Pembrolizumab (pembro) plus low-dose ipilimumab (ipi) for patients (pts) with advanced renal cell carcinoma (RCC): Phase 1 KEYNOTE-029 study.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 510-510 ◽  
Author(s):  
Toni K. Choueiri ◽  
F. Stephen Hodi ◽  
John A. Thompson ◽  
David F. McDermott ◽  
Wen-Jen Hwu ◽  
...  
Keyword(s):  
Low Dose ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Pegylated Interferon ◽  
Prior Therapy ◽  
End Point ◽  
Duration Of Response ◽  
Report Data ◽  
Grade 3 ◽  
Ecog Ps

510 Background: The CTLA-4 antibody ipi and the PD-1 antibody pembro have demonstrated efficacy in pts with advanced malignancies. While these immune checkpoint inhibitors have shown robust activity as monotherapy, combination therapy may further improve outcomes. KEYNOTE-029 (NCT02089685) is a phase 1/2 study designed to assess the safety and efficacy of pembro + ipi or pegylated interferon alfa-2b (IFN-α) in pts with advanced melanoma or RCC. Here we report data from the phase 1 portion of the study in pts with RCC treated with pembro + ipi. Methods: Pts ≥18 years with advanced/unresectable or metastatic clear cell RCC who received ≥1 prior therapy for metastatic disease, had ≥1 measurable lesion per RECIST v1.1, and ECOG PS 0-1 were enrolled. Pts received pembro 2 mg/kg Q3W + low-dose ipi (1 mg/kg Q3W for 4 doses) until disease progression, unacceptable toxicity, investigator/patient decision, or 2 years of pembro treatment. AEs were monitored throughout treatment and for 30 days thereafter and graded per NCI CTCAE v4.0. Primary end point was safety; primary efficacy end point was ORR assessed per RECIST v1.1 by independent central imaging vendor review. Results: As of the March 17, 2016, data cutoff, 10 pts with RCC received pembro + low-dose ipi. 60% were male, 70% were white, median age was 61 years (range, 48-70 years), 40% received 2 prior lines of therapy, and 40% received prior immunotherapy. With a median follow-up of 17.4 months (0.9-23.5 months), 70% of pts experienced treatment-related AEs (TRAEs) of any grade, most commonly fatigue (30%); and 50% experienced grade 3/4 TRAEs, most commonly increased lipase (20%). 50% of pts discontinued pembro because of TRAEs, most commonly increased lipase (40%). There were no treatment-related deaths. ORR was 20% (2 partial responses); median duration of response was not reached (14.1+-17.1 months+). An additional 3 pts had stable disease; disease control rate was 50%. Conclusions: The combination of pembro + low-dose ipi for 4 doses, followed by pembro monotherapy, demonstrates a manageable toxicity profile and preliminary antitumor activity in pts with advanced RCC. Clinical trial information: NCT02089685.

Results of a phase II trial of cetuximab + XELIRI as first-line therapy of patients with advanced and/or metastatic colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4094-4094
Author(s):  
T. H. Cartwright ◽  
P. Kuefler ◽  
A. Cohn ◽  
W. Hyman ◽  
M. Yoffe ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Allergic Reaction ◽  
Metastatic Colorectal Cancer ◽  
First Line ◽  
Prior Therapy ◽  
First Line Therapy ◽  
Duration Of Response ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Reductions

4094 Background: We have previously shown that capecitabine/irinotecan (XELIRI) is effective and well-tolerated in metastatic colorectal cancer (mCRC). Cetuximab, a monoclonal IgG1 antibody that binds to the extracellular domain of EGFR, is active in mCRC alone or in combination with chemotherapy. This study was designed to evaluate if cetuximab (Erbitux®) added to XELIRI improves outcome in first-line treatment of mCRC. Methods: Subjects had histologically confirmed colorectal adenocarcinoma with T4 lesions that were unresectable after preoperative chemoradiation therapy and/or metastases. The study regimen was capecitabine 1700 mg/m2 (850 mg/m2 PO BID Days 1–14), irinotecan 200 mg/m2 IV Day 1 every 3 weeks, and weekly cetuximab (initial dose 400 mg/m2 IV over 120 minutes, subsequent doses 250 mg/m2 over 30 minutes). Results: Between February and October 2005, 70 subjects enrolled. Baseline characteristics: 43 males (61%), median age 61.5 years, and ECOG PS 0/1= 66%/34%; 94% of subjects had adenocarcinoma. Prior therapy; surgery (91%), chemotherapy (20%), or radiotherapy (7%). Responses (pts >2 cycles) were; CR (4%), PR (36%), SD (40%) and PD (20%); 15 patients failed treatment; (n=4 allergic reaction, n=2 MD request, n=2 withdrew consent, n=2 Grade 4 neutropenia, and n=5 other AEs). The overall response rate was 40% and the disease control rate was 80%. Median duration of response was 8.8 months (range, 2.6–15.1) and median time to response was 2.0 months (range, 1.2–8.3). 64% of patients remain alive; of the 25 deaths, 84% were due to PD. No death was drug related. The most frequent Grade 3 and 4 treatment-related adverse events (AEs) included: diarrhea (25%), neutropenia (18%), nausea/vomiting (12%), rash and dehydration (9%, each), HFS and fatigue (7%), and allergic reaction (6%). 54% of patients required dose reductions. To date, 64 patients (91%) have gone off study, primarily due to PD (39%) or AE (33%); 3 patients remain on treatment. Conclusions: The combination of cetuximab and XELIRI is feasible and tolerable in first line mCRC. Toxicities are expected and manageable with dose reductions/delay. Funded in part by Bristol-Myers Squibb, Plainsboro, NJ. No significant financial relationships to disclose.

A phase I study of APL-501, an anti-PD-1 antibody, in patients with recurrent or advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15125-e15125
Author(s):  
Mark Voskoboynik ◽  
Gary Edward Richardson ◽  
Linda R. Mileshkin ◽  
Catriona M. McNeil ◽  
Lisa Horvath ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Median Number ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Grade 3 ◽  
Refractory Solid Tumor ◽  
Ecog Ps

e15125 Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .

Evaluation of safety and tolerability of durvalumab (D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 387-387 ◽  
Author(s):  
Tatsuya Ioka ◽  
Makoto Ueno ◽  
Do-Youn Oh ◽  
Yutaka Fujiwara ◽  
Jen-Shi Chen ◽  
...  
Keyword(s):  
Phase 1 ◽  
Median Number ◽  
Drug Induced ◽  
Tract Cancer ◽  
Optimal Dosing ◽  
Survival Endpoints ◽  
Duration Of Response ◽  
Grade 3 ◽  
D 20 ◽  
Ecog Ps

387 Background: This Phase 1 study (NCT01938612) evaluated D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) in Asian pts, in whom optimal dosing of D and T is undetermined. No dose-limiting toxicities were observed, and durable responses were seen in a dose escalation phase evaluating various D doses and regimens in Japanese pts (Iguchi, ASCO 2015). The study was subsequently expanded to larger cohorts of Asian pts with advanced solid tumors including BTC. Methods: Two regimens were selected for the expansion phase: D monotherapy (10 mg/kg q2w) and D+T (D 20 mg/kg + T 1.0 mg/kg q4w). One cohort of pts with advanced BTC was enrolled to receive D monotherapy followed by a separate cohort that received D+T with additional pts enrolled if efficacy was observed. Safety, response, and survival endpoints were based on investigator assessment. Results: Pts were enrolled to D (N = 42) or D+T (N = 65). Median age was 64 years for the D cohort and 62 years for the D+T cohort, the majority were male, and ECOG PS was 0 or 1: 64% and 36% for pts in the D cohort and 49% and 51% for pts in the D+T cohort, respectively. Median number of prior chemotherapy regimens was 2 for both cohorts. Treatment-related adverse events (trAE) of any grade occurred in 64% and 82% of pts in the D and D+T cohorts. Grade ≥ 3 trAEs occurred in 19% and 23% of pts in the D and D+T cohorts. trAEs led to discontinuation in 2 pts in the D cohort and 5 pts in the D+T cohort. A death due to trAE (drug-induced liver injury) was reported in the D+T cohort, none in the D cohort. In the D cohort, 2 pts had a partial response (PR) and 7 pts had a PR in the D+T cohort; disease control rate at 12 weeks was 16.7% and 32.2%, respectively. Median duration of response for the D cohort was 9.7 months and 8.5 months for the D+T cohort. Median overall survival was 8.1 (95% CI, 5.6-10.1) months and 10.1 (95% CI, 6.2-11.4) months for the D and D+T cohorts, respectively. Conclusions: Both D monotherapy and D+T combination therapy were tolerable for Asian pts with BTC, and no unexpected toxicities were observed with either regimen. Promising clinical benefit was observed with both D and D+T therapy. This study provides valuable information regarding these therapeutic regimens for future studies in pts with BTC. Clinical trial information: NCT01938612.

KEYNOTE-029: Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9545-9545 ◽  
Author(s):  
Matteo S. Carlino ◽  
Victoria Atkinson ◽  
Jonathan S. Cebon ◽  
Michael B. Jameson ◽  
Bernie M. Fitzharris ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Standard Dose ◽  
Phase 1 ◽  
Advanced Melanoma ◽  
Prior Therapy ◽  
Immune Mediated ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Ecog Ps

9545 Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAFV600mutant, and 13% received ≥1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61% (95% CI, 53%-69%); the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685.

Phase II, multicenter trial of nivolumab (Nivo) and brentuximab vedotin (BV) in patients (Pts) with untreated Hodgkin lymphoma (HL) over the age of 60 years or unable to receive standard ABVD chemotherapy: Results of a study of Academic and Community Cancer Research United (ACCRU) RU051505I.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8014-8014 ◽  
Author(s):  
Bruce D. Cheson ◽  
Nancy L. Bartlett ◽  
Betsy LaPlant ◽  
Hun Ju Lee ◽  
Ranjana H. Advani ◽  
...  
Keyword(s):  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Disease Free Survival ◽  
Multicenter Trial ◽  
Brentuximab Vedotin ◽  
Stage Disease ◽  
Upper Limits ◽  
Duration Of Response ◽  
Grade 3 ◽  
Ecog Ps

8014 Background: HL is highly curable with > 90% of pts with limited and > 80% with advanced stage disease experiencing long-term disease-free survival. HL typically occurs in younger pts, yet 15-35% are > 60 yrs and experience a lower response rate, shorter survival, and greater toxicity. BV and checkpoint inhibitors have impressive activity in pts with relapsed and refractory HL. Thus, we initiated a phase II trial of BV-nivo in untreated pts with HL >60 yrs of age or considered unsuitable for standard ABVD therapy. Methods: Inclusion criteria: previously untreated pts with classical HL > 60 yrs or < 60 yrs but considered unsuitable for standard chemotherapy because of a cardiac ejection fraction of < 50%, diffusion capacity < 80%, or creatinine clearance > 30 but < 60 mL/min, or refused chemotherapy; ECOG PS 0-2, ANC >1500/mm3, platelets > 100,000/mm3, hemoglobin > 9 g/dl, bilirubin <1.5 x upper limits of normal (ULN), aspartate/alanine transaminases < 2.5 x ULN, amylase and/or lipase < 1.5 x ULN, and serum creatinine < 2.0 mg/dl. Pts received BV at 1.8 mg/kg (cap at 180 mg) and nivo 3 mg/kg every 21 days for 8 cycles. Response was assessed per the Lugano Classification. Results: The study accrued 46 pts between May 13, 2016-January 30, 2019. Median age of 71.5 yrs, 69.5% had ECOG PS 1 or 2; 64% stage III or IV; 39.1% with B symptoms; 4.3% were < 60 years. Median follow-up was 21.2 months (range 2.9, 38.5), and 35 pts (76.1%) completed all 8 cycles of therapy. At the interim analysis (1st 25 pts) ORR was 64% (52% mCR, 12% pMR) which was lower than the projected 80%. In all 46 pts, 45.7% achieved mCR and 15.2% mPR (ORR 60.9%); in evaluable pts, best ORR was 95% with 68% mCR. No clinical factors predicted response. Neither median duration of response nor median survival has been reached. Median PFS is 21.8 months (17.8, Not reached). 22 pts experienced 33 treatment delays, primarily due to BV. 22 pts experienced peripheral neuropathy (5 grade 3). Grade 4 toxicities included increased transaminases (n = 1), increased lipase and/or amylase (n = 2), pancreatitis (1). One pt died from cardiac arrest, possibly treatment-related. Conclusions: BV-nivo is active in untreated older HL pts with comorbidities. However, efficacy and response durability did not meet pre-specified criteria. Future trials based on these drugs, selecting pts most likely to benefit, may lead to a chemo-free approach for pts with HL. Clinical trial information: NCT02758717 .

First-line durvalumab + monalizumab, mFOLFOX6, and bevacizumab or cetuximab for metastatic microsatellite-stable colorectal cancer (MSS-CRC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 128-128
Author(s):  
Zev A. Wainberg ◽  
Jennifer Robinson Diamond ◽  
Giuseppe Curigliano ◽  
Sanjeev Deva ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase 1 ◽  
Objective Response ◽  
Biologic Agent ◽  
First Line ◽  
Open Label ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps

128 Background: Targeting multiple immune checkpoint pathways and combining checkpoint inhibition with chemotherapy may enhance response in MSS-CRC. In a Phase 1/2, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was added to monalizumab (M; an anti-NKG2A antibody). In dose-exploration cohorts, D+M was added to chemotherapy and a biologic agent (bevacizumab [DMCB] or cetuximab [DMCC]) for first-line treatment of advanced/metastatic MSS-CRC. Initial data showed DMCB was well tolerated and clinically active. Here we report updated efficacy and safety of DMCB and initial safety of DMCC. Methods: Eligible patients (pts) had MSS-CRC ( RAS/BRAF wt with a left-sided colon primary tumor in the DMCC cohort) and ECOG PS 0–1. They received D 1500 mg Q4W, M 750 mg Q2W, mFOLFOX6 Q2W and bevacizumab 5 mg/kg Q2W or cetuximab 250/400 mg/m2 QW (up to 500 mg/m2 Q2W) for up to 3 yr. The primary endpoint was safety and tolerability; secondary endpoints included antitumor activity. Results: As of Aug 26, 2019, 18 pts received DMCB and 17 pts received DMCC. Treatment-emergent adverse events (AEs) occurred in 100.0% of the DMCB cohort (most commonly fatigue, nausea and peripheral neuropathy) and 94.1% of the DMCC cohort (most commonly peripheral neuropathy, rash and dermatitis acneiform). The AEs were grade 3/4 in 77.8% of pts receiving DMCB and 70.6% of pts receiving DMCC, and were serious in 38.9% and 47.1%, respectively. Response was evaluable in 17 pts receiving DMCB; objective response rate was 41.2% (all PRs; Table). Responses occurred early and the median duration of response has not yet been reached. Conclusions: In advanced/metastatic MSS-CRC, first-line DMCB and DMCC had a manageable safety profile and DMCB showed promising preliminary activity. Clinical trial information: NCT02671435. [Table: see text]

scholarly journals Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma

Leukemia ◽  
2017 ◽  
Vol 31 (12) ◽  
pp. 2695-2701 ◽  
Author(s):  
P G Richardson ◽  
C C Hofmeister ◽  
N S Raje ◽  
D S Siegel ◽  
S Lonial ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Low Dose ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Vein Thrombosis ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Deep Vein

Abstract This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1–4 mg days 1–14), bortezomib (1–1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1–8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

scholarly journals Ramucirumab in Combination with Pembrolizumab in Treatment-Naïve Advanced Gastric or GEJ Adenocarcinoma: Safety and Antitumor Activity from the Phase 1a/b JVDF Trial

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2985
Author(s):  
Ian Chau ◽  
Nicolas Penel ◽  
Andres O. Soriano ◽  
Hendrik-Tobias Arkenau ◽  
Jennifer Cultrera ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Combined Positive Score ◽  
Grade 3

Ramucirumab (anti-VEGFR2) plus pembrolizumab (anti-PD1) demonstrated promising antitumor activity and tolerability among patients with previously treated advanced cancers, supporting growing evidence that combination therapies modulating the tumor microenvironment may expand the spectrum of patients who respond to checkpoint inhibitors. Here we present the results of this combination in first-line patients with metastatic G/GEJ cancer. Twenty-eight patients (≥18 years) with no prior systemic chemotherapy in the advanced/metastatic setting received ramucirumab (8 mg/kg days 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks as part of JVDF phase 1a/b study. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Tumors were PD-L1-positive (combined positive score ≥ 1) in 19 and -negative in 6 patients. Eighteen patients experienced grade 3 treatment-related adverse events, most commonly hypertension (14%) and elevated alanine/aspartate aminotransferase (11% each), with no grade 4 or 5 reported. The ORR was 25% (PD-L1-positive, 32%; PD-L1-negative, 17%) with duration of response not reached. PFS was 5.6 months (PD-L1-positive, 8.6 months; PD-L1-negative, 4.3 months), and OS 14.6 months (PD-L1-positive, 17.3 months; PD-L1-negative, 11.3 months). Acknowledging study design limitations, ramucirumab plus pembrolizumab had encouraging durable clinical activity with no unexpected toxicities in treatment-naïve biomarker-unselected metastatic G/GEJ cancer, and improved outcomes in patients with PD-L1-positive tumors.

Marked Activity of Velcade Plus Thalidomide (V+T) in Advanced and Refractory Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1480-1480 ◽  
Author(s):  
Maurizio Zangari ◽  
Bart Barlogie ◽  
Klaus Hollmig ◽  
Athanasios Fassas ◽  
Erik Rasmussen ◽  
...  
Keyword(s):  
Prognostic Markers ◽  
Phase 1 ◽  
Response Rates ◽  
Index Patient ◽  
M Protein ◽  
Prior Therapy ◽  
History Of ◽  
Marked Activity ◽  
Grade 3 ◽  
Protein Reduction

Abstract Based on an index patient who responded to V 1.0 mg/m2 + T 100 mg upon progression on V alone and documented prior resistance to T, a phase 1–2 trial was initiated of the V+T combination in patients with advanced and refractory MM, 79% with a history of cytogenetic abnormalities (CA) including 57% pre-V, 81% with one and 52% with 2 prior transplants (n=79). Due to concerns for synergistic neurotoxicity, V was initially given at a dose of 1.0 mg/m2 on days 1, 4, 8 and 11; with the second cycle on day 21, T was introduced at incremental doses, per cohorts of at least 10 patients, at 50, 100, 150 and 200 mg daily. In the absence of grade 3 neurotoxicity, V was then increased to 1.3 mg/m2 and the same T dose escalation scheme was applied. Accrual to the 7th cohort with V 1.3 mg/m2 + T 150 mg has been completed. Distribution of cohorts is as depicted in the attached table per V and T dose along with overall characteristics. First cycle PR to V alone was 25% including 10% achieving n-CR; maximum response was noted after completion of 2 additional cycles with combined V + T: 40% achieved PR and ~ 20% n-CR, 60% had ≥ 25% M protein reduction. Analysis of response rates by V and T cohorts (V 1.0 mg/m2, n=45; V 1.3 mg/m2, n=34) and T dose (T ≤ 100 mg, n=42; > 100 mg, n=37) revealed no significant differences in response rates: median EFS for all 79 patients is 7 mos and median OS 21 (at 12 mo 67% alive). On multivariate analysis of 17 potentially relevant prognostic markers, prior therapy > 5 yrs (36% of patients) was associated with improved survival (HR 0.4, p=.03) whereas prior T (78% of patients) was associated with inferior post-V+T survival (HR 4.1, p=.05). In addition, V 1.3 mg/m2 reduced the risk of events (HR 0.6, p=.07) and of death (HR 0.3, p=.02).

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