Search

Background: SB3 (trastuzumab-dttb) is a biosimilar approved globally based on its similarity with reference trastuzumab (TRZ) demonstrated by thorough comparability exercises in analytical, biological, and clinical studies. In a randomized, double-blind, multicenter Phase 3 study of 875 patients with HER2-positive early or locally advanced breast cancer in the neoadjuvant setting, equivalent efficacy, similar safety, pharmacokinetics, and immunogenicity between SB3 and TRZ were shown. However, when quality attributes of TRZ were examined, downward drifts in antibody-dependent cell-mediated cytotoxicity activities (ADCC) were observed in the TRZ lots with expiry dates ranging from Aug 2018 to Dec 2019. Some of these lots of the reference product were found to be used in the Phase 3 study. After completing the Phase 3 study, patients from select countries were included in a follow-up observational study to monitor cardiac safety and survival. Here, we report the final survival results, including post-hoc subgroup analysis based on ADCC status, at a median follow-up of 68 months. Methods: During the follow-up observational study, the protocol was amended to include additional patients who originally were enrolled in the Phase 3 study but had not been followed in the observational study, in order to collect a larger sample of survival data. For these additional patients, medical records from the last assessment in the Phase 3 study through the date of enrollment in the follow-up study were collected retrospectively. As post-hoc analysis, patients in the TRZ arm were stratified into two subgroups: patients who received during neoadjuvant treatment at least one vial of TRZ with downward drift in ADCC as “Drifted TRZ”, and the others as “Non-drifted TRZ”. Event-free survival (EFS) and overall survival (OS) were assessed. Results: Of 875 patients randomized in the Phase 3 study, 538 patients (SB3, N=267; TRZ, N=271) were enrolled in the follow-up observational study: 367 patients were initially enrolled in the follow-up study, and 171 patients were additionally enrolled following the protocol amendment. The median follow-up duration was 68 months from randomization in the Phase 3 study. 54 events (20.2%) in the SB3 arm, and 67 events (24.7%) in the TRZ arm were reported (HR 0.84 [0.58, 1.20], p=0.335). 22 deaths (8.2%) and 38 deaths (14%) were reported in SB3 and TRZ arms, respectively (HR 0.61 [0.36, 1.05], p=0.073). In post-hoc analysis, of 271 patients in TRZ arm, 107 patients were grouped as “Non-drifted TRZ”, and 164 patients as “Drifted TRZ”. 19 events (17.8%) in the Non-drifted TRZ group and 48 (29.3%) events in the Drifted TRZ group occurred (HR 2.57 [1.28, 5.14], p=0.008). 9 deaths (8.4%) in the Non-drifted TRZ group and 29 deaths (17.7%) in the Drifted TRZ group were reported (HR 3.87 [1.37, 10.93], p=0.011). No difference was observed between SB3 arm and Non-drifted TRZ group in terms of EFS (HR 1.28 [0.73, 2.22], p=0.391) and OS (HR 0.99 [0.42, 2.31], p=0.975). Conclusions: Comparable long-term efficacy results in EFS and OS were shown at 68 months of follow-up, further supporting biosimilarity of SB3 to the reference product. Currently, these follow-up results represent the longest monitoring data of patients treated with a trastuzumab biosimilar for HER2-positive early or locally advanced breast cancer. Citation Format: Xavier Pivot, Mark D Pegram, Javier Cortes, Diana Lüftner, Gary H Lyman, Giuseppe Curigliano, Igor M Bondarenko, Mikhail Dvorkin, Jin Hee Ahn, Seock-Ah Im, Maria Litwiniuk, Yaroslav V Shparyk, Gwo Fuang Ho, Nikolay V Kislov, Marek Wojtukiewicz, Tomasz Sarosiek, Yee Soo Chae, Jin Seok Ahn, Hyerin Jang, Sujung Kim, Jiwon Lee, Soo Young Lee, Ye Chan Yoon. Final survival analysis of a phase 3 study comparing SB3 (trastuzumab biosimilar) and reference trastuzumab in HER2-positive early or locally advanced 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 P2-13-04.

Background: Avelumab, a human IgG1 anti–PD-L1 monoclonal antibody, has shown antitumor activity and a manageable safety profile in several tumor types. Talazoparib, an orally available PARP inhibitor, is approved for the treatment of patients with deleterious or suspected deleterious germline BRCA1/2-mutated HER2− locally advanced (LA) or metastatic (M) breast cancer (BC). Preclinical data suggest that PARP inhibitors may have synergistic activity when administered in combination with immune checkpoint inhibitors. We report results from patients with LA/MBC enrolled in the phase 1b/2, multicohort JAVELIN PARP Medley study (NCT03330405). Methods: In phase 1b (cohort 1), patients with advanced solid tumors who had received ≥1 prior standard of care chemotherapy (CT) regimen were treated with avelumab 800 mg IV every 2 weeks (Q2W) in combination with talazoparib 1.0 mg orally once daily (QD) (dose de-escalation to 0.75 or 0.5 mg permitted following toxicity). In 2 phase 2 cohorts, eligible patients had either LA/M triple-negative BC (TNBC, cohort 2A) or LA/M hormone receptor positive (HR+), HER2−, DNA damage repair defect-positive BC (cohort 2B). Patients in cohort 2A had received 0 to 2 prior CT regimens (no progression on prior platinum-based CT) and patients in cohort 2B had received prior standard of care hormone therapy in either the adjuvant and/or LA/M setting followed by 0 to 2 prior CT regimens (no progression on prior platinum-based CT). The primary endpoint for phase 1b was first-cycle dose-limiting toxicities (DLTs) and for phase 2 was objective response (investigator assessed per RECIST v1.1). Adverse events (AEs) were characterized using National Cancer Institute Common Terminology Criteria for AEs v4.03. Results: By the data cutoff on December 24, 2018, 34 patients had been treated in cohorts 1 and 2. Twelve patients with advanced solid tumors were treated in cohort 1 (including 2 patients with TNBC); 3 patients (25.0%) had a first-cycle DLT: grade 3 neutropenia, (n=1) and grade 3 thrombocytopenia, (n=2). Best overall response (BOR) was partial response (PR) in 1 patient, stable disease (SD) in 3, progressive disease (PD) in 6, and non-complete response/non-PD in 1 patient with metastatic castration-resistant prostate cancer and non-measurable disease at baseline; 1 patient was not evaluable for response. Both patients with TNBC had a BOR of SD and remained on treatment for ≥9 months. Objective response rate in this pre-treated and heterogenous population was 8.3% (95% CI, 0.2, 38.5). Based on the phase 1b data, the recommended phase 2 dose was avelumab 800 mg Q2W and talazoparib 1 mg QD. By data cutoff, 22 patients had been treated in cohorts 2A (n=19) and 2B (n=3); median age was 56 and 50 years, respectively. In cohort 2A, 12 patients were evaluable for disease assessment; BOR was PR in 1, SD in 6, and PD in 5. All 3 patients in cohort 2B were non-evaluable for response at data cutoff. Treatment-related AEs (TRAEs) of any grade occurred in 11 patients (91.7%) in cohort 1, and 18 (94.7%) patients in cohort 2A. In cohort 2A, the most common TRAEs were anemia (57.9%), nausea (26.3%), fatigue (21.1%) and thrombocytopenia (21.1%); 9 patients (47.4%) had grade ≥3 TRAEs. There were no treatment-related deaths. Safety data from cohort 2B are not reported owing to low patient numbers. Observed pharmacokinetic (PK) data for avelumab 800 mg Q2W were similar to simulated data derived from a population PK model developed using 10 mg/kg dosing. Conclusions: Avelumab 800 mg Q2W administered in combination with talazoparib 1 mg QD in patients with advanced solid tumors, showed preliminary antitumor activity and a manageable safety profile, which was comparable to the safety profiles of the single agents. The study is ongoing; updated safety and efficacy data, and biomarker data will be presented. Citation Format: Timothy A Yap, Panagiotis Konstantinopoulos, Melinda L. Telli, Smita Saraykar, J Thaddeus Beck, Matthew D. Galsky, Jame Abraham, David R. Wise, Mustafa Khasraw, Gabor Rubovszky, Mikhail Dvorkin, Anil A Joy, Mateusz Opyrchal, Daria Stypinski, Colombe Chappey, Ross Stewart, Rossano Cesari, Anita Scheuber, Aditya Bardia. JAVELIN PARP Medley, a phase 1b/2 study of avelumab plus talazoparib: Results from advanced breast cancer cohorts [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 P1-19-03.

Background: At a predefined interim analysis (IA), RATIONALE-303 (NCT03358875) demonstrated improved overall survival (OS) for TIS vs D in the intent-to-treat (ITT), with a manageable safety profile. Disease characteristics, standard of care and treatment/prognosis differ between histologic types of NSCLC. Here, we report on the non-sq population. Methods: 805 patients with histologically confirmed, advanced NSCLC with progressive disease during or after ≥ 1 platinum (Pt)-containing chemotherapy regimen were randomized (2:1) to TIS 200 mg or D 75 mg/m2 every 3 weeks until disease progression, intolerable toxicity, or withdrawal. Histology (sq vs non-sq) was a randomization stratification factor. Dual primary endpoints were OS in the ITT and PD-L1 ≥ 25% populations. A prespecified IA was conducted after ~426 deaths (76% of planned events). Efficacy and safety were assessed in 435 randomized patients with non-sq histology. Results: Baseline characteristics of non-sq patients were balanced between treatment arms and similar to the ITT population. As of August 10, 2020, at median follow-up of 20 and 17 months (mo), respectively, median (95% CI) OS was longer with TIS (18.6 mo [15.41, 23.16]) vs D (13.8 mo [9.43, 17.94]) in the non-sq ITT population, and objective response rate (ORR) and duration of response (DoR) were also improved for TIS vs D (Table). 95.5% (TIS) and 97.9% (D) of patients had ≥ 1 treatment-emergent adverse event (TEAE) and 39.0% (TIS) and 70.9% (D) of patients had ≥ Grade 3 TEAEs. The most common TEAEs were anemia, aspartate aminotransferase increased and alanine aminotransferase increased (TIS arm), and alopecia, anemia and neutrophil count decreased (D arm). Conclusions: TIS prolonged OS, consistent with the overall ITT population, with a favorable safety profile in patients with advanced non-sq NSCLC who progressed after a Pt-containing regimen. Table Efficacy* TIS (n=287) D (n=148) Median OS, mo (95% CI) 18.6 (15.41, 23.16) 13.8 (9.43, 17.94) OS HR (95% CI)† 0.71 (0.538, 0.929) P=0.0064‡,§ Median PFS, mo (95% CI) 2.5 (2.14, 4.01) 3.6 (2.17, 4.14) PFS HR (95% CI)† 0.84 (0.660, 1.062) P=0.0686‡,§ ORR, n (%) 60 (20.9) 14 (9.5) Median DoR, mo (95% CI) 11.7 (6.80, 14.65) 6.2 (2.10, 7.16) Safety** TIS (n=287) D (n=141) TEAEs ≥ 15% of patients in either arm, n (%) All grades ≥ Grade 3 All grades ≥ Grade 3 Anemia 76 (26.5) 11 (3.8) 56 (39.7) 6 (4.3) AST increased 64 (22.3) 5 (1.7) 18 (12.8) 0 (0.0) ALT increased 63 (22.0) 4 (1.4) 24 (17.0) 0 (0.0) Cough 59 (20.6) 4 (1.4) 25 (17.7) 0 (0.0) Weight decreased 44 (15.3) 2 (0.7) 13 (9.2) 0 (0.0) Decreased appetite 41 (14.3) 3 (1.0) 26 (18.4) 0 (0.0) Hypoalbuminemia 37 (12.9) 0 (0.0) 23 (16.3) 0 (0.0) Nausea 37 (12.9) 0 (0.0) 22 (15.6) 0 (0.0) Constipation 31 (10.8) 0 (0.0) 22 (15.6) 0 (0.0) Asthenia 29 (10.1) 1 (0.3) 29 (20.6) 8 (5.7) Neutrophil count decreased 8 (2.8) 1 (0.3) 53 (37.6) 36 (25.5) White blood cell count decreased 8 (2.8) 0 (0.0) 42 (29.8) 26 (18.4) Neutropenia 7 (2.4) 3 (1.0) 44 (31.2) 38 (27.0) Leukopenia 6 (2.1) 0 (0.0) 38 (27.0) 22 (15.6) Alopecia 0 (0.0) 0 (0.0) 70 (49.6) 2 (1.4) *Efficacy analysis set - non-sq patients; †Stratified; ‡One-sided stratified log-rank test; §Descriptive P-value; **Safety analysis set - non-squamous patients ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI; confidence interval; DoR, duration of response; HR, hazard ratio; mo, months; NE, not evaluable; ORR, objective response rate; PFS, progression-free survival; TEAE, treatment-emergent adverse event Data cut-off: August 10, 2020 Citation Format: Ying Cheng, Dingzhi Huang, Zhiyong Ma, Yun Fan, Jie Wang, Xinmin Yu, Mikhail Dvorkin, Gareth Rivalland, Yiyuan Ma, Yan Wang, Yan Ma, Caicun Zhou. Tislelizumab (TIS) versus docetaxel (D) in patients with previously treated advanced non-squamous (non-sq) non-small-cell lung cancer (NSCLC): Subanalysis from the RATIONALE-303 phase 3 randomized clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT553.

Background: Lorlatinib improved progression-free survival (PFS) and demonstrated intracranial (IC) activity in patients (pts) with untreated advanced ALK+ NSCLC in the interim analysis of the randomized, Phase 3, CROWN study of lorlatinib vs crizotinib. We report updated 36-month follow-up data. Methods: 296 pts with previously untreated advanced ALK+ NSCLC were randomized 1:1 to oral lorlatinib (100 mg QD; n=149) or crizotinib (250 mg BID; n=147), stratified by presence of CNS metastases (mets) and ethnicity. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints included overall survival, PFS by investigator, and objective response (OR), IC-OR, IC time to progression (IC-TTP), duration of response (DR), IC-DR (all by BICR), and safety. Results: At data cutoff (Sep 20, 2021), median duration of follow-up for PFS was 36.7 months for lorlatinib and 29.3 months for crizotinib. Median PFS by BICR was NR (95% CI, NR-NR) for lorlatinib and 9.3 months (95% CI, 7.6-11.1) for crizotinib (HR, 0.27; 95% CI, 0.18-0.39). PFS by investigator results were similar (Table). For pts with brain mets at baseline (n=37 lorlatinib/n=39 crizotinib), the HR for IC-TTP for lorlatinib vs crizotinib was 0.10 (95% CI, 0.04-0.27), and for pts without brain mets (n=112/n=108) was 0.02 (95% CI, 0.002-0.14). OR, IC-OR, DR, and IC-DR were all improved with lorlatinib vs crizotinib (Table). All-cause grade 3-4 adverse events (AEs) and AEs leading to treatment discontinuation were reported in 76% and 7% of pts with lorlatinib and 57% and 10% of pts with crizotinib, respectively. No new safety signals emerged. Conclusions: These updated long-term data from CROWN confirm the efficacy of lorlatinib over crizotinib in pts with treatment-naïve ALK+ NSCLC, with no new safety signals detected, and support the use of lorlatinib in pts with untreated ALK+ NSCLC with and without brain mets. Summary of other efficacy resultsa Clinical trial information: NCT03052608 Funding: Pfizer Inc. ITT population Lorlatinib(n=149) Crizotinib(n=147) % alive without progression at:12 mo (95% CI) 78 (70–84) 38 (29–47) 24 68 (60–75) 22 (14–30) 36 64 (55–71) 19 (12–27) Median PFS by investigator, mo (95% CI) NR (NR–NR) 9.1 (7.4–10.9) HR (95% CI) 0.19 (0.13–0.27) Confirmed OR, n (%) [95% CI] 115 (77) [70–84] 86 (59) [50–67] Median DR,b mo (95% CI) NR (NR–NR) 9.6 (9.0–12.9) Patients with measurable or nonmeasurable brain metastases at baseline (n=37) (n=39) Median PFS, mo (95% CI) NR (18.2–NR) 7.2 (3.7–9.2) HR (95% CI) 0.21 (0.10–0.44) Confirmed IC-OR, n (%) [95% CI] 24 (65) [48–80] 7 (18) [8–34] Complete response, n (%) 22 (60) 5 (13) Median IC-DR,b mo (95% CI) NR (NR–NR) 9.4 (6.0–11.1) Patients without brain metastases at baseline (n=112) (n=108) Median PFS, mo (95% CI) NR (NR–NR) 11.0 (9.0–14.6) HR (95% CI) 0.29 (0.19–0.44) aBy blinded independent central review unless stated otherwise. bIn patients with a confirmed complete or partial response. CI, confidence interval; DR, duration of response; HR, hazard ratio; ITT, intention- to-treat; NR, not reached; IC, intracranial; OR, objective response; PFS, progression-free survival. Citation Format: Benjamin Solomon, Todd Bauer, Tony Mok, Geoffrey Liu, Julien Mazieres, Filippo de Marinis, Yasushi Goto, Dong-Wan Kim, Yi-Long Wu, Mikhail Dvorkin, Jacek Jassem, Froylán López-López, Ross Soo, Anna Polli, Elisa Dall'O, Laura Iadeluca, Francesca Toffalorio, Enriqueta Felip. Updated efficacy and safety from the phase 3 CROWN study of first-line lorlatinib vs crizotinib in advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT223.

Results From RATIONALE 303: A Global Phase 3 Study of Tislelizumab (TIS) vs Docetaxel (TAX) as Second- or Third-Line Therapy for Patients With Locally Advanced or Metastatic NSCLC Background: Anti-PD-1/L1 therapies have improved OS by 2-4 mo vs TAX in patients (pts) with advanced NSCLC who progressed after platinum regimens. TIS is an anti-PD-1 antibody engineered to minimize FcγR binding on macrophages, a mechanism of T-cell clearance and potential anti-PD-1 resistance. Methods: RATIONALE 303 (BGB-A317-303; NCT03358875) compared efficacy and safety of TIS vs TAX as 2 or 3L therapy for pts with advanced NSCLC. Patients without oncogenic driver mutation who failed at least 1 prior systemic therapy including a platinum regimen were randomized 2:1 to receive TIS 200 mg IV Q3W (Arm A) or TAX 75 mg/m2 IV Q3W (Arm B). Dual primary endpoints were OS in the ITT analysis set and OS in the PD-L1 high (≥25% TC) analysis set. A prespecified interim analysis (IA) was conducted after ≈426 deaths (76% of planned events); in the IA, formal OS superiority testing was conducted only in the ITT. The IA results are presented. Results: Overall, 805 pts were randomized (n=535, TIS; n=270, TAX); demographics were generally balanced between arms. With a 19-mo median follow-up (441 OS events), median OSITT was significantly longer in Arm A vs B (17.2 vs 11.9 mo; HR=0.64 [95% CI: 0.53, 0.78]; P Conclusions: RATIONALE 303 demonstrated that, as 2 or 3L therapy in pts with advanced NSCLC, TIS was tolerable and prolonged OS by 5-7 mo with improved PFS and ORR vs TAX regardless of histology or PD-L1 expression. ITT Analysis Set (N=805)Arm A Tislelizumab (n=535)Arm B Docetaxel (n=270)EfficacyMedian OS, mo17.211.9OS difference, mo5.3HR (95% CI)a0.64 (0.53, 0.78)P-valuea,b Citation Format: Caicun Zhou, Dingzhi Huang, Xinmin Yu, Yunpeng Liu, Yun Fan, Yongqian Shu, Zhiyong Ma, Ziping Wang, Ying Cheng, Jie Wang, Sheng Hu, Zhihua Liu, Mikhail Dvorkin, Elena Poddubskaya, Umut Disel, Andrey Akopov, Yiyuan Ma, Yan Wang, Zhenyu Pan, Cunjing Yu, Gareth Rivalland. Results from RATIONALE 303: A global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT039.