS of 6.3 mos [ 43 ]. Although responses rates were higher than the previously treated cohort of the KEYNOTE-086 trial, OS was comparable, and cyclophosphamide failed to reduce Tregs on correlative analysis.…”