Phase (Ph) 1b/2 evaluation of olaratumab in combination with gemcitabine and docetaxel in advanced soft tissue sarcoma (STS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11517-11517
Author(s):  
Steven Attia ◽  
Victor Manuel Villalobos ◽  
Nadia Hindi ◽  
Brian Andrew Van Tine ◽  
Andrew J. Wagner ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Parameter Estimates ◽  
Second Line ◽  
Line Therapy ◽  
Significant Difference ◽  
Ecog Ps

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m2, d1 and d8) and D (75 mg/m2, d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer

Chemotherapy ◽  
2016 ◽  
Vol 62 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Ying Wang ◽  
Jieqiong Liu ◽  
Weijuan Jia ◽  
Shunrong Li ◽  
Nanyan Rao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Objective Response ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Second Line ◽  
First Line ◽  
Line Therapy ◽  
Significant Difference ◽  
Early Use

Background: The aim of this study was to evaluate the efficacy of vinorelbine-based regimens as first-, second- and more-line therapies in advanced breast cancer (ABC) and to analyze the best timing of vinorelbine treatment. Methods: A total of 71 ABC patients were retrospectively reviewed. Of these, 35 patients were treated with vinorelbine-based regimens as first-line chemotherapy, and 36 patients were treated with vinorelbine-based regimens as second-line or more-line therapy. The primary end point of the study was progression-free survival (PFS). Results: No difference was found in baseline characteristics between the two groups (p > 0.1 for all comparisons). There was a significant difference in the objective response rate (ORR; p = 0.006) and clinical benefit rate (CBR; p = 0.013) between the first-line group and the second- or more-line groups. In the vinorelbine first-line group, the ORR was 68.6% (24 patients), and in the second-line or more-line groups the ORR was 36.1% (13 patients). A significant difference in PFS between the first-line group and the second-line or more-line groups was also observed (p = 0.030). The median PFS in the overall population was 6.3 ± 1.32 months (95% CI 3.69-8.90). The median PFS was 11.1 ± 3.76 months (95% CI 3.73-18.47) in the first-line group compared with 5.2 ± 1.35 months (95% CI 2.54-7.85) in the second-line or more-line groups. In patients treated with vinorelbine-trastuzumab combination as the first-line therapy, a complete response was observed in 1 patient (12.5%) and partial response in 5 patients (62.5%), giving an ORR of 75.0%. Progressive disease was observed in 1 patient (12.5%), and stable disease in 1 patient (12.5%), leading to a CBR of 87.5%. The median PFS was 13.8 ± 2.75 months (95% CI 8.42-19.18), and median OS was 37.0 ± 11.6 months (95% CI 14.18-59.82). No significant difference was found in overall survival (OS) between the groups (p = 0.612). Conclusion: For ABC patients, no significant difference in median OS was found between the early use and delayed use of vinorelbine-based regimens, but the short-term efficacy and PFS of vinorelbine-based regimens were significantly better in the early use group than in the delayed use group.

Results of the JAVELIN Gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2− advanced gastric or gastroesophageal junction cancer (GC/GEJC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 278-278 ◽  
Author(s):  
Markus H. Moehler ◽  
Mikhail Dvorkin ◽  
Mustafa Ozguroglu ◽  
Min-hee Ryu ◽  
Alina Simona Muntean ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Clinical Activity ◽  
Primary Analysis ◽  
Open Label ◽  
Phase 3 ◽  
Post Induction

278 Background: We report the primary analysis of JAVELIN Gastric 100, which compared avelumab (anti–PD-L1) maintenance after 1L CTx vs continued CTx in patients (pts) with GC/GEJC. Methods: In this global, open-label, phase 3 trial (NCT02625610), eligible pts had previously untreated, unresectable, locally advanced/metastatic (LA/M) HER2− GC/GEJC. Pts without progressive disease (PD) after 12 weeks of 1L oxaliplatin/fluoropyrimidine induction were randomized 1:1 to avelumab 10 mg/kg Q2W switch maintenance or continued CTx, stratified by region (Asia vs non-Asia). Primary endpoint was overall survival (OS) post induction in all randomized or PD-L1+ (≥1% of tumor cells, 73-10 assay) pts. Results: 805 pts received induction CTx and 499 pts were randomized (avelumab, n = 249; CTx, n = 250). At data cutoff (Sep 13, 2019), minimum follow-up was 18 months. In the avelumab and CTx arms, median OS post induction/randomization was 10.4 months (95% CI 9.1-12.0) vs 10.9 months (95% CI 9.6-12.4), hazard ratio (HR) 0.91 (95% CI 0.74-1.11; p = 0.1779); 24-month OS rates were 22.1% (95% CI 16.8-28.0) vs 15.5% (95% CI 10.8-20.9), respectively. The HR for OS in PD-L1+ pts (n = 54) was 1.13 (95% CI 0.57-2.23). No OS trend was seen in Asian pts (n = 114; HR 0.90 [95% CI 0.59-1.36]) or other subgroups, except for a potential benefit with avelumab in pts with no metastatic sites at randomization (n = 60; HR 0.52 [95% CI 0.28-0.98]). Progression-free survival was similar between arms (HR 1.04 [95% CI 0.85-1.28]). In the avelumab vs CTx arms, objective response rates (post randomization only) were 13.3% (95% CI 9.3-18.1) vs 14.4% (95% CI 10.3-19.4), and 12-month rates for duration of response were 62.3% (95% CI 40.9-77.9) vs 28.4% (95% CI 13.2-45.7), respectively. Treatment-related adverse event rates (all grades/grade ≥3) were 61.3%/12.8% with avelumab and 77.3%/32.8% with CTx. Conclusions: Avelumab maintenance showed clinical activity and favorable safety vs continued CTx in pts with LA/M GE/GEJC; however, JAVELIN Gastric 100 did not meet its primary objective of demonstrating superior OS in the randomized or PD-L1+ population. Clinical trial information: NCT02625610.

An overview of SELECTTION: Survey of European lung cancer evaluating choice of treatment and tolerability in observed second-line non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18204-18204
Author(s):  
E. F. Smit ◽  
A. Vergnenegre ◽  
J. Arellano ◽  
K. Kraaij ◽  
A. Kral ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Options ◽  
Locally Advanced ◽  
Real Life ◽  
Primary Objective ◽  
Treatment Discontinuation ◽  
Line Treatment ◽  
Second Line ◽  
Significant Difference ◽  
Choice Of Treatment

18204 Background: In addition to established second-line treatments for NSCLC in Europe, docetaxel and pemetrexed; erlotinib, has recently been approved. The only study directly comparing alternative options in second-line NSCLC showed no significant difference in efficacy between docetaxel and pemetrexed (median survival 7.9 vs 8.3 months, p = 0.226) but significant differences in toxicity profile (Hanna et al, 2004). It is of interest to observe how different second-line treatment options are used in real life settings, particularly length of therapy, reasons for discontinuation and its impact on patient’s outcomes. Methods: In observational studies patients are not assigned to different treatments at random and physicians and patients decide on treatment. A careful design is paramount to ensure the correct interpretation of data obtained. SELECTTION is the first observational, non-interventional, prospective study to be carried out in Europe in second-line NSCLC treatment. The primary objective of SELECTTION is to assess the time from treatment initiation to treatment discontinuation. Secondary objectives are to observe the reasons for treatment discontinuation and assess its impact on patient’s outcomes. A total of 13 countries will participate including: France, Portugal, Germany, Denmark, and UK with approximately 200 sites enrolling 950 patients. Information regarding patients and disease characteristics and treatment history are collected. Patients may be enrolled if they have received first-line chemotherapy for locally advanced or metastatic NSCLC, and have subsequently progressed, are at least 18 years old and are about to initiate second line treatment. Treatment cohorts will be constructed based on the distribution of patients across second-line treatments by physician decision. Results: At this stage details about design and analyses planned as well as evolution of the study, will be presented. Conclusions: SELECTTION will provide a unique set of data on how patients with stage IIIb\/IV NSCLC previously treated with chemotherapy, are treated in routine clinical practice. No significant financial relationships to disclose.

Axitinib versus sorafenib as second‑line therapy in Asian patients with metastatic renal cell carcinoma (mRCC): Results from a registrational study.

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA4537-LBA4537
Author(s):  
Shukui Qin ◽  
Feng Bi ◽  
Ying Cheng ◽  
Jun Guo ◽  
Xiu Bao Ren ◽  
...  
Keyword(s):  
Objective Response ◽  
Phase Iii ◽  
Second Line ◽  
Second Line Therapy ◽  
Phase Iii Trial ◽  
Asian Patients ◽  
Line Therapy ◽  
Independent Review ◽  
Previously Treated ◽  
Ecog Ps

LBA4537 Notice of Retraction: "Axitinib versus sorafenib as second-line therapy in Asian patients with metastatic renal cell carcinoma (mRCC): Results from a registrational study." Abstract LBA4537, published in the 2012 Annual Meeting Proceedings Part II, a supplement to the Journal of Clinical Oncology, has been retracted by Shukui Qin, MD, on behalf of all authors of the abstract. The adjudication portion of the Independent Review Committee (IRC) tumor assessments were incomplete for some of the ongoing patients in the study reported in the abstract and the adjudication could not be completed in time for presentation at the 2012 ASCO Annual Meeting. Background: An earlier phase III trial in 723 patients with previously treated mRCC demonstrated significantly longer progression-free survival (PFS) for axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, compared with sorafenib. We conducted a multicenter, randomized, open-label trial to estimate PFS for axitinib and sorafenib in 204 Asian patients with previously treated mRCC. Methods: Patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 and measurable, clear-cell, mRCC that had progressed after 1 prior first-line systemic regimen (sunitinib or cytokines) were randomly assigned (2:1) to 28-day cycles of axitinib 5 mg twice daily (BID) or sorafenib 400 mg BID. Axitinib dose reductions and stepwise dose titrations to 7 mg BID and then 10 mg BID, as tolerated, were allowed; sorafenib dose reductions to 400 mg daily or every other day were also allowed. Primary endpoint was PFS per independent review committee. Results: Patients were stratified by ECOG PS and prior first-line systemic therapy: 135 received axitinib and 69 received sorafenib.Baseline patient characteristics included median age 56 years, 70% male, 99% Asian, and 63% ECOG PS 0. Prior therapy included sunitinib (45%) or cytokines (53%). Median PFS was 6.4 months (95% confidence interval: 4.6, 8.3) with axitinib and 4.8 months (2.8, 6.5) with sorafenib. Objective response rates were 23.7% with axitinib and 10.1% with sorafenib. All-grade adverse events in ≥15% of patients (axitinib, sorafenib) included hypertension (50%, 36%), weight decreased (37%, 33%), diarrhea (34%, 30%), hand-foot syndrome (32%, 57%), decreased appetite (30%, 20%), hypothyroidism (28%, 23%), fatigue (27%, 23%), proteinuria (21%, 20%), dysphonia (19%, 9%), cough (16%, 16%), rash (15%, 28%), pyrexia (7%, 16%), alopecia (3%, 22%). Conclusions: Asian patients receiving axitinib as second-line therapy for mRCC had a similar PFS and objective response rate as in a previous global phase III trial, with an acceptable safety profile.

Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5013-5013 ◽  
Author(s):  
Sumanta K. Pal ◽  
Neeraj Agarwal ◽  
Yohann Loriot ◽  
Cristina Suarez Rodriguez ◽  
Parminder Singh ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Mucosal Inflammation ◽  
Clinical Activity ◽  
Mri Scans ◽  
Metastatic Sites ◽  
Ecog Ps

5013 Background: Cabozantinib (C), an inhibitor of MET, AXL, and VEGFR, has been shown to promote an immune-permissive environment and has shown promising clinical activity in combination with immune checkpoint inhibitors (ICIs) in solid tumors including renal cell carcinoma and urothelial carcinoma (UC). ICI monotherapy is approved for patients (pts) with locally advanced or metastatic UC with disease progression after platinum-containing chemotherapy. COSMIC-021, a multi-center phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from Cohort 2 in UC pts with prior platinum-containing chemotherapy. Methods: Eligible pts had ECOG PS 0-1 and had progressed on or after a platinum-containing chemotherapy (including pts with disease recurrences < 12 months after the end of perioperative chemotherapy). Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints include safety, duration of response (DOR), PFS, and OS. Results: As of Dec 20, 2019, 30 pts with advanced UC were enrolled with a median follow-up of 16.5 mo (range 12, 21). Median age was 66 yrs (range 44, 84), 73% were male, and 60% had ECOG PS 1. Primary tumor sites were bladder (80%), renal pelvis (10%), and ureter (10%); the most frequent metastatic sites included lung (40%) and liver (27%). Fourteen pts (47%) had received ≥2 prior systemic anticancer therapies. The most common treatment-related AEs (TRAEs) of any grade were asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%). Grade 3/4 TRAEs occurred in 57% of pts, with no grade 5 TRAEs. Confirmed ORR per RECIST v1.1 was 27% (8 of 30 pts), including 2 pts with CR. DCR (CR+PR+SD) was 64%. Median DOR was not reached, with the longest DOR ongoing at 14.3+ mos. Median PFS was 5.4 mo (range 0.0+, 17.3+). Conclusions: C in combination with A demonstrated encouraging clinical activity in pts with advanced UC with an acceptable safety profile. Additional cohorts of pts with advanced UC are being explored in the study. Clinical trial information: NCT03170960 .

Ifosfamide, carboplatin, and etoposide (ICE) in combination with regional hyperthermia (RHT) in chemotherapy-pretreated nonresponders with locally advanced high-risk soft tissue sarcoma (HR-STS)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10581-10581
Author(s):  
C. Nickenig ◽  
V. Buecklein ◽  
L. H. Lindner ◽  
S. Abdel-Rahman ◽  
M. Kuhlencordt ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Hematological Toxicity ◽  
Second Line ◽  
First Line ◽  
Regional Hyperthermia ◽  
First Line Therapy ◽  
Line Therapy ◽  
Secondary Endpoints ◽  
Free Rate

10581 Background: Regional hyperthermia (RHT) improves outcome in combination with neoadjuvant chemotherapy as first-line therapy in locally advanced HR-STS (Issels et al., Abstract 10009, ASCO 2007). Efficacy of ICE combined with RHT as second-line treatment strategy in pts with locally advanced HR-STS pretreated with anthracycline-based chemotherapy ± RHT was evaluated. Methods: Between 9/97 and 6/08, 49 pts were treated with ICE + RHT (median age: 51 years, range: 21–74 years), with high-grade (G2 24 pts; G3 25 pts) STS histology (20 Lipo-Sa; 6 Leiomyo-Sa, 6 MPNST, 5 NOS, 2 DSRCT, 10 others). As first-line therapy 35 pts had received chemotherapy combined with RHT and 14 pts without RHT. Second-line ICE consisted of 1.5 g/m2 ifosfamide, 100 mg/m2 carboplatin, and 150 mg/m2 etoposide on days 1–4 combined with RHT on two days and was repeated on day 28 (4–6 cycles). Besides toxicity, primary and secondary endpoints were objective response (OR) (RECIST), progression free rate (PFR) at 3 and 6 months, and overall survival (OS). Results: Pts received a median of 4 ICE cycles (range 1–8) in combination with RHT. Hematological toxicity grade III (11 pts)/ IV (23 pts) occurred in 34 pts (69 %), 3 pts (6 %) suffered from therapy-related deaths due to infection during cytopenia (2 pts) or postsurgery-related complications (1 pt). In 35 of 49 pts evaluable for OR, 26% achieved objective remission (1 CR + 8 PR), 51% showed stable disease (18 SD) and 23% progressive disease (8 PD). OR rates after initial chemotherapy with or without RHT were 17 % (4 PR of 24 pts) and 45% (1 CR + 4 PR of 11 pts), respectively (p=0.13). Irrespective of pretreatment, for all pts the PFR after 3 and 6 months was 87% (CI95=96%-77%) and 76% (CI95=88%-63%) and median OS was 22 months (CI95=29–16 months). Conclusions: Second-line ICE combined with RHT is feasible and effective in pts with locally advanced HR-STS non-responding to first-line anthracycline-based chemotherapy with or without RHT. (Supported by Deutsche Krebshilfe and HelmholtzZentrum münchen - German Research Center for Environmental Health) No significant financial relationships to disclose.

Systemic therapy for advanced clear cell renal cell carcinoma (ccRCC) after progression on immune-oncology plus VEGF targeted therapy combinations (IO-VEGF).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4576-4576
Author(s):  
Yasser Ged ◽  
Ruby Gupta ◽  
Cihan Duzgol ◽  
Natalie Shapnik ◽  
Almedina Redzematovic ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Systemic Therapy ◽  
Objective Response ◽  
Cleveland Clinic ◽  
Primary Objective ◽  
Rank Test ◽  
Cancer Center ◽  
Clinical Activity ◽  
Cell Renal Cell Carcinoma ◽  
Line Of Therapy

4576 Background: IO-VEGF combinations are the backbone for current and future therapeutic developments in RCC with several IO-VEGF regimens reporting positive results in phase 3 trials. However, limited data exists on outcomes to subsequent therapy in patients progressing on IO-VEGF regimens. Methods: A retrospective analysis was performed on patients with ccRCC at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic Cancer Institute who initiated systemic therapy post IO-VEGF regimens including combinations with VEGFR tyrosine kinase inhibitors (IO-TKI) and combinations with anti-VEGF monoclonal antibodies (IO-mAB). Patients treated on unreported clinical trials were excluded from the outcomes analysis. The primary objective was to evaluate the overall survival (OS) post IO-VEGF. The secondary objectives included objective response rate (ORR) and progression-free survival (PFS) according to RECIST v1.1. Kaplan-Meier methods and the log-rank test were used to evaluate time from start of systemic therapy post IO-VEGF to the event of interest. Results: Fifty-nine patients were treated after discontinuation of IO-VEGF regimens. Prior IO-VEGF regimens included IO-mAB (n = 35, 59%) and IO-TKI (n = 24, 41%). IMDC scores at the start of next line of therapy were favorable in 20%, intermediate in 60% and poor in 20%. Next line of therapy included VEGFR-TKI monotherapy (n = 45, 76%), VEGFR-TKI based combinations (n = 6, 10%), mTOR inhibitors (n = 3, 5%), and unreported clinical trials (n = 5, 9%). VEGFR-TKI containing regimens (n = 51) included cabozantinib (n = 22), axitinib (n = 17), lenvatinib/everolimus (n = 4), pazopanib (n = 4), and others (n = 4). Median OS was 24.5 months (95% CI 12-NE) with a 12 months OS rate of 63%. The ORR was 27% (14/51) and the median PFS was 6.8 months (95% CI 4.8-11). No difference in post IO-VEGF OS was observed when comparing IO- TKI vs IO-mAB (log rank p = 0.7). Conclusions: Post combination IO-VEGF treatment, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs continue to show clinical activity similar to historic experiences of patients post VEGF monotherapy.

Phase II study of sitravatinib in combination with nivolumab in patients undergoing nephrectomy for locally-advanced clear cell renal cell carcinoma (ccRCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS686-TPS686
Author(s):  
Jose A. Karam
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Suppressor Cells ◽  
Primary Objective ◽  
Clinical Activity ◽  
Open Label ◽  
Cell Renal Cell Carcinoma

TPS686 Background: Sitravatinib is a receptor tyrosine kinase inhibitor (RTKI) that targets multiple closely related RTK pathways including VEGFR, PDGFR, KIT, MET and the TAM receptors (TYRO3, AXL and MERTK) Nivolumab is a monoclonal antibody against PD-1 and releases PD-1-mediated inhibition of T-cell proliferation and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment nivolumab’s efficacy. Mechanisms by which sitravatinib may augment an antitumor immune response include enhanced antigen presentation; depletion of immunosuppressive regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) via inhibition of split kinases VEGFR and KIT; and shifting tumor-associated macrophages from an immunosuppressive M2 to a pro-immunogenic M1 phenotype via inhibition of TAM RTKs. Each of these factors converge on promoting T effector cell expansion, tumor infiltration and an antigen-specific anti-tumor immune response. Methods: This open-label, non-randomized, preoperative window of opportunity Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with locally-advanced ccRCC undergoing nephrectomy. Study treatment consists of 2 weeks of sitravatinib monotherapy followed by 4 weeks of the combination. Sitravatinib is administered orally daily at 120 mg; nivolumab intravenously every 2 weeks at 240 mg. The primary objective is to evaluate clinical activity using percentage of pts achieving a presurgical point-in-time objective response. Secondary objectives include evaluation of safety and tolerability, and determination of the immune effects of sitravatinib monotherapy and the combination through serial tissue and blood collections (temporal changes in PD-L1 expression, selected cytokines and immune cell populations including MDSCs, Tregs and ratio of M1:M2 macrophages). The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03680521.

The efficacy of anti-PD-1 combined with temozolomide in unresectable, advanced melanoma from one center.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22007-e22007
Author(s):  
Tu Hu ◽  
Wei Sun ◽  
Yu Xu ◽  
Zhi-Guo Luo ◽  
Yong Chen
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Unknown Primary ◽  
Second Line ◽  
Front Line ◽  
Second Line Therapy ◽  
Free Survival ◽  
Line Therapy ◽  
Significant Difference

e22007 Background: Anti-PD1/PDL-1 immunotherapy has led to a new era of the unresectable, advanced melanoma treatment. However, there are still a significant part of patients suffer from primary or secondary drug resistance to immunotherapy. We sought to explore the efficacy and safety of anti-PD-1 plus Temozolomide in unresectable, advanced melanoma patients. Methods: Patients with unresectable, advanced melanoma were treated with anti-PD-1 plus Temozolomide, Temozolomide/DTIC based chemotherapy, or anti-PD-1 alone between 1 May, 2018 and 31 January, 2020. Data were retrospectively reviewed and statistically analyzed for best ORR and progression free survival, as well as toxicities. Results: Seventy-seven individuals were identified, including 37 (48.1%) with acral melanoma, 20 (26.0%) with cutaneous melanoma, 16 (20.8%) with mucosal melanoma and 4 (5.2%) with melanoma of unknown primary. Thirty-three (46.8%) patients had received postoperative adjuvant treatment before progression, and none of them had received anti-PD-1 treatment. The objective response rate of anti-PD-1 plus Temozolomide (n = 5, 41.7%) was higher than Temozolomide/DTIC (n = 1, 5%) or anti-PD-1 alone (n = 6, 20.7%) in the front-line therapy and second-line therapy (42.9%, 0%, 23.5%, respectively). Similar results were found in the third-line therapy. Although no significant difference was detected among these groups in the front-line therapy, the progression free survival of anti-PD-1 plus Temozolomide (median, 7 months) was higher than Temozolomide/DTIC (median, 2.5 months) (p = 0.009), while showing no significant difference with anti-PD-1 (median, 4.5 months) (p = 0.267) in the second-line therapy. The incidence of grade 3/4 toxicity was 8% (anti-PD-1 plus Temozolomide), 20.7% ( Temozolomide/DTIC) and 23.8% (anti-PD-1) respectively, mainly immunogenic pneumonia (0%, 0%, 10.3%) and hepatotoxicity (0%, 4.8%, 6.9%), and no significant difference was found among these groups. Conclusions: The efficacy of combination of anti-PD-1 and Temozolomide is better than Temozolomide/DTIC or anti-PD-1 alone in advanced melanoma and does not increase the toxicity. Therefore, Anti-PD-1 combined with Temozolomide may be used as front-line regimen in advanced melanoma.

Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 92-92 ◽  
Author(s):  
Yung-Jue Bang ◽  
Talia Golan ◽  
Chia-Chi Lin ◽  
Yoon-Koo Kang ◽  
Zev A. Wainberg ◽  
...  
Keyword(s):  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Duration Of Treatment ◽  
Serious Adverse Event ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps

92 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This global phase 1 trial evaluates the combination of R (anti-VEGFR2) and D (anti-PD-L1) in pts with G/GEJ by simultaneously targeting these two processes. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02572687) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on 1 or 2 lines of systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 expression was assessed using the SP-263 IHC; MSI status was determined using PCR. Enrolled pts received R (8 mg/kg IV) and D (750 mg IV) every two weeks on a 28-day cycle. Primary objective was to assess safety and tolerability of R+D; preliminary efficacy was also examined. Results: As of 26-May-2017, 29 G/GEJ adenocarcinoma pts were treated. The median age was 55 y; 69% were male; 66% had ECOG PS of 1; 48% had PD-L1 ≥25% expression in tumor or immune cells, 3.5% were MSI-high; and 72% received study treatment as second line for advanced disease. Median duration of treatment was 2.5 mo for R and 3.0 mo for D. Treatment-emergent adverse events (TEAEs) occurred in 29 (100%) pts and 21 (72%) pts experienced grade 3/4 TEAEs, while treatment-related AEs (TRAE) occurred in 24 (83%) pts; none resulted in treatment discontinuation. Ten (35%) pts had grade 3 TRAEs, and no grade 4 or 5. All grade TRAEs occurring in ≥10% of pts were hypertension (34%), fatigue (31%), headache (24%), diarrhea (21%), pyrexia (10%) and decreased appetite (10%). Five pts (17%) reported a serious adverse event related to study treatment. Preliminary efficacy data (RECIST v1.1) showed 5 of 29 pts (17%) achieved a confirmed PR. Only 1 responding pt was MSI high. The overall response rate for pts with PD-L1 ≥25% was 36%. Median PFS was 2.6 mo (95% CI, 1.45 to 6.28). As of data cut-off, 6 pts (21%) remain on treatment. Conclusions: R+D generated no unexpected toxicity, and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02572687.

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