Investigator-assessed Objective Response Rate Research Articles

LBA57 - Tailored immunotherapy approach with nivolumab in advanced renal cell carcinoma (TITAN-RCC)

BackgroundNivolumab (N) + ipilimumab (I) has been approved for the 1st line treatment of IMDC intermediate and poor risk advanced RCC. However, administration of N+I in a fixed regimen with 4 induction cycles may result in more treatment related adverse events (AEs) compared with N alone. It is hypothesized that a tailored approach starting treatment with N alone and using N+I as immunotherapeutic boost will improve efficacy outcomes as compared to N alone and reduce AEs. MethodsThis multicentric European study enrolled 258 1st and 2nd line (after TKI) pts with IMDC intermediate and poor risk, advanced clear cell RCC between Oct. 2016 and Dec. 2018. Pts started with N 240mg Q2W induction. Pts with early significant PD (week 8) or either SD or PD at week 16 received 2-4 N+I boost cycles. Responders (PR/CR) to N monotherapy continued with maintenance with N+I boosts only for progression. The primary endpoint is confirmed investigator assessed objective response rate (ORR) per RECIST independent in 1st and 2nd line. Secondary endpoints include activity of N monotherapy, remission rate with N+I boosts, safety, overall survival and QoL. Results108 1st and 99 2nd line pts were analyzed for efficacy. Median age was 65 y (range 20-87). 70 % were intermediate and 27 % poor risk. Confirmed ORR with 1st line N monotherapy was 28.7 % (95 % CI 20 - 38). Best overall response (BOR) after N induction ± N+I boosts was 37 % (95 % CI 28 - 47) and 28 % (95 % CI 20 - 38) in 1st and 2nd line, respectively. 102 pts received N+I boosts for either SD (n=35) or PD (n=67) until week16. Of these, 12 (12 %) and 54 (53%) had a PR/CR and SD, respectively. Two (6%) pts entering boosts for SD had PD afterwards compared to 51% with early PD. Treatment-related AEs will be presented.TableLBA57Table1st line (n=108)2nd line (n=99)n (%)Nivo mono ORRN ± N+I BORNivo mono ORRN ± N+I BORComplete response2 (1.9)2 (1.9)04 (4.0)Partial response29 (26.9)38 (35.2)18 (18.2)24 (24.2)Stable disease26 (24.1)26 (24.1)23 (23.2)25 (25.3)Progressive disease13 (12.0)38 (35.2)16 (16.2)43 (43.4)Early PD/Boost W822 (20.4)26 (26.3)Not evaluable*16 (14.8)4 (3.7)16 (16.2)3 (3.0)*Including patients with early end of study e.g. due to death or immune related AEs ConclusionsTITAN–RCC is the first study to assess the impact of a tailored approach using N+I as an immunotherapeutic boost. In 1st line, this significantly improved ORR compared to N mono. Further follow-up is ongoing to characterize duration and depth of response. Clinical trial identificationEudraCT: 2016-002307-26. Legal entity responsible for the studyAIO-Studien-gGmbH, Berlin, Germany. FundingBristol-Myers Squibb GmbH & Co.KGaA. DisclosureM. Grimm: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Amgen; Honoraria (self): Apogepha; Honoraria (self): Astellas; Honoraria (self): AstraZeneca; Honoraria (self): Bayer HealthCare; Honoraria (self): Hexal; Honoraria (self), Advisory / Consultancy: Intuitive Surgical; Honoraria (self): Janssen Cilag; Honoraria (self): Ipsen Pharma; Honoraria (self): Medac; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: ONO Pharma; Honoraria (self): Pfizer; Honoraria (self): Sanofi Aventis. M. Schmidinger: Honoraria (self): Astellas; Honoraria (self): BMS; Honoraria (self): EISAI; Honoraria (self): Eusa Pharma; Honoraria (self): Exelexis; Honoraria (self): Ipsen; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche. I. Duran Martinez: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Non-remunerated activity/ies: Ipsen; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Pharmacyclyc; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD. G. Baretton: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer. P. Barthelemy: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Janssen Cilag; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Astellas. B. Melichar: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. L. Albiges: Honoraria (institution): Pfizer; Honoraria (institution): Novartis; Honoraria (institution): BMS; Honoraria (institution): Ipsen; Honoraria (institution): Roche; Honoraria (institution): MSD; Honoraria (institution): AstraZeneca. All other authors have declared no conflicts of interest.

LBA62 - Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358

LBA62 - Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358

685TiP - A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumours

685TiP - A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumours

1589TiP - KEYNOTE-495/KeyImPaCT: A randomized, biomarker-directed, phase II trial of pembrolizumab-based therapy for non–small cell lung cancer (NSCLC)

BackgroundKEYNOTE-495 is a randomized, open-label, phase II trial (NCT03516981) evaluating the clinical activity and safety of pembrolizumab (pembro)-based combination (combo) therapy in patients (pts) with treatment-naive, advanced NSCLC in biomarker-defined response groups. This biomarker-based approach is based on 2 validated, independent, next-generation biomarkers (T cell–inflamed gene expression profile [GEP] and tumor mutational burden [TMB]) and can help determine the differential efficacy of pembro-based combo therapy, based on the composite biomarker profile, and inform precision immunotherapy in the future. Trial designIn this group-sequential, adaptive randomized trial, pts (N∼288) receive pembro 200mg Q3W intravenously (IV) combined with MK-4280 (anti–LAG-3) 200mg Q3W IV, lenvatinib (lenv) 20mg PO QD, or MK-1308 (anti–CTLA-4) 25mg Q6W IV for 35 cycles (∼2 years); pts in the lenv arm may receive lenv monotherapy until disease progression or toxicity. After biomarker screening, pts are assigned to 1 of 4 groups—TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh—then randomized to 1 of 3 pembro-based regimens; adaptive design elements are used to adjust randomization based on objective responses. Eligible pts are ≥18 years of age with histologically or cytologically confirmed treatment-naive, advanced NSCLC; documented absence of EGFR and B-Raf mutations and ALK and ROS1 gene rearrangements; measurable disease per RECIST v1.1; and ECOG PS 0-1. Response is assessed by imaging Q9W for the first year and Q12W thereafter using RECIST v1.1. Primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Multiple interim analyses may be performed given the group-sequential design. Enrollment is ongoing. Clinical trial identificationNCT03516981: Trial initiation, October 1, 2018. Editorial acknowledgementHolly C. Cappelli, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA); funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. DisclosureM. Gutierrez: Advisory / Consultancy: Eli Lilly, Foundation One, Essanex, Guardant 360; Speaker Bureau / Expert testimony: Merck, BMS. M.D. Hellmann: Advisory / Consultancy: Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati, and Shattuck Labs; Shareholder / Stockholder / Stock options: Shattuck Labs; Research grant / Funding (institution): BMS; Travel / Accommodation / Expenses: AstraZeneca, BMS; Non-remunerated activity/ies, A patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx.: MSK. M.A. Gubens: Advisory / Consultancy: AbbVie, ARIAD, AstraZeneca, BMS, Roche/Genentech, Heron, Mersana, Novartis, Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene, Merck, Novartis; Research grant / Funding (institution): OncoMed, Roche. C. Aggarwal: Advisory / Consultancy: BMS, Celgene, Roche/Genentech, AstraZeneca. D.S.W. Tan: Honoraria (self): Novartis, Bayer, Boehringer Ingelheim, AstraZeneca, BMS, Roche, Takeda, Pfizer; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, GSK, Pfizer; Advisory / Consultancy: Novartis, Bayer, Boehringer Ingelheim. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda; Advisory / Consultancy: Blue Print Medicines, Celgene, Guardant Health. J.C. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, BMS, Ono Pharmaceuticals ; Advisory / Consultancy: Merck Serono, Celgene, Merrimack, Yuhan Pharmaceuticals, Daiichi Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals Blueprint Medicines. E.B. Garon: Research grant / Funding (self), Clinical trial funding: Merck, AstraZeneca, BMS. A. Basso: Full / Part-time employment: Merck . H. Ma: Full / Part-time employment: Merck . L. Fong: Research grant / Funding (self): Merck . A. Snyder: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck . J. Yuan: Full / Part-time employment: Merck . R.S. Herbst: Advisory / Consultancy: AbbVie, AstraZeneca, Biodesix, BMS, Eli Lilly, EMD Serano, Roche/Genentech, Heat Biologics, Junshi, Loxo Oncology Merck, Nektar, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum, Symphogen, Tesaro ; Research grant / Funding (self): AstraZeneca, Eli Lilly, Merck; Advisory / Consultancy, Scientific Advisory Boards: Neon Therapeutics, Infinity Pharmaceuticals, NextCure; Officer / Board of Directors: Junshi Pharmaceuticals. All other authors have declared no conflicts of interest.

Abstract CT158: ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer

Abstract Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib has demonstrated clinical activity in patients with ovarian cancer with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity [LOH high]). ATHENA (NCT03522246) is evaluating rucaparib + the anti-PD-1 antibody nivolumab as maintenance treatment following front-line platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for evaluating this combination includes the following: tumors with a deleterious BRCAmutation express novel, tumor-specific protein sequences (neoantigens), which can attract PD-L1-expressing, tumor-infiltrating lymphocytes; ovarian tumors with HRD have more neoantigens relative to HR-proficient tumors and may respond preferentially to immune checkpoint inhibitors; and rucaparib combined with anti-PD-1 or anti-PD-L1 demonstrated improved antitumor activity in a syngeneic ovarian cancer BrKras (BRCA1-/-; TP53-/-; MYC; KRAS-G12D; AKT) model. Furthermore, it is hypothesized that DNA damage induced by PARP inhibition may increase neoantigens regardless of HRD status. Methods: Eligible patients must have completed first-line platinum doublet chemotherapy and surgery. Patients had to have achieved an investigator-assessed response without disease progression or rising CA-125 at any time during first-line platinum doublet treatment. Cytoreductive surgery (R0 permitted) could have been completed either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking). Patients will be randomized 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg BID + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumor HRD status (BRCA mutant, non-BRCA mutant/LOH high, non-BRCA mutant/LOH low, or non-BRCA mutant/LOH indeterminate), posttreatment disease status (residual vs no residual disease), and timing of surgery (primary vs interval debulking). The primary endpoint of investigator-assessed progression-free survival (per RECIST version 1.1) will be evaluated in 3 independent comparisons between arms: A vs B, A vs D, and B vs D. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, investigator-assessed duration of response, and safety. Enrollment is ongoing; patients (n≈1000) will be enrolled at >270 sites worldwide. Citation Format: Shannon N. Westin, Rebecca S. Kristeleit, Robert L. Coleman, Keiichi Fujiwara, Amit M. Oza, David M. O’Malley, Thomas J. Herzog, Frederik Marmé, Ana Oaknin, Ramez Eskander, Domenica Lorusso, Tamar Safra, Jacob Korach, Kevin K. Lin, Danny Shih, Lisa Caunt, Sandra Goble, Stephanie Hume, Lara Maloney, Iain McNeish, Bradley J. Monk. ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer [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 CT158.

Abstract CT227: KEYNOTE-495/KeyImPaCT: Phase II biomarker-directed precision oncology study of pembrolizumab-based combination therapy for non-small cell lung cancer

Abstract Background: Immune checkpoint-based therapy has revolutionized the care of patients with NSCLC. Pembrolizumab-based combination therapy aims to improve clinical outcomes over pembrolizumab monotherapy. Identification of biomarkers associated with improved response to different combination therapies may improve overall outcomes and yield a more precise approach to the use of immunotherapies in NSCLC. To test the clinical usefulness of a biomarker-informed pembrolizumab-based combination therapy, this phase 2 KEYNOTE-495 trial (NCT03516981) will be carried out in patients with treatment-naive, advanced NSCLC. Methods: KEYNOTE-495 is a randomized, multicenter, open-label, Phase II trial. Tumor tissue from patients with treatment-naive, advanced NSCLC will be initially screened for 2 validated, independent, next-generation biomarkers: T cell-inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on the results of this biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab combined with MK-4280 (anti-LAG-3) or lenvatinib. This is a group-sequential, adaptive randomization trial. Response will be assessed by tumor imaging every 9 weeks for the first year, then every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment or before initiation of a new anticancer treatment, whichever occurs first. Treatment arms may be terminated during the interim analysis because of safety, prespecified futility criteria, or both. The primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 8 countries and will continue until ~192 patients are randomly assigned within each biomarker-defined group to determine optimal treatment for each subgroup. Citation Format: Martin Gutierrez, Matthew D. Hellmann, Matthew Gubens, Charu Aggarwal, Daniel Shao Weng Tan, Enriqueta Felip, Joanne Wing Yan Chiu, Jong-Seok Lee, James Chih-Hsin Yang, Edward Garon, Andrea D. Basso, Hua Ma, Lawrence Fong, Alex Snyder, Jianda Yuan, Roy S. Herbst. KEYNOTE-495/KeyImPaCT: Phase II biomarker-directed precision oncology study of pembrolizumab-based combination therapy for non-small cell lung cancer [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 CT227.

ZUMA-8: A phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

TPS7566 Background: Despite treatment advances, CLL is largely incurable. First-line targeted therapy with ibrutinib mostly produces durable remissions, but high-risk disease or many prior therapies increases relapse risk (Ghia P, et al. Haematologica. 2014). Relapse after ibrutinib is associated with a poor outcome (Maddocks KJ, et al. JAMA Oncol. 2015). Allogeneic stem cell transplantation potentially offers long-term remissions but has a high risk of morbidity/mortality (Shustik C, et al. Ann Hematol. 2017). Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) with a CD28 costimulatory domain may be efficacious against CLL (Kochenderfer JN, et al. Blood. 2012). KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for R/R hematologic malignancies and may offer longer durable remissions with manageable safety in pts with R/R CLL. ZUMA-8 is a Phase 1/2 multicenter study for pts with R/R CLL. Methods: Adult pts must have R/R CLL with ≥ 2 prior treatment regimens, disease progression on ibrutinib, ECOG 0-1, and adequate organ function. Phase 1 will enroll 12-18 pts to assess dose-limiting toxicities (DLTs) with a 6 + 3 dose escalation/de-escalation design; 30 more pts may be enrolled to further assess safety. Phase 2 will enroll ≈60 pts to evaluate efficacy and safety. Pts will undergo leukapheresis followed by optional bridging therapy. Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) conditioning chemotherapy will be given on Days -5, -4 and -3. KTE-X19 will be given on Day 0 at 0.5, 1 or 2 × 106 KTE-X19 cells/kg. The primary endpoint is incidence of DLTs for Phase 1 and independent review committee-assessed objective response rate (ORR) per iwCLL 2018 criteria for Phase 2. Secondary endpoints include complete remission (CR) rate, investigator-assessed ORR, minimal residual disease (MRD) negativity rate, MRD-negative CR rate, duration of response, progression-free survival, overall survival, safety, and patient-reported outcomes (Phase 2). Serum cytokine and blood KTE-X19 cell levels over time and level of anti-KTE-X19 antibodies are exploratory endpoints. Accrual is ongoing. Clinical trial information: NCT03624036.

Outcomes of patients (pts) ≥ 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL).

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.

Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase II clinical trial–Updated report on progression-free and overall survival.

9066 Background: ROS1 rearrangements are found in 1% of non-small cell lung cancer (NSCLC) patients. Early clinical trials in the US and East Asia have proven the therapeutic efficacy of crizotinib in this subset of patients. EUCROSS is the first prospective European trial to evaluate the acitivity of crizotinib in ROS1-positive lung cancer. Here we present an updated analysis of the investigator-assessed progression-free survival (PFS) and overall survival (OS). Methods: EUCROSS is a multi-centre, single arm phase 2 trial (NCT02183870). Key eligibility criteria: ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation). Treatment with crizotinib was initiated at a dose of 250 mg twice daily. Primary endpoint of the trial: investigator-assessed objective response rate (ORR) in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1). Key endpoints of this report: updated PFS and OS and updated molecular characterization of tumour tissue. Results: Thirty-four patients received treatment with crizotinib and were included in the intention-to-treat analysis. Four patients were excluded from the primary endpoint analysis due to violation of eligibility criteria (response-evaluable set, N = 30). Median follow-up period was 44.9 months. At the time of data cut-off for this report 19 patients (63%) discontinued treatment due to progression or death. Investigator ORR was 70% (95% CI, 51–85; 21/30), disease control rate was 90% (95% CI, 73.5-97.9; 27/30) and median PFS was 19.4 months (95% CI, 10.1-31.2). Median OS was not reached, but 24-months-OS probability was 66% (95% CI, 48.3-82.9). Tissue of 18 patients was available for hybrid-capture-based sequencing. Co-occurring genetic aberrations were found in 61% (11/18). TP53 mutations were most frequent (28%; 5/18). PFS (24-months probability, TP53-mut. 0% vs. TP53 wild-type (wt) 61%; p = 0.0219) and OS (24-months, TP53-mut. 40% vs. TP53 wt 83%; p = 0.015) were significantly shorter in TP53-mutant patients. Differences in OS and PFS stratified by number of prior treatment lines (0-1 vs. > = 2), brain metastases (yes vs. no) or CD74-rearrangement ( CD74- ROS1 vs. other fusion type) status were not significant. Conclusions: Updated PFS and OS results show that crizotinib is highly effective in ROS1-rearranged lung cancer. Co-occurring TP53 mutations were associated with a significantly worse outcome. Clinical trial information: NCT02183870.

Biomarker-directed precision oncology of pembrolizumab-based combination therapy for non-small cell lung cancer: Phase II KEYNOTE-495/KeyImPaCT study.

TPS9117 Background: Pembrolizumab-based combination immunotherapy aims to improve clinical outcomes over pembrolizumab monotherapy. A biomarker-based therapeutic approach may be associated with improved response to different combination therapies of immune checkpoint inhibitors and may improve overall outcomes in NSCLC. The randomized, multicenter, open-label, phase 2 KEYNOTE-495 trial ( NCT03516981 ) will evaluate the clinical usefulness of biomarker-informed, pembrolizumab-based combination therapy in patients with treatment-naive, advanced NSCLC. Methods: This is a group-sequential, adaptive randomization trial. Patients will have histologically or cytologically confirmed treatment-naive, advanced NSCLC, documented absence of EGFR and B-Raf mutations and ALK and ROS1 gene rearrangements, measurable disease per RECIST v1.1, and ECOG PS 0-1. Tumor tissue from patients will be initially screened for 2 validated, independent, next-generation biomarkers: T cell–inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on results of biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab 200 mg Q3W intravenously (IV) combined with either MK-4280 200 mg Q3W (anti–LAG-3) IV or lenvatinib 20 mg orally once daily, with the randomization assignment adaptively modified based on interim efficacy analyses. Response will be assessed by imaging every 9 weeks for the first year and every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. Treatment arms may be terminated during the interim analysis due to safety, prespecified futility criteria, or both. Primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 8 countries. Clinical trial information: NCT03516981.

Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Clinical update.

3521 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI provided robust and durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg every 2 weeks + low-dose IPI 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had any grade TRAEs leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: NIVO + low-dose IPI demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. NIVO + low-dose IPI may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

CA224-060: A randomized, open label, phase II trial of relatlimab (anti-LAG-3) and nivolumab with chemotherapy versus nivolumab with chemotherapy as first-line treatment in patients with gastric or gastroesophageal junction adenocarcinoma.

TPS4143 Background: Blockade of the immune checkpoint receptor programmed death-1 (PD-1) has shown clinical benefit in multiple tumor types. Nivolumab (anti–PD-1) has demonstrated a survival advantage versus (vs) placebo in patients (pts) with advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) (Kang YK et al. Lancet 2017;390:2461–71). Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates effector T-cell function and is a marker of T-cell exhaustion. Preliminary data in melanoma suggest that combining nivolumab with relatlimab (anti–LAG-3) could improve efficacy without substantially increasing toxicity vs nivolumab especially, but not exclusively, in LAG-3-expressing pts (Ascierto PA et al. Ann Oncol 2017;28(S5):LBA18). Furthermore, LAG-3 expression was as high as 33% in an analysis of solid tumors including GC (Edwards R et al. J Immunother Cancer 2017;5(S3):P510). Study CA224-060 will assess the clinical efficacy and safety of relatlimab and nivolumab with chemotherapy for first-line treatment of GC or GEJC. Methods: This is a randomized, open-label, multicenter, phase 2 study of relatlimab and nivolumab with oxaliplatin-based chemotherapy vs nivolumab with oxaliplatin-based chemotherapy. Approximately 250 adult pts with untreated, locally advanced, unresectable or metastatic GC or GEJC will be enrolled. To be randomized, pts must have tumor tissue for analysis of biomarkers, LAG-3 status, and PD-L1 combined positive score. Key exclusion criteria include HER2-positive status, untreated CNS metastases, or significant cardiovascular disease. The primary endpoint is objective response rate (ORR) using RECIST v.1.1 by blinded independent central review in LAG-3-expressing pts. Other endpoints include investigator-assessed ORR, ORR in LAG-3-negative pts, duration of response, overall survival, progression-free survival, and safety and tolerability. Efficacy signals in biomarker subgroups will be explored. Currently, 26 sites are activated with 15 randomized pts. Clinical trial information: NCT03662659.

Erdafitinib in high-risk patients (pts) with advanced urothelial carcinoma (UC).

4543 Background: The pan-FGFR inhibitor erdafitinib exhibited a robust objective response rate (ORR) and tolerability among pts with FGFR2/3-altered advanced UC in the BLC2001 (NCT02365597) phase 2 study (Siefker-Radtke ASCO 2018 #4503). Here we report a post hoc subgroup analysis to explore efficacy among high-risk pts. Methods: The analysis included 99 BLC2001 pts who received the optimized dose regimen of 8 mg/d continuous (pharmacodynamically guided uptitrated to 9 mg/d per serum phosphate). Results for ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were analyzed by select baseline variables, with high-risk defined as age >75 y, ECOG PS 2, hemoglobin <10 g/dL, visceral metastases, and 2 or 3 Bellmunt risk factors. Results: Efficacy results (Table) show investigator-assessed ORR >36% and median PFS >5 mo across all subgroups except ECOG PS 2. OS data are immature but generally follow the trend of PFS. With the exception of ECOG 2, there were no differences in G3/4 serious AE proportions by subgroup. Conclusions: The post hoc subgroup findings support that erdafitinib generally provides comparable efficacy in high-risk pts with FGFR-altered advanced UC as the overall population. Clinical trial information: NCT02365597. [Table: see text]

Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial

IntroductionROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS). Patients and MethodsThe trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue. ResultsThirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51–85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1–not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7–20.0 versus 24.1 months, 95% CI: 10.1–not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%). ConclusionsCrizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients.

Abstract PD1-11: nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer

Abstract Background Abemaciclib is a selective CDK4 & 6 inhibitor approved on a continuous dosing schedule for HR+, HER2- advanced breast cancer (ABC) as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET). A previous Phase 1b (NCT01394016) cohort of HR+ ABC patients (pts) demonstrated efficacy of abemaciclib monotherapy (150mg and 200mg Q12H starting dose); given the small sample size and nonrandomized design the impact of the starting dose was unclear. nextMONARCH 1 (NCT02747004) evaluated abemaciclib in 2 monotherapy arms, in a randomized setting. Abemaciclib has been associated with dose-dependent early onset diarrhea that is well managed with antidiarrheal therapy. nextMONARCH 1 also explored the 200mg Q12H abemaciclib dose in combination with prophylactic loperamide to reduce incidence/severity of diarrhea and dose adjustments. A third arm evaluated abemaciclib + tamoxifen as a strategy to overcome endocrine resistance. Methods nextMONARCH 1 is a multicenter, randomized, open-label, Phase 2 study of abemaciclib or abemaciclib + tamoxifen in women with HR+, HER2- ABC who have progressed on or after prior ET and previously received chemotherapy. Pts were stratified by presence of liver metastases and prior use of tamoxifen in the advanced setting. Randomization was 1:1:1 to abemaciclib 150mg Q12H + daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B); or abemaciclib 200mg Q12H + prophylactic loperamide (Arm C). Key eligibilities were ≥2 chemotherapy regimens (1-2 administered in metastatic setting), measurable disease and no prior treatment with CDK4 & 6 inhibitors. Primary objective was progression free survival (PFS). Key secondary objectives included objective response rate (ORR), dclinical benefit rate (CBR), and safety. PFS analysis tested superiority of Arm A to C at ∼110 events across the 2 arms assuming a hazard ratio (HR) of 0.667 to achieve ∼80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR is <1.2. Results 234 pts were randomized to Arms A (n=78), B (n=79) and C (n=77). 166 PFS events have been observed (A: 57; B: 54; C: 55). Median PFS was 9.1 months in Arm A, 6.5 in Arm B and 7.4 in Arm C (A vs C: HR=.815, 95% CI, .556-1.193, p=.293; B vs C: HR=1.045, 95% CI, .711-1.535 p=.811). Investigator-assessed ORR was 34.6%, 24.1% and 32.5% (confirmed ORR: 25.6%, 19.0%, 28.6%) and CBR was 61.5%, 49.4% and 51.9% in Arms A, B and C, respectively. Prophylactic loperamide reduced the incidence and severity of diarrhea (C: 62.3%, Gr 3: 7.8%) compared to MONARCH 1 (90.2%, Gr 3: 19.7%, Dickler et al. 2017) resulting in similar rates of diarrhea with 150mg abemaciclib without prophylaxis (A: 53.8%, Gr 3: 1.3%; B: 67.1%, Gr 3: 3.8%). The adverse event profile across arms was generally consistent with other breast studies of abemaciclib. Conclusions nextMONARCH 1 confirmed single-agent activity of abemaciclib in heavily pretreated pts with HR+, HER2- ABC. Efficacy of abemaciclib monotherapy at 150mg was similar to 200mg. Combining tamoxifen with abemaciclib did not demonstrate a statistically significant improvement in PFS compared to abemaciclib monotherapy. Addition of prophylactic loperamide to abemaciclib 200mg resulted in diarrhea similar to 150mg without prophylaxis. Citation Format: Hamilton E, Cortes J, Dieras V, Ozyilkan O, Chen S-C, Petrakova K, Manikhas A, Jerusalem G, Hegg R, Lu Y, Bear MM, Johnston EL, Martin M. nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer [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 PD1-11.

Abstract OT2-06-04: MORPHEUS: A phase Ib/II trial platform evaluating the safety and efficacy of multiple cancer immunotherapy combinations in patients with hormone receptor–positive and triple-negative breast cancer

Abstract Background: Cancer immunotherapy (CIT) has significantly improved overall survival across multiple tumor types, but only subsets of patients experience durable response with single-agent CIT. Combinations of CIT with targeted therapy or chemotherapy may be needed in order to target multiple cancer immune escape mechanisms simultaneously, thus providing personalized treatment options that extend clinical benefit to more patients. The MORPHEUS platform includes multiple phase Ib/II trials designed to identify early signals of safety and activity of CIT combinations. Using a randomized trial design, multiple CIT combination arms are compared with a single standard-of-care control arm. These trials have the flexibility to open new treatment arms with novel CIT combinations as they become available and to close arms that show minimal activity or unacceptable toxicity. Here we describe MORPHEUS trials in patients with metastatic or unresectable locally advanced hormone receptor–positive (HR+BC) or triple-negative breast cancer (TNBC), 2 patient populations in need of more treatment options. Trial design: MORPHEUS-HR+BC (NCT03280563) will enroll patients with metastatic or unresectable locally advanced HR+BC who have progressed during or after first-line treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor and whose tumors do not express human epidermal growth factor 2 (HER2). MORPHEUS-TNBC (NCT03424005) will enroll patients with metastatic or unresectable locally advanced TNBC who have progressed during or after first-line treatment with chemotherapy. For both studies, key inclusion criteria include Eastern Cooperative Oncology Group performance status of 0-1 (stage 1) or 0-2 (stage 2) and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key exclusion criteria include prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, and symptomatic, untreated, or actively progressing central nervous system metastases. Patients in both trials will be randomized to one of the CIT atezolizumab combination arms or a control arm (up to 5 arms in HR+BC and up to 6 arms in TNBC). Patients experiencing loss of clinical benefit or unacceptable toxicity in stage 1 may be eligible to switch to a different CIT atezolizumab combination arm in stage 2. Primary endpoints are safety measures and investigator-assessed objective response rate per RECIST v1.1. Progression-free survival, overall survival, duration of response, clinical benefit rate (HR+BC) or disease control rate (TNBC) are among the secondary endpoints. Exploratory biomarkers will also be examined. Citation Format: Yardley DA, Abu-Khalaf M, Boni V, Brufsky A, Emens LA, Gutierrez M, Hurvitz S, Im S-A, Loi S, McCune SL, Schmid P, O'Hear C, Zhang X, Vidal GA. MORPHEUS: A phase Ib/II trial platform evaluating the safety and efficacy of multiple cancer immunotherapy combinations in patients with hormone receptor–positive and triple-negative breast cancer [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 OT2-06-04.

Abstract PD1-03: Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial

Abstract Background: Human epidermal growth factor receptor 3 (HER3) is overexpressed in a variety of solid tumors, including breast cancer. However, there are no approved HER3-targeted anti-cancer therapies. U3-1402 is a HER3-targeted antibody drug conjugate with a novel peptide-based cleavable linker attached to a potent topoisomerase I inhibitor payload. It has a high drug-to-antibody ratio (7:1 to 8:1), a novel linker which is stable in plasma and selectively cleaved by lysosomal cathepsins up-regulated in cancer cells, and a payload with a short systemic half-life. The ongoing, phase 1/2 study (NCT02980341) was initiated to evaluate the safety, tolerability, and efficacy of U3-1402 in HER3-overexpressing metastatic breast cancer (MBC). The study has 3 parts: Dose Escalation, Dose Finding, and Dose Expansion. Here we report updated results from Dose Escalation and Dose Finding. Methods: In Dose Escalation, the dose of U3-1402 was escalated based on dose-limiting toxicity data (between 1.6 and 8.0 mg/kg) and guided by the modified Continuous Reassessment Method. In Dose Finding, patients were treated with 1 of 2 doses (4.8 mg/kg or 6.4 mg/kg) identified during Dose Escalation. In both parts, U3-1402 was administered via IV infusion in 21-day cycles. The primary objectives were to determine the safety and tolerability of U3-1402, the maximum tolerated dose (MTD), and the recommended dose for expansion. Efficacy assessments included investigator-assessed objective response rate (ORR; proportion of complete response [CR] + partial response [PR]) per RECIST v1.1 and disease control rate (DCR; proportion of CR + PR + stable disease). Efficacy-evaluable patients received ≥1 dose of U3-1402 and had pre- and post-treatment tumor assessments. Pharmacokinetics and the anti-drug antibodies were also assessed. Results: As of 1 June 2018, a total of 42 patients received U3-1402 across Dose Escalation and Dose Finding (34 and 8 patients, respectively). Overall, 12 patients have discontinued treatment (9 due to progressive disease, 1 due to clinical progression, 1 due to Grade 2 pneumonitis, and 1 due to withdrawal of consent). A total of 30 patients remain on treatment (33.3% [14/42] for ≥6 months). The median (range) age was 54.5 (30–81), and majorities of patients had an ECOG performance status of 0 (76.2%; 32/42) and had received ≥5 prior anti-cancer regimens (78.6%; 33/42). Among efficacy-evaluable patients, the ORR was 46.3% (19/41) and the DCR was 90.2% (37/41). Grade ≥3 treatment-related AEs (TEAEs) were reported in 61.9% (26/42) patients. TEAEs (>50% in treated patients) regardless of causality (any grade, Grade ≥3) included nausea (83.3%, 4.8%), thrombocytopenia (71.4%, 33.3%), decreased appetite (64.3%, 7.1%), neutropenia (59.5%, 26.2%), and leukopenia (57.1%, 19.0%). The MTD was not reached; dose limiting toxicities included events of decreased platelet count and increases in AST or ALT. Conclusions: In a preliminary analysis of this ongoing phase 1/2 clinical trial, U3-1402 demonstrated antitumor activity in a substantial number of heavily pretreated HER3-expressing MBC patients, and U3-1402 treatment was associated with a manageable safety profile. Citation Format: Masuda N, Yonemori K, Takahashi S, Kogawa T, Nakayama T, Iwase H, Takahashi M, Toyama T, Saeki T, Saji S, Inoue K, Onuma H, Tajima N, Shiose Y, Chen S, Guevara F, Yu C, Ueno S, Iwata H. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial [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 PD1-03.

A phase II, randomised study of mFOLFOX6 with or without the Akt inhibitor ipatasertib in patients with locally advanced or metastatic gastric or gastroesophageal junction cancer

BackgroundAkt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC. Patients and methodsIn this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)–low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway–activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments. ResultsIn 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7–7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2–8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81–1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway–activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively. ConclusionsIpatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed. Trial registrationClinicalTrials.gov (NCT01896531).

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Preliminary Results from the Phase 2 CheckMate 436 Trial

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Preliminary Results from the Phase 2 CheckMate 436 Trial

Pyrotinib or Lapatinib Combined with Capecitabine in Women with HER2-Positive Metastatic Breast Cancer Previously Treated with Taxanes, Anthracyclines, And/Or Trastuzumab: An Open-Label, Randomised, Phase 2 Study

Background: Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumour activity and acceptable tolerability in a phase 1 breast cancer trial. We assessed the efficacy and tolerability of pyrotinib versus lapatinib, both with capecitabine, in women with HER2-positive metastatic breast cancer. Methods: This open-label, multicentre, randomised phase 2 study was conducted at 11 hospitals in China in patients with HER2-positive relapsed or metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab, and two or fewer chemotherapy regimens. Using stratified block randomisation, patients were assigned (1:1) to receive either 400 mg pyrotinib or 1250 mg lapatinib orally once daily for 21-day cycles in combination with capecitabine (1000 mg/m2 orally twice daily on days 1-14). The primary endpoint (investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1) and safety were assessed in patients who received ≥1 dose of study treatment. Findings: Between May 29, 2015 and March 15, 2016, 128 eligible patients were randomly assigned to the pyrotinib (n=65) or lapatinib (n=63) treatment groups. The objective response rate was 78·5% (95% CI 68·5-88·5) with pyrotinib and 57·1% (95% CI 44·9-69·4) with lapatinib (treatment difference 21·3%, 95% CI 4·0-38·7; p=0·01). The most frequent grade 3-4 adverse events were hand-foot syndrome in 16 (24·6%) of 65 patients in the pyrotinib group vs 13 (20·6%) of 63 in the lapatinib group; diarrhoea (ten [15·4%] vs three [4·8%]); and decreased neutrophil count (six [9·2%] vs two [3·2%]). Interpretation: These findings support the use of pyrotinib plus capecitabine as an effective treatment option for pre-treated relapsed or metastatic breast cancer. Clinical Trial Number: This trial is registered with ClinicalTrials.gov (NCT02422199) and is closed to new participants Funding Statement: Jiangsu Hengrui Medicine Co., Ltd., CAMS Initiative for Innovative Medicine (CAMS-12M-1-010) and Grant No. 2015ZX09101007003 from National Science and Technology Major. Declaration of Interests: JZ and XZ are employed by Jiangsu Hengrui Medicine Co., Ltd. All other authors report no potential conflicts. Ethics Approval Statement: If a patient agreed to participate, she was required to provide written informed consent before enrollment. Investigations were performed in accordance with Chinese laws and regulations and the Helsinki declaration, after approval by the local ethics committee at each participating site.