CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9134-TPS9134
Author(s):  
Joel W. Neal ◽  
Palak Kundu ◽  
Tomohiro Tanaka ◽  
Ida Enquist ◽  
Sid Patel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Phase Iii ◽  
Clinical Activity ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recist 1.1 ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Previously Treated

TPS9134 Background: Patients with mNSCLC who progress on anti–PD-L1/PD-1 therapy administered in combination with or after platinum-based chemotherapy (PBC) are mainly treated with docetaxel or pemetrexed monotherapy. These therapies only have modest clinical activity, leaving a high unmet medical need. Cabozantinib, a tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment and may enhance the efficacy of PD-L1/PD-1 inhibitors, offering a promising second/third-line therapeutic opportunity for patients with mNSCLC. In a Phase Ib multi-cohort study (COSMIC-021; NCT03170960), cabozantinib plus atezolizumab (anti–PD-L1) showed an acceptable safety profile and promising efficacy (ORR: 27%; mDOR: 5.7 mo [range: 2.6-6.9]; disease control rate [CR + PR + SD]: 83%) in 30 patients with mNSCLC who had progressed after prior anti–PD-L1/PD-1 therapy plus chemotherapy (Neal et al. J Clin Oncol 2020). The Phase III CONTACT-01 study will further evaluate the efficacy and safety of atezolizumab plus cabozantinib versus docetaxel monotherapy in patients with mNSCLC who have progressed during or after prior treatment with anti–PD-L1/PD-1 therapy and PBC. Methods: CONTACT-01 (NCT04471428) is a Phase III, multi-center, randomized, open-label study that will enroll ≈350 patients from 150 to 200 sites internationally. Key eligibility criteria include histologically or cytologically confirmed mNSCLC, disease progression with concurrent or sequential anti–PD-L1/PD-1 treatment and PBC, measurable disease (RECIST 1.1), ECOG PS of 0-1 and the availability of tissue specimens for centralized PD-L1 testing or known PD-L1 status using a health authority–approved PD-L1 assay. Patients with NSCLC previously treated with cabozantinib, docetaxel or anti–PD-L1/PD-1 + VEGFR TKIs are excluded. Patients with known sensitizing EGFR/ALK mutations and active or untreated CNS metastases are also excluded. Patients will be randomized 1:1 to receive either atezolizumab (1200 mg IV every 3 weeks) + cabozantinib (40 mg orally once daily) or docetaxel (75 mg/m2 IV every 3 weeks). The primary endpoint is OS. Secondary endpoints include investigator-assessed PFS, ORR and DOR per RECIST 1.1; TTD in patient-reported physical function and global health status (EORTC QLQ-C30); investigator-assessed PFS rates at 6 months and 1 year; OS rates at 1 and 2 years; safety and PK. Clinical trial information: NCT04471428.

Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9635-TPS9635
Author(s):  
Ivor John Percent ◽  
Craig H. Reynolds ◽  
Kartik Konduri ◽  
Matthew Thomas Whitehurst ◽  
Emmanuel A. Nidhiry ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Prior Treatment ◽  
Phase Iii ◽  
Rank Test ◽  
Clinical Activity ◽  
Open Label ◽  
Ecog Performance Status ◽  
Platinum Based Chemotherapy

TPS9635 Background: Sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and split (VEGFR2/KIT) family receptor tyrosine kinases (RTKs), as well as MET. Inhibition of TAM RTKs may promote the depletion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) and repolarize tumor associated macrophages towards the pro-inflammatory M1 phenotype. Inhibition of the split RTKs may reduce immunosuppressive regulatory T cells in addition to MDSCs within the TME. Given these pleiotropic immune-stimulating effects, sitravatinib may reverse resistance to checkpoint inhibitor therapy (CIT) and augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study (MRTX-500) demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on or after CIT. Methods: Global, randomized, open-label, Phase 3 study of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have progressed on or after CIT. Pts must have also received platinum-based chemotherapy either in combination with CIT or prior to CIT. Pts are randomized (1:1) to receive oral sitravatinib 120 mg once daily in continuous 28-day cycles combined with nivolumab IV 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m2 IV every 3 weeks. Patients are stratified based on number of prior treatment regimens in the advanced setting, ECOG performance status, and presence of brain metastases. Key eligibility criteria include duration of treatment of CIT of at least 4 months, discontinuation of prior treatment with CIT < 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is overall survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will review safety at regular intervals and efficacy at a planned interim analysis based on OS. Enrollment is ongoing. Clinical trial information: NCT03906071 .

Imatinib failure-free survival (IFS) in patients with localized gastrointestinal stromal tumors (GIST) treated with adjuvant imatinib (IM): The EORTC/AGITG/FSG/GEIS/ISG randomized controlled phase III trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10500-10500 ◽  
Author(s):  
Paolo Giovanni Casali ◽  
Axel Le Cesne ◽  
Andres Poveda Velasco ◽  
Dusan Kotasek ◽  
Piotr Rutkowski ◽  
...  
Keyword(s):  
High Risk ◽  
Kinase Inhibitor ◽  
Phase Iii ◽  
Open Label ◽  
Eligibility Criteria ◽  
Secondary Resistance ◽  
Significance Level ◽  
End Point ◽  
Consensus Classification ◽  
Advanced Gist

10500 Background: In 2004 we launched an open-label randomized trial with adjuvant IM for 2 yrs in localized, surgically resected, high/intermediate-risk GIST. Methods: Pts were randomized between 2 yrs of IM, 400 mg daily, and no further therapy after surgery. The primary end-point was OS, while RFS, RFI and toxicity were secondary end-points. Main eligibility criteria were: age >18 yrs, PS 0-2, localized CD117-positive GIST, intermediate or high risk according to the 2002 Consensus classification, R0 or R1 surgical margins, no previous medical therapy. Pts were stratified by risk, tumor site and margins. An accrual of 400 pts was planned, then escalated to 900. Given the prognostic improvement of advanced GIST pts, in 2009 the study IDMC authorized to change the primary end-point into IFS, whose failure was defined as the time when a different tyrosine kinase inhibitor (TKI) is started. We report on a planned interim analysis carried out after 115 events according to the new primary end-point, with a significance level of 1.5%. Hazard ratios (HR) and p-values were adjusted for stratification factors. Results: 908 pts were randomized between 2005 and 2008, 454 to IM and 454 to observation arm; 835 pts were eligible. 17% of pts treated with IM stopped early due to toxicity or refusal. With a median follow-up of 4.7 yrs, 5-yr IFS was 87% in the IM-arm vs 84% in the control arm (HR=0.80, 98.5% CI [0.51; 1.26], p=0.23); RFS was 84% vs 66% at 3 yrs, and 69% vs 63% at 5 yrs (p<0.001); 5-yr OS was 100% vs 99%. Among 528 pts with high-risk GIST by local pathology, 5-yr IFS was 79% vs 73% (p=0.11), and 77% vs 73% (p=0.44) amongst 336 high-risk GIST pts by centrally reviewed pathology. Conclusions: This study confirms that adjuvant IM has an overt impact on short-term freedom from relapse. In the high-risk subgroup, a non-statistically significant trend in favor of the adjuvant arm was observed in terms of IFS. This new end-point for the adjuvant setting, i.e. survival free from any failure of the first employed TKI, was designed to incorporate secondary resistance, i.e. the currently main factor adversely affecting prognosis of advanced GIST pts. Clinical trial information: NCT00103168.

A phase 3, open-label, randomized study of nivolumab plus ipilimumab or standard of care (SOC) versus SOC alone in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC; CheckMate 901).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS539-TPS539 ◽  
Author(s):  
Matt D. Galsky ◽  
Thomas Powles ◽  
Shengting Li ◽  
Delphine Hennicken ◽  
Guru Sonpavde
Keyword(s):  
Randomized Study ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Clinical Activity ◽  
Open Label ◽  
Phase 3 ◽  
Tumor Biopsy ◽  
Primary Endpoints ◽  
Platinum Based Chemotherapy ◽  
Independent Review

TPS539 Background: Cisplatin-containing regimens have been SOC for mUC for nearly 40 years, but durable responses are rare with such treatments. Furthermore, a large proportion of pts with unresectable/mUC are ineligible for cisplatin therapy. Treatment approaches conferring longer-term disease control and extending to broader mUC pt populations are urgently needed. Recently, the programmed death-1 (PD-1) inhibitor, nivolumab, induced durable responses in pts with unresectable/mUC progressing despite platinum-based chemotherapy, and nivolumab combined with ipilimumab (a CTLA-4 inhibitor) demonstrated acceptable safety and clinical activity. This phase 3 study will evaluate nivolumab + ipilimumab and nivolumab + SOC vs SOC in previously untreated pts with unresectable/mUC (NCT03036098). Methods: Key inclusion criteria: cisplatin-eligible and -ineligible pts with measurable disease, no prior systemic chemotherapy for unresectable/mUC, and evaluable tumor biopsy. Key exclusion criteria: active brain metastases, autoimmune disease, and prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways. Cisplatin-eligible and -ineligible pts will be randomized 1:1 to arm A (nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks up to 4 doses, followed by nivolumab 480 mg every 4 weeks until disease progression or unacceptable toxicity) or arm B (gemcitabine-cisplatin or gemcitabine-carboplatin for up to 6 cycles). Additional cisplatin-eligible pts will be randomized to arm C (nivolumab 360 mg + gemcitabine-cisplatin every 3 weeks for up to 6 cycles, followed by nivolumab 480 mg) or arm D (gemcitabine-cisplatin for up to 6 cycles). Stratification factors: PD-1 ligand 1 status, cisplatin eligibility, and liver metastasis. Co-primary endpoints: overall and progression-free survival (OS and PFS) by blinded independent review committee (BIRC) in cisplatin-ineligible pts receiving nivolumab + ipilimumab vs SOC, and PFS by BIRC in cisplatin-eligible pts receiving nivolumab + SOC vs SOC. Enrollment began March 2017 with a target of 897 pts. Clinical trial information: NCT03036098.

Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1002-1002 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Sara A. Hurvitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Phase Iii ◽  
Open Label ◽  
Cns Disease ◽  
Patient Reported

1002 Background: NALA (ClinicalTrials.gov NCT01808573) is a multinational, randomized, open-label, phase III trial of neratinib (an irreversible pan-HER tyrosine kinase inhibitor [TKI]) + capecitabine (N+C) vs lapatinib (a reversible dual TKI) + capecitabine (L+C) in patients with stage IV HER2+ metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens for MBC. Methods: Patients were randomized 1:1 to N (240 mg qd po) + C (750 mg/m2 bid po) or L (1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints were investigator-assessed PFS; objective response rate (ORR); duration of response (DoR); clinical benefit rate (CBR); time to intervention for symptomatic metastatic central nervous system (CNS) disease; safety; and patient-reported health outcomes. Results: 621 patients were randomized (307 to N+C; 314 to L+C). The risk of disease progression or death was reduced by 24% with N+C vs L+C (HR = 0.76; 95% CI 0.63–0.93; p = 0.006); 6- and 12-month PFS rates were 47.2% vs 37.8% and 28.8% vs 14.8% for N+C vs L+C, respectively. OS rates at 6 and 12 months were 90.2% vs 87.5% and 72.5% vs 66.7% for N+C vs L+C, respectively (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086). ORR in patients with measurable disease at screening was improved with N+C vs L+C (32.8% vs 26.7%; p = 0.1201), as was CBR (44.5% vs 35.6%; p = 0.0328) and DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004). Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; p = 0.043) was delayed with N+C vs L+C. Treatment-emergent adverse events (TEAEs) were similar between arms, but there was a higher rate of grade 3 diarrhea with N+C vs L+C (24.4% vs 12.5%). TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). Conclusions: N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease. Tolerability was similar between the two arms, with no new safety signals observed. Clinical trial information: NCT01808573.

SAVOIR: A phase III study of savolitinib versus sunitinib in pts with MET-driven papillary renal cell carcinoma (PRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5002-5002
Author(s):  
Toni K. Choueiri ◽  
Daniel Yick Chin Heng ◽  
Jae-Lyun Lee ◽  
Mathilde Cancel ◽  
Remy B Verheijen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Chromosome 7 ◽  
Phase Iii ◽  
Open Label ◽  
Grade 3 ◽  
Dose Modifications

5002 Background: PRCC is the most common type of non-clear cell RCC, accounting for 10–15% of renal malignancies. As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach. In a single-arm Phase II study, savolitinib (AZD6094, HMPL‐504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in pts with MET-driven PRCC (Choueiri et al. JCO 2017). The Phase III SAVOIR study (NCT03091192) further assessed savolitinib vs standard of care sunitinib in pts with MET-driven PRCC. Methods: In this open-label (sponsor blinded), randomized study, pts with centrally confirmed MET-driven ( MET and/or HGF amplification, chromosome 7 gain and/or MET kinase domain mutations), metastatic PRCC were randomized to savolitinib 600 mg once daily (QD), or sunitinib 50 mg QD 4 weeks on / 2 weeks off. Primary objective was progression-free survival (PFS; RECIST 1.1 by blinded independent central review). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety and tolerability. Results: After external data on predicted PFS with sunitinib in pts with MET-driven disease became available, study enrollment was closed. At data cutoff (Aug 2019), only 60 of the planned 180 pts were randomized (savolitinib n = 33; sunitinib n = 27). Most had chromosome 7 gain (savolitinib 91%; sunitinib 96%) and no prior therapy (savolitinib 85%; sunitinib 93%). PFS, OS, and ORR were numerically improved with savolitinib vs sunitinib (Table). CTCAE grade ≥3 adverse events (AEs) were reported in 42% and 81% of pts; dose modifications were related to AEs in 30% and 74% of pts with savolitinib and sunitinib respectively. After discontinuation, 36% of all savolitinib and 19% of all sunitinib pts received subsequent anticancer therapy. Conclusions: Although pt numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade ≥3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Clinical trial information: NCT03091192 . [Table: see text]

AcceleRET Lung: A phase III study of first-line pralsetinib in patients (pts) with RET-fusion+ advanced/metastatic non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9633-TPS9633 ◽  
Author(s):  
Benjamin Besse ◽  
Enriqueta Felip ◽  
Corinne Clifford ◽  
Melinda Louie-Gao ◽  
Jennifer Green ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Survival Duration ◽  
First Line ◽  
Open Label ◽  
Eligibility Criteria ◽  
Multiple Tumor ◽  
Platinum Based Chemotherapy

TPS9633 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1-2% of NSCLC, but no selective RET inhibitors are approved for use. The investigational RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multikinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), pts with RET-fusion+ NSCLC treated with 400 mg once daily (QD) of pralsetinib (N = 80) after platinum-based chemotherapy achieved an overall response rate (ORR) of 61% (95% CI 50, 72; 2 responses pending confirmation) per independent central review. In addition, a promising ORR of 73% (all centrally confirmed responses) was attained in the treatment naïve cohort (N = 26). Most treatment-related adverse events were grade 1-2 across the entire safety population treated at 400 mg QD (N = 354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). Methods: Approximately 250 pts with metastatic RET-fusion+ NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and ECOG PS. Key eligibility criteria include no prior systemic treatment for metastatic disease; RET-fusion+ tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per RECIST v1.1. Pts randomized to SOC will be permitted to cross-over to receive pralsetinib upon disease progression. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Recruitment has begun with sites (active or planned) in North America, Europe and Asia. Clinical trial information: NCT04222972 .

Phase III study of first-line pembrolizumab (pembro) plus lenvatinib (len) in patients (pts) with advanced urothelial carcinoma (UC) ineligible for platinum-based chemotherapy: LEAP-011.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS597-TPS597
Author(s):  
Yohann Loriot ◽  
Arjun Vasant Balar ◽  
Ronald De Wit ◽  
Jorge A. Garcia ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Previous Treatment ◽  
Phase Iii ◽  
End Points ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Ecog Ps ◽  
To Receive

TPS597 Background: KEYNOTE-052 (NCT02335424) results led to pembro, a PD-1 inhibitor, to become the standard of care for cisplatin-ineligible pts with locally advanced or metastatic UC with tumors expressing PD-L1 and for pts unable to receive platinum-based chemotherapy regardless of PD-L1 status. Len, a potent, multiple-receptor, tyrosine kinase inhibitor has activity in multiple solid tumors. KEYNOTE-146 (NCT02501096) results showed promising efficacy and manageable safety with pembro+len in previously treated pts with advanced UC, regardless of PD-L1 status. Methods: LEAP-011 (NCT03898180) is a randomized phase 3 study to assess efficacy and safety of pembro+len, compared with pembro+placebo, in pts with advanced UC. An estimated 694 pts will be enrolled. Adults (≥18 years) with histologically confirmed locally advanced unresectable or metastatic UC who are either cisplatin-ineligible with tumors expressing PD-L1 (combined positive score [CPS] ≥10) or ineligible to receive any platinum-based chemotherapy are eligible. Pts are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 analysis. Previous treatment with systemic chemotherapy for advanced UC is not permitted, except in cases of recurrence after 1 year of platinum-based chemotherapy for either muscle-invasive bladder cancer (neoadjuvant) or after radical cystectomy (adjuvant). Pts will be randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 cycles (~2 y) plus either len 20 mg or placebo orally once daily. Pts will be stratified as follows: ineligible for any platinum containing chemotherapy and ECOG PS 2 (CPS ≥10 vs <10); cisplatin ineligibility and CPS ≥10 (ECOG 0-1 vs 2). Radiologic assessment will include CT/MRI of the chest, abdomen, and pelvis, and bone imaging. Responses will be assessed per RECIST v1.1 by blinded independent central review (BICR). Coprimary end points are PFS and OS. Secondary end points are objective response rate, duration of response, and disease control rate per RECIST v1.1 by BICR; patient-reported outcomes; and safety. Tissue-and blood-based biomarkers will be explored. Accrual began May 6, 2019. Clinical trial information: NCT03898180.

Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7509-7509 ◽  
Author(s):  
Julie R. Brahmer ◽  
Leora Horn ◽  
Scott Antonia ◽  
David R. Spigel ◽  
Leena Gandhi ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Response Duration ◽  
Tumor Burden ◽  
Clinical Activity ◽  
Ecog Performance Status ◽  
Activated T Cells ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

7509 Background: BMS-936558 is a fully human mAb that blocks the programmed death-1 (PD-1) co-inhibitory receptor expressed by activated T cells. We report here that BMS-936558 mediates antitumor activity in heavily pretreated patients (pts) with advanced NSCLC, a tumor historically not considered to be responsive to immunotherapy. Methods: BMS-936558 was administered IV Q2WK to pts with various solid tumors, including NSCLC, at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. Pts with advanced NSCLC previously treated with at least 1 prior chemotherapy regimen were eligible. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 75 NSCLC pts were treated at 1 (n=17), 3 (n= 19), or 10 mg/kg (n=39). ECOG performance status was 0/1/2 in 24/49/2 pts. Tumor histology was squamous (n=17), non-squamous (n=52), or unknown (n=6). The number of prior therapies was 1 (n=9), 2 (n=20), ≥3 (n=45), or unknown (n=1). Ninety-five percent of pts had received platinum-based chemotherapy and 40% had a prior tyrosine kinase inhibitor. Sites of metastatic disease included lymph node (n=50), liver (n=12), lung (n=62), and bone (n=13). Median duration of therapy was 10 wk (max 100 wk). Common related AEs were fatigue (17%), nausea (11%), pyrexia (7%), pruritus (7%), dizziness (7%), and anemia (7%). The incidence of grade 3-4 related AEs was 8%. There was 1 drug-related death due to pulmonary toxicity. Clinical activity was observed at all dose levels (Table) and in multiple histologies. Several pts had prolonged SD. Some had a persistent decrease in overall tumor burden in the presence of new lesions and were not categorized as responders. At the time of data lock, of 10 OR pts, 3 had responses lasting ≥6 mo and 5 were on study with response duration of 1.8-5.5 mo. Conclusions: BMS-936558 is well tolerated and has encouraging clinical activity in pts with previously treated advanced NSCLC. Further development of BMS-936558 in pts with advanced NSCLC is warranted. [Table: see text]

Phase II study of sitravatinib in combination with nivolumab in patients with advanced or metastatic urothelial carcinoma (UC) after checkpoint inhibitor therapy (CIT).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS498-TPS498
Author(s):  
Gurjyot K. Doshi ◽  
Nicholas J. Vogelzang ◽  
Donald A. Richards ◽  
Daniel Chong ◽  
David R. Shaffer ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Primary Objective ◽  
Rational Approach ◽  
Clinical Activity ◽  
Phase 2 ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Phase 2 Study

TPS498 Background: Combination therapy with agents targeting molecular and cellular mechanisms of CIT resistance is a rational approach to restoring CIT efficacy in patients (pts) with immunotherapy-resistant UC. Sitravatinib is a tyrosine kinase inhibitor (TKI) that targets multiple closely-related receptor tyrosine kinase (RTK) pathways, including the split RTKs VEGFR-2 and KIT, as well as the TAM (TYRO3, AXL, and MER) RTKs. Inhibition of the split RTKs enhances antitumor activity by reduction of immunosuppressive regulatory T cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME). Inhibition of TAM RTKs further restores a more immune-supportive TME by depletion of MDSCs and repolarization of tumor-associated macrophages to the M1 phenotype associated with secretion of pro-inflammatory cytokines. Given these pleiotropic immune-activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing CIT clinical activity in pts with immunotherapy-resistant UC. This combination has been shown to be safe and tolerable in an ongoing Phase 2 study in pts with metastatic non-small cell lung cancer. Methods: This open-label Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with advanced or metastatic UC who experienced disease progression on or after CIT as the most recent systemic therapy. Enrollment is stratified by prior receipt of platinum-based chemotherapy. If the initial 2 cohorts are of high interest for efficacy, the protocol allows for addition of new cohorts to include pts previously treated with selected immunotherapies (anti-CTLA-4, anti-OX40 or anti–CD137 therapy) or who are CIT-naïve. The primary objective is Objective Response Rate. A Predictive Probability Design will be applied allowing for expansion to 40 pts per cohort. Sitravatinib is administered orally daily in continuous 28-day cycles at 120 mg; nivolumab intravenously at 240 mg every 2 weeks or 480 mg every 4 weeks. Status: The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03606174.

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