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Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (>12 mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here. Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria; PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for >12 mo. In these 63 pts, median age was 64 yr and 70% had received ≥1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table); all 4 pts were PD-L1+ (≥1% expression on tumor cells). Across the LTE cohort, ORR was 66.7%; PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for >12 mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in ≥15% of pts. Most TRAEs were of mild or moderate severity; arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade ≥3 TRAEs reported with tislelizumab LTE. Conclusion Tislelizumab remained well tolerated for >12 mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status. PD-L1+ (n=35)PD-L1- (n=22)Missing (n=6)Total (N=63)CR4004 (6.3%)PR2113438 (60.3%)SD99220 (31.7%)PD1001 (1.6%)Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD stable disease. Citation Format: Jayesh Desai, Benjamin Markman, Michael Friedlander, Hui Gan, Lisa Horvath, Amanda Townsend, Michael Millward, Michael Jameson, Chia-Jui Yen, Ming-Mo Hou, Jeannie Hou, John Wu, Liang Liang, Sanjeev Deva. Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT084.

Purpose: To evaluate whether PIK3CA mutations and/or PTEN loss predict better clinical outcomes to phase I trials of PI3K/AKT/mTOR inhibition-based therapies in patients with metastatic, recurrent or refractory cervical cancers. Methods: Outcome analyses were conducted on 36 consecutive patients with advanced cervical cancers who were initially seen in a designated Phase I clinic at MD Anderson Cancer Center from 1/1/2006 to 6/30/2012, and tested for PIK3CA mutations and/or PTEN loss in a CLIA-certified molecular diagnostic laboratory, in accordance with the IRB guidelines. All data were obtained from patients’ electronic medical records. Results: All patients (n=36) had received at least one systemic therapy before the referral. Approximately 50% of tested patients (n=18/36) harbored PIK3CA mutations (n=9/34, 26% including seven E545K, one E542K, and one E545K/D549H in squamous cell carcinoma [7/19, 37%], adenocarcinoma [1/12, 8%] and small cell carcinoma [1/1, 100%]) and/or PTEN loss (n=12, 63%). Six patients were removed from further analyses because they did not enroll to a phase I study (n=2) or had only one negative result while the other test was not done (n=4). At their initial phase I therapy, the patients with PIK3CA mutations and/or PTEN loss (n=18) achieved four PR and seven SD ≥ 6 months (61% CR/PR/SD≥6months) with a median progression-free survival (PFS) of 6.7 months, compared to one CR and one SD ≥ 6 months (17% CR/PR/SD≥6months, p=0.026) with a median PFS of 2.5 months (p=0.001) in patients without PIK3CA mutations and/or PTEN loss (n=12). Analyses in patients receiving mTOR inhibitor-based phase I regimens showed that patients with PIK3CA mutations and/or PTEN loss (n=10) achieved three PR and four SD ≥ 6 months (70% CR/PR/SD≥6months) with a median PFS of 6.6 months, compared to one SD ≥ 6 months (17% CR/PR/SD≥6months, p=0.119) with a median PFS of 3.2 months (p=0.014) in patients without PIK3CA mutations and/or PTEN loss who received mTOR inhibitor-based phase I regimens (n=6); or one PR and three SD ≥ 6 months (50% CR/PR/SD≥6months, p=0.63) with a median PFS of 5.3 months (p=0.86) in patients with PIK3CA mutations and/or PTEN loss who did not receive mTOR inhibitor-based phase I regimens (n=8). Conclusions: The most frequent PIK3CA mutation in patients with advanced cervical cancers was E545K. Matched therapy using mTOR inhibitor-based regimens led to dramatic clinical responses, and a significantly longer PFS in patients with PIK3CA mutations and/or PTEN loss. Thus, targeting aberrant PI3K pathway is warranted for further evaluation in patients with advanced cervical cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B191. Citation Format: Ming-Mo Hou, Xiaochun Liu, Sarina A. Piha-Paul, Filip Janku, Jennifer Wheler, Aung Naing, Diane Bodurka, Kathleen Schmeler, Karen Lu, Ralph Zinner, David Hong, Funda Meric-Bernstam, Razelle Kurzrock, Siqing Fu. Target-matched therapies in patients with advanced cervical cancers harboring PIK3CA mutations and/or PTEN loss. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B191.