Objective Response Rate In Pts Research Articles

FOLFOXIRI versus FOLFOX or FOLFIRI with targeted therapy in patients with mutant BRAF metastatic colorectal cancer: A systematic review and meta-analysis

Introduction. Based on the subgroup analysis of the TRIBE study FOLFOXIRI with bevacizumab is the recommended option for patients (pts) with mBRAF metastatic colorectal cancer (mCRC) in the 1st line. However, subgroup analysis of other studies showed conflicting results. Therefore, we performed systemic review and meta-analysis to compare efficacy FOLFOXIRI and doublets with targeted therapy in pts with mBRAF mCRC in terms of progression free survival (PFS), objective response rate (ORR) and overall survival (OS).Methods. We performed a search of all prospective randomizes studies in PubMed, ASCO and ESMO congresses for all years before May, 2020, compared FOLFOXIRI plus bevacizumab or anti-EGFR antibodies and FOLFOX or FOLFIRI with targeted agents at the 1st line with information of the BRAF status. Primary outcome was hazard ratio (HR) for PFS and 95% confidence interval (CI); secondary – HR for OS and odds ratio (OD) for ORR. Fixed effects were used for analysis. Meta-analysis was conducted by Review Manager Ver. 5.3.Results. We identified 6 trials (CHARTA, STEAM, TRIBE, TRIBE2, VISNU, METHEP2), which included 158 pts with mBRAF (FOLFOXIRI – 82 (52%) and doublets – 76 (48%). According to results of the meta-analysis there was a tendency for higher ORR in pts with FOLFOXIRI (OR 2.07, 95% CI 0.61–7.06; p = 0.24; I2 = 27%, p for heterogeneity 0.26; 3 trials). However we didn’t find any significant improvement in PFS (HR 0.89, 95% CI 0.64–1.23; p = 0.48; I2 = 0%, p for heterogeneity 0.63; 5 trials) or OS (HR 0.9, 95% CI 0.37–1.19; p = 0.048; I2 = 71%, p for heterogeneity 0.06; 2 trials) in the group of triplet.Conclusions. FOLFOXIRI with targeted therapy did not show significant improvement in the PFS and OS in pts with mBRAF compared with FOLFOX or FOLFIRI with targeted antibodies. A prospective randomized trial is needed to determine the optimal chemotherapy regimen at the 1st line for pts with mBRAF mCRC.

466P FOLFOXIRI versus FOLFOX or FOLFIRI with targeted therapy in patients with mutant BRAF metastatic colorectal cancer: A systematic review and meta-analysis

Based on the subgroup analysis of the TRIBE study FOLFOXIRI with bevacizumab is the recommended option for patients (pts) with mBRAF metastatic colorectal cancer (mCRC) in the 1st line. However, subgroup analysis of other studies showed conflicting results. Therefore, we performed systemic review and meta-analysis to compare efficacy FOLFOXIRI and doublets with targeted therapy in pts with mBRAF mCRC in terms of progression free survival (PFS), objective response rate (ORR) and overall survival (OS). We performed a search of all prospective randomizes studies in PubMed, Embase, and Cochrane library for all years before May 2020, compared FOLFOXIRI plus bevacizumab or anti-EGFR antibodies and FOLFOX or FOLFIRI with targeted agents at the 1st line with information of the BRAF status. Primary outcome was hazard ratio (HR) for PFS and 95% confidence interval (CI); secondary – HR for OS and odds ratio (OD) for ORR. Fixed effects were used for analysis. Meta-analysis was conducted by «Review Manager» Ver. 5.3. We identified 6 trials (CHARTA, STEAM, TRIBE, TRIBE2, VISNU, VOLFI), which included 163 pts with mBRAF (FOLFOXIRI – 83 (51%) and doublets – 80 (49%). According to results of the meta-analysis there was a tendency for higher ORR in pts with FOLFOXIRI (OR 2.95, 95% CI 0.97-8.95; p = 0.06; I2 = 33%, p for heterogeneity 0.21; 4 trials). However we didn’t find any significant improvement in PFS (HR 0.91, 95% CI 0.66-1.24; p = 0.54; I2 = 0%, p for heterogeneity 0.74; 6 trials) or OS (HR 0.75, 95% CI 0.39-1.46; p = 0.4; I2 = 51%, p for heterogeneity 0.15; 2 trials) in the group of triplet. FOLFOXIRI with targeted agents did not show statistical significant improvement in the PFS and OS in pts with mBRAF compared with FOLFOX or FOLFIRI with targeted antibodies. A prospective randomized trial is needed to determine the optimal chemotherapy regimen at the 1st line for pts with mBRAF mCRC.

A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01.

4000 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. Early studies have shown promising activity in advanced HER2-expressing tumors. DESTINY-CRC01 (DS8201-A-J203; NCT03384940) is a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC. Methods: Pts with centrally confirmed HER2-expressing, RAS–wild type mCRC that progressed on ≥ 2 prior regimens received T-DXd 6.4 mg/kg every 3 weeks (q3w) in 3 cohorts (A: HER2 IHC 3+ or IHC 2+/ISH+; B: IHC 2+/ISH−; C: IHC 1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A; secondary endpoints included, disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and ORR in cohorts B and C. Results: At data cutoff (Aug 9, 2019), 78 pts (A, 53; B, 7; C, 18) had received T-DXd. Median age was 58.5 y (range, 27-79 y), 52.6% of pts were male, and 89.7% had left colon or rectum cancer; median number of prior regimens was 4 (range, 2-11); all pts had prior irinotecan. Median treatment duration was 3.5 mo (95% CI, 2.1-4.3 mo; cohort A, 4.8 mo [95% CI, 3.9-5.8 mo]); 38.5% of pts remained on T-DXd treatment. The confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6%-59.6%) in cohort A, including 1 CR and 23 PRs; median DOR was not reached (95% CI, 4.2 mo-NE). The ORR in pts with prior anti-HER2 treatment was 43.8% (7/16 pts; 95% CI, 19.8%-70.1%). The DCR was 83.0% (44/53 pts; 95% CI, 70.2%-91.9%); median PFS was 6.9 mo (95% CI, 4.1 mo-NE); median OS was not reached. No responses were observed in cohorts B or C. Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 61.5% of pts (48/78); the most common (≥10%) were decreased neutrophil count (21.8%) and anemia (14.1%). Seven pts (9.0%) had TEAEs leading to drug discontinuation. Five pts (6.4%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (2 grade 2; 1 grade 3; 2 grade 5 [the only drug-related deaths]). Conclusions: Overall, T-DXd 6.4 mg/kg q3w demonstrated remarkable activity in pts with HER2-expressing mCRC refractory to standard therapies, with a safety profile consistent with previous results. ILD is an important risk and requires careful recognition and intervention. Clinical trial information: NCT03384940 .

A phase Ib study of abemaciclib in combination with pembrolizumab for patients (pts) with stage IV Kirsten rat sarcoma mutant (KRAS-mut) or squamous non-small cell lung cancer (NSCLC) (NCT02779751): Interim results.

9562 Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase 4 and 6 inhibitor. In preclinical models, abemaciclib induced intratumor immune inflammation and synergized with PD-1 blockade to enhance antitumor efficacy in anti-PD-L1 refractory disease. Here, we report the safety and antitumor activity of abemaciclib plus the approved NSCLC treatment pembrolizumab in 2 cohorts for pts with nonsquamous and squamous NSCLC. Methods: Eligible pts for this nonrandomized, open-label, multicohort, phase 1b study were either chemotherapy-naive with ≥ 1% tumor cell (TC) PD-L1 staining, KRAS-mut nonsquamous NSCLC (Cohort A) or had a squamous subtype and received ≤ 1 prior platinum-containing chemotherapy regimen (Cohort B) for metastatic NSCLC. Primary endpoint was safety; secondary objectives included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-five pts with NSCLC were enrolled in each cohort. Most pts (68%) in Cohort B had received 1 prior line of chemotherapy. Safety profiles observed in both cohorts were largely consistent with previous reports for abemaciclib and pembrolizumab monotherapy. Grades 3/4 AEs in Cohorts A and B, respectively, included ALT increase (6 pts [24%]/ 0 pts), diarrhea (3 pts [12%]/ 0 pts), neutropenia (3 pts [12%]/ 0 pts), and pneumonitis (3 pts [12%]/ 1 pt [4%]). Six pts in Cohort A (24%) and 2 pts in Cohort B (8%) had a confirmed partial response for a disease control rate (CR+PR+SD) of 52% and 64%, respectively. In Cohort A, the ORR in pts with strong (≥50% TC) PD-L1 staining (n = 13) was 31% vs. 17% in pts with weak (1-49% TC) PD-L1 expression (n = 12). Median PFS and OS were 7.6 months (95% CI: 1.6, NR) and 22.0 months (95% CI: 9.9, NR) in Cohort A and 3.3 months (95% CI: 1.4, 5.2) and 6.0 months (95% CI: 3.7, 13.1) in Cohort B, respectively. Conclusions: Abemaciclib plus pembrolizumab resulted in a numerical higher rate of transaminase elevations and pneumonitis. Antitumor activity was remarkable in the KRAS-mut nonsquamous NSCLC but not noticeably higher as compared to historical data for pembrolizumab monotherapy. Clinical trial information: NCT02779751 .

Effect of comorbidities/comedications on treatment outcomes with sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC): Subgroup analyses from the STAR-TOR registry.

631 Background: Sunitinib remains an important treatment option for mRCC, but the effect of comorbidities/comedications on sunitinib treatment outcomes have not been fully explored. Methods: Data were collated from STAR-TOR, an ongoing real-world registry. Cutoff date for analysis was 19 June 2019. This subgroup analysis assessed the presence or absence of hypertension (HTN), and the use or non-use of statins and proton pump inhibitors (PPIs), determined at the time of entry to the registry. Treatment endpoints were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). OS and PFS were analyzed by Kaplan-Meier methods. Differences within subgroups were tested using Log-rank test for OS and PFS, and Fisher’s exact test for ORR. Results: 557 sunitinib-treated pts were analyzed; 366 had HTN and 191 did not, 130 used statins and 427 did not, and 165 used PPIs and 392 did not. Median (m) OS (95% confidence intervals) was similar in pts with and without HTN (25.4 [21.1, 31.5] vs 21.5 [15.2, 28.0] months; p = 0.215). mPFS (8.0 [6.5, 9.9] vs 6.3 [5.4, 8.2] months; p = 0.140) and ORR (31.2% vs 30.9%; p = 1.000) were also similar in pts with and without HTN. mOS was similar in pts who used statins vs those who did not (27.8 [20.2, 35.4] vs 24.0 [19.4, 27.3] months; p = 0.884), while mPFS was significantly longer in pts who used statins (9.4 [6.5, 13.6] vs 6.9 [5.7, 8.2] months; p = 0.044). ORR was 37.8% vs 29.0% in pts who did and did not use statins (p = 0.072). mOS was significantly shorter in pts who used PPIs vs those who did not (20.2 [14.9, 28.3] vs 25.7 [22.7, 33.0] months; p = 0.021). mPFS (5.8 [4.6, 8.2] vs 8.0 [6.5, 9.8] months; p = 0.091) and ORR (26.6% vs 33.0%; p = 0.177) were similar in pts who did and did not use PPIs. Conclusions: In sunitinib-treated pts with mRCC in a real-world registry, mPFS was significantly longer and there was a trend toward better ORR in pts who used statins, whereas mOS was significantly shorter and there was a trend toward shorter mPFS in pts who used PPIs. Common comedications may affect sunitinib treatment outcomes in pts with mRCC.

1186PD - Safety and efficacy of the oral CXCR4 inhibitor X4P-001 + axitinib in advanced renal cell carcinoma patients: An analysis of subgroup responses by prior treatment

1186PD - Safety and efficacy of the oral CXCR4 inhibitor X4P-001 + axitinib in advanced renal cell carcinoma patients: An analysis of subgroup responses by prior treatment

LBA52 - Efficacy and safety of nivolumab in combination with docetaxel in men with metastatic castration-resistant prostate cancer in CheckMate 9KD

LBA52 - Efficacy and safety of nivolumab in combination with docetaxel in men with metastatic castration-resistant prostate cancer in CheckMate 9KD

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.

Avelumab treatment in metastatic urothelial carcinoma: Post-hoc analysis of high-risk populations in the phase Ib JAVELIN Solid Tumor Study.

428 Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, patients (pts) in various subgroups had a favorable objective response rate (ORR) with avelumab. Here, we report further post hoc analyses of safety and efficacy outcomes with avelumab in high-risk mUC subgroups. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Best overall response (per RECIST 1.1) was adjudicated by an independent review committee. ORR, disease control rate (DCR), progression-free survival (PFS), and adverse event (AE) profiles for pre-specified subgroups of high-risk pts were compared. Results: 242 pts with mUC received avelumab and were followed up for ≥2 years (data cutoff, Apr 2018). No difference was found in ORR between pts with renal insufficiency (creatine clearance [CrCl], <60 mL/min; n=107) and pts with CrCl ≥60 mL/min (n=131; 17.8% [95% CI: 11.0-26.3] vs 15.3% [95% CI: 9.6-22.6]) or between pts with upper (n=56) vs lower tract tumors (n=186; 14.3% [95% CI: 6.4-26.2] vs 17.2% [95% CI: 12.1-23.4]). ORR in pts with baseline liver metastases (n=83) was 6.0% (95% CI: 2.0-13.5) vs 22.0% (95% CI: 15.8-29.3) in pts without (n=159). ORR in elderly pts (≥75 years; n=68) was 25.0% (95% CI: 15.3-37.0) vs 13.2% (95% CI: 8.6-19.2) in younger pts (n=174). ORR in pts with albumin ≥35 g/L (n=197) was 19.8% (95% CI: 14.5-26.1) vs 2.2% (95% CI: 0.1-11.8) in pts with <35 g/L (n=45). Except for the albumin levels and age subgroups (where the trend in ORR was not confirmed), subgroups showed DCR and PFS that were consistent with ORR trends. AE profiles did not exhibit any higher risk of adverse effects in these subgroups. Conclusions: Responses to avelumab occurred in select assessed subgroups previously defined as poor prognostic or high risk, suggesting that immunotherapy may achieve comparable efficacy irrespective of factors such as site of disease and renal status; no difference in safety profiles was identified. Clinical trial information: NCT01772004.

Alterations of DNA damage response (DDR) genes correlate with favorable response and overall survival (OS) in anti-PD-1/PD-L1-treated advanced urothelial cancer (UC).

438 Background: DDR gene alterations may contribute to higher tumor mutational burden (TMB) via genomic instability in addition to APOBEC mutagenesis. We previously showed that ATM mutations correlated with shorter OS in UC, while Teo et al. showed patients (pts) with DDR alterations benefited from PD-1/PD-L1 blockade in advanced UC. Here, we aimed to validate those findings and further explore the prognostic role of ATM mutations in advanced UC treated with anti-PD-1/PD-L1 agents. Methods: The study included 53 pts who had FoundationOne tumor tissue genomic sequencing and anti-PD-1/PD-L1 therapy. Fisher exact test was used to test difference in objective response rate (ORR). OS was measured from time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: The cohort had a median age of 66 (range 21–81) with 34% females and 64.2% platinum-based chemotherapy. DDR alterations (including ATM) were present in 49.1% pts (26/53) and favored a higher ORR (37.5% vs. 23.1%, p = 0.26). Compared with those without DDR alterations, pts with DDR alterations (excluding ATM) seemed to have longer OS, although significance was not reached likely due to a short follow-up time (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations seemed to favor higher response rate to PD-1/PD-L1 blockade (ORR, 40% vs. 28.9%, p = 0.6), but was associated with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006) in overall pts and in subgroups with/without platinum-based chemotherapy (data not shown). Pts with ≥ 3 DDR alterations (including ATM) had substantial higher TMB (13.9–72.2 perMb, median 22.6) and benefited the most from PD-1/PD-L1 blockade with 80% ORR vs. 24.4% ORR in pts with < 3 DDR alterations. Conclusions: Our study supported that DDR alterations are associated with higher response rate and prolonged OS in advanced UC pts receiving anti-PD-1/PD-L1 agents, likely from impact on TMB. However, ATM alterations correlated with poor prognosis also in those pts. Further studies are needed to assess the clinical utility of DDR alterations in directing therapies in UC.

Efficacy and safety of enzalutamide (ENZA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate (Abi): A multicenter, single-arm, open-label study.

165 Background: This phase 4, multicenter, single-arm, open-label study evaluated the efficacy and safety of ENZA in patients (pts) with progressing mCRPC previously treated with Abi. Methods: All pts maintained castration therapy with luteinizing hormone-releasing hormone for the duration of the trial or had a bilateral orchiectomy. Pts were required to have progressive disease at study entry and ≥ 24 weeks of Abi treatment prior to receiving 160 mg/day ENZA. Prior chemotherapy was allowed. The primary end point was radiographic progression-free survival (rPFS). The secondary end points were overall survival (OS), prostate-specific antigen (PSA) response, and time to PSA progression. Safety was also assessed. Results: A total of215 pts were enrolled; 214 were treated with ENZA (median age, 73 years). The analysis was performed on data up to 48 weeks after the last pt started ENZA treatment. Median duration of prior Abi therapy was 54 weeks. The median duration of ENZA treatment was 5.7 months: 12 months in PSA responders and 4.6 months in non-PSA responders. 16% of pts received treatment for ≥ 1 year. The most common reason for treatment discontinuation was disease progression (65%). Median rPFS was 8.1 months (95% CI 6.1, 8.3). Median OS was not reached in the overall population and 75% of pts were alive 1 year after treatment initiation. PSA response (confirmed or unconfirmed) rate was 26.5% (48/181). The median time to PSA progression was 5.7 months (95% CI 5.6, 5.8). The overall objective response rate in pts with measurable disease at study entry was 12%. The most common treatment emergent adverse events (TEAEs) were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). ENZA was primarily discontinued due to TEAEs in 8% of pts. No seizures were reported. Conclusions: In this study, ENZA remained active in pts with mCRPC previously treated with Abi. Median rPFS in pts with prior chemotherapy was consistent with previously reported data of ENZA in pts with mCRPC and prior chemotherapy/Abi therapy.Reported TEAEs were consistent with the known safety profile of ENZA. Clinical trial information: NCT02116582.

Checkmate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (Nivo) plus ipilimumab (Ipi) versus oxaliplatin plus fluoropyrimidine in patients (Pts) with previously untreated advanced or metastatic gastric (G) or gastroesophageal junction (GEJ) cancer.

TPS213 Background: The combination ofoxaliplatin and fluoropyrimidine is a standard-of-care (SOC) first-line treatment of pts with metastatic G/GEJ cancer, resulting in a median overall survival (OS) of 8–11 months and objective response rate (ORR) of 30%–50%. This is accompanied by up to 77% grade 3/4 toxicities. Therefore, new treatment options are needed to improve survival and decrease toxicity in G/GEJ cancer. Nivo, a fully human IgG4 monoclonal antibody (mAb) that targets programmed death 1 (PD-1) and ipi, a fully human IgG1 mAb that targets cytotoxic T-lymphocyte–associated protein 4, have demonstrated manageable safety profiles and efficacy in multiple tumor types and may have a synergistic effect. In a phase 1/2 study in chemotherapy-refractory pts with G/GEJ/esophageal cancer with or without PD-1 ligand 1 (PD-L1) expression, second-line nivo 1 mg/kg + ipi 3 mg/kg demonstrated a manageable safety profile and resulted in 26% ORR (44% ORR in pts with PD-L1+ tumors), median OS of 6.9 months, and a 34% OS rate at 12 months (Janjigian Y, et al. J Clin Oncol. 2016;34[suppl][abstract 4010]). This open-label, phase 3 trial will evaluate nivo + ipi as first-line therapy for pts with G/GEJ cancer (CheckMate 649; NCT02872116). Methods: In this study, 870 pts aged ≥ 18 years with untreated advanced or metastatic G/GEJ cancer with or without PD-L1 expression will be randomized to receive nivo + ipi (4 doses; followed by nivo monotherapy) or investigator’s choice of capecitabine/oxaliplatin (XELOX) or fluorouracil/leucovorin/oxaliplatin (FOLFOX). Tumor tissue for determination of PD-L1 status must be provided from ≤ 6 months before study treatment. Pts receiving chemotherapy or radiotherapy for G/GEJ cancer within the last 6 months or pts with suspected autoimmune disease, uncontrolled medical disorder, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ tumors. Secondary endpoints include OS in all pts and progression-free survival and time to symptom deterioration in all pts and pts with PD-L1+ tumors. Clinical trial information: NCT02872116.

482TiP Global, Phase 3 study of first-line durvalumab (MEDI4736) + tremelimumab vs standard of care platinum-based chemotherapy in advanced/metastatic NSCLC: NEPTUNE

Background There is an urgent need for improved first-line therapy for advanced EGFR and ALK wild-type NSCLC, for which current molecularly targeted therapies are not indicated. Blockade of programmed cell death-1 (PD-1) and cytotoxic T- lymphocyte-associated antigen-4 (CTLA-4) immune checkpoints represents a promising anticancer therapeutic strategy. As PD-1 and CTLA-4 regulate immune responses by different mechanisms, targeting both pathways provides the potential for additive or synergistic effects. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb against CTLA-4. In a Phase 1b study (NCT02000947), durvalumab + tremelimumab demonstrated a manageable tolerability profile in advanced NSCLC, with clinical activity observed both in pts with high levels of tumour PD-L1 expression and in pts with low/no tumour PD-L1 expression. Trial design: NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study assessing durvalumab + tremelimumab vs standard of care in immunotherapy- and chemotherapy-naïvepts with advanced/metastatic EGFR and ALK wild-type NSCLC. Pts with either PD-L1 high expression or PD-L1 low/no expression (≥25% or < 25% of tumour cells with membrane staining, respectively) will be randomised (1:1) to durvalumab (20 mg/kg i.v. q4w for upto12 months) + tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or platinum-based doublet chemotherapy. Stratification factors are PD-L1 expression level, histology and smoking history. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of pts alive and progression free at 12 months by investigator assessment (RECIST v1.1); time to second progression; OS, PFS and ORR in pts with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing. Clinical trial indentification NCT02542293 Legal entity responsible for the study AstraZeneca PLC Funding AstraZeneca Disclosure T. Mok: SB/Grants/Res/Stock/Hono/rEmploy: AZ Roche/Genentech, Pfizer EL BI MSD Amgen Janssen Clovis GSK Novartis BMS PrIME SFJ Roche MSD BioMarin ACEA Vertex BMS geneDecode OncoGenex Celgene Sanomics Merck Serono MSD GSK BMS Aveo & Biodesix CUHK. P. Schmid: Research: Roche, Genentech, AZ, Astellas, Medivation, Novartis, Oncogenex. G. de Castro, Jr: Speakers Bureau: AstraZeneca, MSD, BMS Consultant: Roche, MSD. K. Syrigos: Honoraria: BMS, Novartis, Roche, BI. C. Martin: Speakers Bureau: BMS, BI N. Yamamoto: Grants/ Research Support: Chugai, BI, Ono Pharmaceutical CO Consultant: AZ, Chugai, BI, Ono Pharmaceutical CO Honoraria: AZ, Chugai, BI, MSD, Ono Pharmaceutical Co. O. Arén: Honoraria: BMS. R. Ramlau: Consultant: MSD, Roche, El Lilly, BI Honoraria: MSD, Roche, El Lilly, BI. L. Trani: Employee: AZ. All other authors have declared no conflicts of interest.

Abstract CT002: Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL)

Abstract Background: This phase II trial (CheckMate 069) demonstrated a statistically significant improvement in objective response rate (ORR) and progression-free survival (PFS) with the combination of NIVO+IPI vs. IPI alone in treatment-naïve patients (pts) with BRAF wild-type MEL (Postow et al. N Engl J Med 2015;372:2006). ORR was 61% for NIVO+IPI vs 11% for IPI alone (P&amp;lt;0.0001). Here, we report updated efficacy data and the first overall survival (OS) results from this study. Methods: Pts (N = 142) were randomized 2:1 (with stratification by BRAF mutation status) to receive either NIVO 1 mg/kg + IPI 3 mg/kg or IPI 3 mg/kg + placebo every 3 weeks x 4 doses, followed by NIVO 3 mg/kg or placebo, respectively, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed ORR in pts with BRAF wild-type tumors. Secondary endpoints included PFS in pts with BRAF wild-type tumors, ORR in pts with BRAF V600 mutation-positive tumors, and safety. OS was an exploratory endpoint. The most recent database lock occurred in August of 2015, representing a minimum follow-up of 18 months. Results: In the current analysis, median PFS in BRAF wild-type pts had not yet been reached with the NIVO+IPI combination and was 4.3 months for IPI alone (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.20-0.57; P&amp;lt;0.0001). The 12- and 18-month PFS rates were, respectively, 55.1% and 53.4% for NIVO+IPI vs. 16.2% and 8.1% for IPI alone. At 18 months of follow-up, OS rates in BRAF wild-type pts were 73% for NIVO+IPI vs. 56% for IPI alone, and median OS had not been reached in either group (HR: 0.56; 95% CI: 0.29-1.10; P = 0.089). While 26 of 46 pts (57%) randomized to the IPI group had crossed over to receive NIVO alone upon disease progression, sensitivity analyses showed similar OS results when these pts were censored. In all randomized pts, median change from baseline in target lesions was a 70% reduction for NIVO+IPI vs. a 5% increase for IPI alone. Median duration of response was not reached in either group. Grade 3-4 treatment-related adverse events were reported more frequently with NIVO+IPI (55%) than with IPI alone (22%), and led to discontinuation in 30% and 9% of pts, respectively. Treatment-related select AEs in the combination arm were consistent with the initial report and most resolved with immune-modulating medications (&amp;gt;85% across organ categories). Conclusions: In this updated analysis, NIVO+IPI continued to show improved PFS vs. IPI alone, with an apparent plateau after 12 months in the combination group. At 18 months of follow-up, there was a trend toward higher OS rates in pts who received combination therapy. Further efficacy updates, including 2-year OS rates, will be presented according to BRAF mutation status and for all randomized pts. Citation Format: Michael Postow, Jason Chesney, Anna Pavlick, Caroline Robert, Kenneth Grossmann, David McDermott, Gerald Linette, Nicolas Meyer, Jeffrey Giguere, Sanjiv Agarwala, Montaser Shaheen, Marc Ernstoff, David Minor, April Salama, Matthew Taylor, Patrick Ott, Joel Jiang, Christine Horak, Paul Gagnier, Jedd Wolchok, F. Stephen Hodi. Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL). [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 CT002.

Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): Results from the CheckMate-032 study.

6 Background: Patients (pts) with GC/GEC often present with A/M disease, which has a poor prognosis, with 1-year survival &lt; 30%, and few treatment options. Nivolumab is a fully human anti-PD-1 IgG4 monoclonal antibody with a favorable safety profile and efficacy in melanoma, non–small-cell lung cancer, and renal cell carcinoma. The phase I/II, open-label CheckMate-032 study evaluated nivolumab ± ipilimumab in pts with solid tumors. Here, we report initial results for pts with GEC/GC receiving nivolumab monotherapy. Methods: Pts with A/M histologically confirmed GC/GEC, irrespective of PD-L1 status, were assigned to receive nivolumab alone (3 mg/kg IV Q2W) and treated until disease progression (PD) or intolerable toxicity. The primary endpoint was objective response rate (ORR); other endpoints included safety, progression-free survival, overall survival (OS), and biomarker status. Results: 59 pts were enrolled and treated with single-agent nivolumab. Median age was 60 y (range 29–80), and 83% of pts received ≥ 2 prior regimens. At database lock, 10 pts were on active treatment; 49 pts discontinued (PD, n = 40; unrelated adverse events, n = 4; treatment-related adverse events [TRAEs], n = 2; other, n = 3). Pts received a median of 4 doses (range 1–25). ORR was 12% (n = 7/58; 1 complete response, 6 partial responses); 12 pts (21%) had stable disease. Among responders, median duration of response was 7.1 mo (95% CI, 3.0–13.2). Median OS was 6.8 mo (95% CI, 3.3–12.4); 12-mo OS rate was 38% (95% CI, 23.2–52.7). 39% of tumor samples were PD-L1 positive ( ≥ 1% cutoff). ORRs in pts with PD-L1-positive and -negative tumors were 18% and 12%, respectively. TRAEs occurred in 66% of pts; most were Grade 1/2. Grade 3/4 TRAEs occurred in 14% of pts and included pneumonitis, fatigue, diarrhea, vomiting, hypothyroidism, and increased aspartate and alanine aminotransferase and alkaline phosphatase levels. No treatment-related deaths occurred. Conclusions: Nivolumab monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated pts with GC/GEC. Objective responses occurred in pts with PD-L1-positive and -negative tumors. Clinical trial information: NCT01928394.

A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results

A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results

Dose-response relationship in phase I clinical trials: A European Drug Development Network (EDDN) collaboration study.

3084 Background: Alkylating agents have a strong dose effect relationship and this concept is used for development of novel cytotoxic (CTX) drugs. However, the need to reach MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study we aimed to evaluate the relationship between dose and efficacy in a large cohort of phase I patients (pts) with refractory solid tumors. Methods: We retrospectively collected data on 2232 consecutive pts treated in phase I trials in 14 European institutions in 2005 - 2007. Inclusion criteria for this analysis were: a) pts treated within single agent studies where MTD was defined; b) RECIST response available. We used logistic and Cox regression models to study the relationship of dose (as continuous variable of % of MTD) with objective response rate (ORR), disease control rate (DC) and overall survival (OS). The clinical tumor growth rate (CTGR) - a log ratio of time between advanced disease diagnosis and phase I entry to number of treatment lines- was used to identify the impact of slow growing tumors on DC. Results: 1,015 pts were eligible (MTA 72%; CTX 28%). The ORR was 3% and DC at 3 and 6 months was 25% and 11%. Median CTGR was 22 weeks. There was no difference between ORR in pts receiving MTA or CTX but the DC rate at 3 and 6 months was higher for MTA (28% and 12%) than CTX (17% and 6%; p<0.01). This difference was attributed to the higher number of pts with slow growing tumors (CTGR > 20 weeks) treated with MTA (59%) vs. CTX (48%; p=0.001). Higher doses were associated with ORR to CTX agents (median dose: responders 92% vs. non-responders 62%; OR=6.4, p=0.06) but not to MTA. There was a relationship between dose and OS for CTX agents (univariate Cox regression HR=0.63 [95%CI 0.43-0.93], p=0.02) but not for MTA (HR=1.06 [95%CI 0.87-1.27], p=0.55). However in the multivariate model adjusted for clinical and demographic variables no relationship was found between dose and OS for either MTA or CTX. Conclusions: These results support current development of novel CTX agents based on MTD. We found no direct relationship between higher doses and ORR or OS with MTA in unselected pts. There is an urgent need to identify better biomarkers to guide dose escalation trials of MTA.

Tumor biomarker analyses from the phase III ZODIAC study of docetaxel (D) plus or minus vandetanib (VAN) in second-line advanced NSCLC.

7516 Background: VAN is a once-daily oral inhibitor of VEGFR, EGFR, and RET signaling. VAN (100 mg/day) + D significantly prolonged PFS in ZODIAC, which included prospective exploratory analyses of potential relationships between clinical outcome and tumor biomarkers. Methods: Pts (n=1,391) with stage IIIB/IV NSCLC (mean age, 58 yrs; 30% female; any histology) were randomized to VAN + D or D + placebo (P). Prespecified analyses were performed on archival tumor samples (n=570) from consenting pts (n=958): EGFR protein expression by immunohistochemistry (IHC, n=362), EGFR gene copy number by fluorescent in situ hybridization (FISH, n=348), and EGFR (n=347) and KRAS (n=330) gene mutation status (wild-type [WT] or mutation [MT]) by the ARMS assay. Results: Baseline characteristics of pts with evaluable tumor samples were generally consistent with all pts. High EGFR protein expression (≥1% tumor cells stained, IHC+) was detected in 318 (88%) evaluable samples, 123 (35%) samples were FISH+ (defined as high EGFR gene polysomy or EGFR gene amplification), 50 (14%) samples had EGFR MT (exons 18–21), and 43 (13%) samples had KRAS MT (exons 12–13). Consistent trends toward improved PFS, overall survival and objective response rate for pts with EGFR FISH+ or EGFR MT tumors were seen with VAN + D vs D + P (Table). No consistent trends for differential benefits were associated with EGFR protein expression or KRAS mutation status. Conclusions: Exploratory analyses suggest that EGFR gene copy number (FISH+) and EGFR mutation status (EGFR MT) may have some predictive value in identifying pts who receive most benefit from VAN + D in second-line NSCLC. n PFS OS ORR HR, 97.58% CI HR, 97.52% CI HR, 97.5% CI All 1,391 0.79, 0.70–0.90 0.91, 0.78–1.07 1.84, 1.29–2.64 EGFR IHC+ 318 0.80, 0.61–1.04 0.77, 0.55–1.07 1.68, 0.84–3.39 IHC- 44 0.82, 0.38–1.79 1.08, 0.45–2.62 2.17, 0.30–15.85 FISH+ 123 0.61, 0.39–0.94 0.48, 0.28–0.84 3.90, 1.02–14.82 FISH- 225 1.20, 0.87–1.65 1.13, 0.78–1.64 1.20, 0.46–3.10 MT 50 0.51, 0.25–1.06 0.46, 0.14–1.57 3.34, 0.80–13.89 WT 297 0.99, 0.76–1.31 0.93, 0.67–1.28 0.98, 0.41–2.33 KRAS MT 43 1.04, 0.51–2.15 0.78, 0.35–1.75 1.81, 0.11–30.83 WT 287 0.75, 0.57–1.00 0.87, 0.61–1.22 1.88, 0.89–3.97 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca Genzyme

SWOG 0514: A phase II study of sorafenib (BAY 43–9006) as single agent in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinomas

4639 Background: There are no standard chemotherapeutic regimens for incurable biliary adenocarcinomas. Gemcitabine and fluoropyrimidine- based chemotherapy results in occasional responses and a median survival approaching 6 months. Given the presence of b- raf mutations and overexpression of VEGF in biliary cancers, we initiated a study to evaluate the efficacy of sorafenib, a multitargeted tyrosine kinase inhibitor of c and b-Raf, VEGFR-2/3 and PDGFR, in pts with metastatic biliary cancers. Methods: Pt eligibility included adequate organ function and no prior treatment for metastatic disease. The primary end-point was objective response rate (RR). Secondary endpoints were overall survival (OS) and progression free survival (PFS). A two-stage design was used to detect a difference in the null hypothesis of 5% response probability and the alternative 20% response probability. If at least one confirmed response occurred after the first 25 pts, another 25 were to be accrued. Sorafenib was administered at 400 mg PO BID continuously. A cycle was defined as 28 days of therapy, and radiological assessment was done every 2 cycles. Results: 36 pts were enrolled during the first stage of accrual. 5 pts were ineligible. 52% were female. Median age was 57.8 years (range 33.8–81.5). Adverse events: 1 pt died with grade 4 supraventricular tachycardia and venous thromboembolism. Grade 3/4 toxicities were noted in 20 pts (66.7%) and included hand-foot syndrome in 4 pts (13%), while thrombosis/embolism, elevated liver transaminases, and abdominal pain were each seen in 3 pts (10% for each). Reversible posterior leukoencephalopathy syndrome, GI perforation, and GI hemorrhage were each seen in 1 pt (3% for each). 2 pts (6%) had an unconfirmed partial response and 9 pts (29%) had stable disease. 27 pts have progressed. Median PFS was 2 months (95% CI: 2–4 months). 14 pts have died, with a median survival estimate of 6 months (95% CI: 4–10 months). Conclusions: Sorafenib did not result in a clinically significant objective RR in pts with gallbladder and cholangiocarcinoma but demonstrated an impact on survival that may be comparable to commonly used chemotherapy regimens. No significant financial relationships to disclose.