Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma.

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA4-LBA4 ◽  
Author(s):  
P. B. Chapman ◽  
A. Hauschild ◽  
C. Robert ◽  
J. M. G. Larkin ◽  
J. B. A. G. Haanen ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Response Duration ◽  
Final Analysis ◽  
Multicenter Trial ◽  
Geographic Region ◽  
Phase Iii ◽  
Open Label

LBA4 Background: About 50% of melanomas have an activating V600EBRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in V600EBRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with V600EBRAF mutation. Methods: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m2, IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. Results: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of vemurafenib. The confirmed RR was 48.4% and 5.5% to vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date. Benefit in OS, PFS, and RR was seen in all subgroups examined. Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib. At the time of data analysis, 66% of vemurafenib pts and 25% DTIC pts were still on treatment. The most common toxicities of vemurafenib were: diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. Conclusions: Vemurafenib is associated with significantly improved OS and PFS compared to DTIC in pts with previously untreated, V600EBRAF-mutated metastatic melanoma.

A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients with metastatic melanoma: A subanalysis based on BRAF status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9030-9030 ◽  
Author(s):  
Evan Hersh ◽  
Michele Del Vecchio ◽  
Michael Paul Brown ◽  
Richard Kefford ◽  
Carmen Loquai ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Performance Status ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Mutation Status ◽  
Phase Iii Trial

9030 Background: Activating mutations of BRAF V600 can be found in 40%-50% of melanomas and are related to poor prognosis. In a phase 3 trial for the treatment of metastatic melanoma (MM) in chemotherapy-naive patients, nab-paclitaxel (nab-P) vs dacarbazine (DTIC) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), assessed by independent radiological review (IRR), and a trend toward prolonged overall survival (OS) at the interim survival analysis. The study also explored the effect of BRAF status on the efficacy parameters. Methods: Chemotherapy-naive patients with stage IV melanoma (M1c stage 65%; elevated LDH 28%) and ECOG performance status 0-1 were randomized to nab-P 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or DTIC 1000 mg/m2 on day 1 of each 21-day cycle (n = 265) independent of BRAF status. Prespecified subgroup analyses of final PFS and interim OS in subgroups by BRAF status (V600E mutant, wild-type, or unknown) were performed. Results: BRAF mutation status was balanced between the treatment arms, with 36% and 38% of patients with known BRAF mutation status in the nab-P and DTIC arms, respectively. Patient characteristics were also balanced within BRAF subgroups. As shown in the Table, advantage in the nab-P arm vs DTIC arm was observed for both PFS and interim OS regardless of BRAFmutation status. Poststudy BRAF inhibitor treatment was also balanced. Conclusions: In this phase III trial, treatment effect was independent of BRAF mutation status, benefiting all patients who received nab-P vs DTIC. Therefore nab-P should be considered in the armamentarium for all chemotherapy-naive patients with MM. Clinical trial information: NCT00864253. [Table: see text]

Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8502-8502 ◽  
Author(s):  
Paul B. Chapman ◽  
Axel Hauschild ◽  
Caroline Robert ◽  
James M. G. Larkin ◽  
John B. A. G. Haanen ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Final Analysis ◽  
Multicenter Trial ◽  
Data Safety Monitoring Board ◽  
Phase Iii ◽  
Open Label ◽  
Response Data ◽  
Primary Endpoints ◽  
Unresectable Stage

8502^ Background: We previously reported results of the planned OS interim analysis for BRIM-3 (50% of the planned 196 deaths required for final analysis) at which time the independent Data Safety Monitoring Board recommended release of results due to compelling efficacy (hazard ratio [HR] for death, 0.37 [95% CI 0.26–0.55]); p<0.0001 and PFS HR 0.26 [95% CI 0.20–0.33]; p<0.0001) and that DTIC-treated patients be permitted to cross over to receive vem. Median follow-up for vem patients was 3.75 months, and longer follow-up would estimate median OS more reliably. Updated OS with median 6.2 months follow-up and 199 total deaths showed HR for death 0.44 (95% CI 0.33–0.59) favoring vem and median OS for vem not reached. We report here the results of an updated OS analysis performed in Nov 2011 with ~10 months median follow-up on vem. Methods: 675 patients with previously untreated, unresectable Stage IIIC or IV melanoma that tested positive for BRAFV600E mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) from Jan to Dec 2010 to vem (960 mg po bid) or DTIC (1000 mg/m2 IV q3w). Co-primary endpoints were OS and PFS. OS data for DTIC patients who crossed over to vem were censored at the time of crossover. Results: Median lengths of follow-up on vem and DTIC were 10.5 months (range 0.4–18.1) and 8.4 months (range <0.1–18.3), respectively. There were 334 deaths. Median OS rates with vem and DTIC were 13.2 months (95% CI 12.0–15.0) and 9.6 months (95% CI 7.9–11.8), respectively. 12-month OS rates were 55% for vem and 43% for DTIC. HR for death was 0.62 (95% CI 0.49–0.77) in favor of vem. 81 DTIC patients crossed over to vem. 44 (13%) vem and 65 (19%) DTIC patients received ipilimumab post-progression. Conclusions: With longer follow-up, vem treatment continues to be associated with improved OS in the BRIM-3 study. An updated analysis, with estimated median follow-up of ~13 months and including response data, will be conducted in Apr 2012 and presented at the meeting.

Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA8500-LBA8500 ◽  
Author(s):  
Axel Hauschild ◽  
Jean Jacques Grob ◽  
Lev V. Demidov ◽  
Thomas Jouary ◽  
Ralf Gutzmer ◽  
...  
Keyword(s):  
Safety Profile ◽  
Kinase Inhibitor ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Phase Iii ◽  
Primary Analysis ◽  
Open Label ◽  
Duration Of Response ◽  
Independent Review

LBA8500^ Background: Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety profile in phase I/II studies in patients (pts) with BRAFV600E-mutated metastatic melanoma (MM). This phase III trial (NCT01227889) compared progression-free survival (PFS) in pts with advanced MM treated either with dabrafenib or dacarbazine (DTIC). Methods: Pts with previously untreated, unresectable stage III or IV BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg po bid) or DTIC (1000 mg/m2, IV, q3w). Primary endpoint was investigator-assessed PFS. Primary analysis for PFS was planned after 102 events. Pts on the DTIC arm were allowed to cross over once progression was confirmed by independent review (IR). Secondary endpoints included PFS by IR, overall survival (OS), response rate (RR), duration of response, safety and pharmacokinetics. Results: 250 pts were enrolled at 93 centers globally from February to September 2011. 187 were randomized to dabrafenib and 63 to DTIC. 141pts were on study treatment at the data cut-off at December 19, 2011 (dabrafenib n = 127; DTIC n = 14), including 21/28 DTIC pts crossed over to dabrafenib. Median age was 52 years, 31% of pts were ECOG >1, 66% M1c, 33% LDH > ULN. Demographics were well balanced between the two arms. At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). The hazard ratio for PFS was 0.30 (95% CI: 0.18–0.53; p < 0.0001). Median PFS was 5.1 months for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all subgroups evaluated. Common adverse events (AEs) on the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas (24%). Serious AEs (> 1%) on the dabrafenib arm included pyrexia (4%), squamous cell carcinomas (6%), and new primary melanomas (2%). Conclusions: Dabrafenib demonstrated a significant improvement in PFS and ORR over DTIC with an acceptable safety profile.

A Phase III Study Comparing Thalidomide/Cyclophosphamide/ Dexa Vs Thalidomide/Dexa Vs Thalidomide/Melphalan/Prednisone In De Novo Multiple Myeloma Patients Not Eligible for ASCT

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5117-5117 ◽  
Author(s):  
Edvan Crusoe ◽  
Angelo Maiolino ◽  
Rosane Bittencourt ◽  
Dorotea Beatriz Fantl ◽  
James Maciel ◽  
...  
Keyword(s):  
Latin American ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Response Duration ◽  
Phase Iii ◽  
Patient Treatment ◽  
Open Label ◽  
Secondary Endpoints

Abstract Abstract 5117 Background- Thalidomide (Thal) is a pro-apoptotic, immunoregulatory and antiangiogenic agent for MM. Although it is used since the 90's, the optimal combined treatment remains inconclusive. This is a preliminary analysis of the first Latin American prospective open-label study comparing three different combinations with Thal for MM patients not eligible for autologous SCT. Patients and Methods- Eligible patients were randomized to one of the three arms and received nine 28-days induction cycles. All patients received Thal(100–200mg/d) and one of the following: A- Cyclo (50mg/d)+ Dexa (40mg/D1-4, 15–18 in cycles 1 and 2, D1-4 in cycles 3 to 9), B- Dexa (40mg/D1-4, 9–12, 17–20 in cycles 1,3,5,7 and 9, D1-4 in even cycles) or C- Mel (4mg/m2/7d)+ Pred (40mg/m2/7d). Thereafter, they were randomized to maintenance treatment until progression disease or unacceptable toxicity, as follows: A1-Thal (100mg/d)+Pred (50mg/each other day) or B1-(Thal 100mg/d). All patients received aspirin as thromboprophylaxis and sulpha-trimetroprim as prophylaxis for infection. If indicated, they received biphosphonate monthly for 24 months, and then quarterly. Before study initiation, informed consent was obtained from patients and evaluation was performed at the end of each cycle. The primary endpoint were response rate and response duration. The secondary endpoints were safety, OS and PFS. IMWG index was utilized to analyze response criteria. SPSS 15.0 for windows® were used for statistical analysis. Results- Enrolment started on February 2007, and a total of 60 patients have been included. Median age at randomization was 71 (56–84) years-old, and 52% of patients were female. Durie-Salmon stages were 12% II, 82% III and ISS stages were 47% II and 28% III. Fifty-one per cent of patients presented IgG monoclonal component. There were no significant differences comparing response > VGPR and treatment arms after three, six and nine cycles. However, the PFS is significant when compared CTD/MPT and TD arms (p=0.01). There was no difference in OS. Discussion- This analysis showed that Thal combinations are effective in MM patient treatment. We have not observed different responses between the tree arms. The progression free survival is significant in favor of alkylating combination than thal+dexa (p=0.01). Toxicity was manageable and balanced between the tree different arms. We would like to thank Dr. Jesus San Miguel and Dra. Maria-Victoria Mateos who have collaborated in this study. Disclosures: No relevant conflicts of interest to declare.

ELOQUENT-2: A phase III, randomized, open-label trial of lenalidomide/dexamethasone (Len/Dex) with or without elotuzumab (Elo) in relapsed or refractory multiple myeloma (RR MM) (CA204-004).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8112-TPS8112
Author(s):  
Sagar Lonial ◽  
Paul Gerard Guy Richardson ◽  
Philippe Moreau ◽  
Robert Z. Orlowski ◽  
Jesùs F. San-Miguel ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Response Duration ◽  
Surface Glycoprotein ◽  
Phase Iii ◽  
Open Label ◽  
Cell Surface Glycoprotein ◽  
Open Label Phase ◽  
Related Quality ◽  
Duration Of Response

TPS8112 Background: MM remains incurable and patients (pts) typically relapse or become refractory to current treatments. Novel regimens are needed to improve pt outcomes. Elo is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells. Len/Dex is approved for treatment of relapsed MM and an objective response rate (ORR) of ~60% was reported in phase III trials of this combination in RR MM. In a phase II study (N=73) of Elo (10 or 20 mg/kg) in combination with Len/Dex in pts with RR MM, the 10 mg/kg group (n=36) demonstrated an ORR of 92% and median progression-free survival (PFS) that was not reached after a median follow-up of 14.1 months. Encouraging activity was seen in patients with high-risk cytogenetics and/or stage 2-3 disease. Based on these data, a randomized, open-label phase III trial has been initiated to determine if the addition of Elo to Len/Dex will improve PFS in patients with RR MM compared with Len/Dex alone. Methods: Pts (N=640) with RR MM and 1-3 prior therapies are eligible, including pts with mild or moderate renal impairment. Pts are randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days 1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 in subsequent cycles. Dex 8 mg IV + 28 mg PO is used during the weeks with Elo. Treatment will continue until disease progression, death, or withdrawal of consent. Patients will be followed for tumor response every 4 weeks until progressive disease and then survival every 12 weeks. The primary endpoint is PFS (90% power for a hazard ratio [experimental to control arm] of 0.74) and the secondary endpoints are ORR and overall survival. Exploratory endpoints are safety, time to response, duration of response, time to subsequent therapy, health-related quality of life, and pharmacokinetics and immunogenicity of Elo. Potential biomarkers will also be assessed. As of January 10th, 2012, 107 pts were enrolled and 68 pts were treated. NCT01239797.

Randomized, Multicenter, Open-Label Study of Oxaliplatin Plus Fluorouracil/Leucovorin Versus Doxorubicin As Palliative Chemotherapy in Patients With Advanced Hepatocellular Carcinoma From Asia

2013 ◽  
Vol 31 (28) ◽  
pp. 3501-3508 ◽  
Author(s):  
Shukui Qin ◽  
Yuxian Bai ◽  
Ho Yeong Lim ◽  
Sumitra Thongprasert ◽  
Yee Chao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Palliative Chemotherapy ◽  
Locally Advanced ◽  
Local Treatment ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
End Point

Purpose To determine whether FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) administered as palliative chemotherapy to patients with advanced hepatocellular carcinoma (HCC) provides a survival benefit and efficacy versus doxorubicin. Patients and Methods This multicenter, open-label, randomized, phase III study in mainland China, Taiwan, Korea, and Thailand involved 371 patients age 18 to 75 years who had locally advanced or metastatic HCC and were ineligible for curative resection or local treatment. They were randomly assigned at a ratio of one to one to receive either FOLFOX4 (n = 184) or doxorubicin (n = 187). The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR) by RECIST (version 1.0), and safety. Results At the prespecified final analysis, median OS was 6.40 months with FOLFOX4 (95% CI, 5.30 to 7.03) and 4.97 months with doxorubicin (95% CI, 4.23 to 6.03; P = .07; hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.02). Median PFS was 2.93 months with FOLFOX4 (95% CI, 2.43 to 3.53), and 1.77 months with doxorubicin (95% CI, 1.63 to 2.30; P < .001; HR, 0.62; 95% CI, 0.49 to 0.79). RR was 8.15% with FOLFOX4 and 2.67% with doxorubicin (P = .02). On continued follow-up, the trend toward increased OS with FOLFOX4 was maintained (P = .04; HR, 0.79; 95% CI, 0.63 to 0.99). Toxicity was consistent with previous experiences with FOLFOX4; proportions of grade 3 to 4 adverse events were similar between treatments. Conclusion Although the study did not meet its primary end point, the trend toward improved OS with FOLFOX4, along with increased PFS and RR, suggests that this regimen may confer some benefit to Asian patients, but an OS benefit cannot be concluded from these data.

ELOQUENT-1: A phase III, randomized, open-label trial of lenalidomide/dexamethasone with or without elotuzumab in subjects with previously untreated multiple myeloma (CA204-006).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8113-TPS8113 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Thierry Facon ◽  
Paul Gerard Guy Richardson ◽  
Robert Z. Orlowski ◽  
Jesùs F. San-Miguel ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Response Duration ◽  
Surface Glycoprotein ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Cell Surface Glycoprotein ◽  
Prior Therapy

TPS8113 Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells. In a MM xenograft mouse model, the combination of Elo + lenalidomide (Len) significantly reduced tumor volume in a synergistic manner compared with either agent alone. In a phase 2 study (N=73) of Elo (10 or 20 mg/kg) in combination with Len and low-dose-dexamethasone (Dex) in pts with RR MM, the 10 mg/kg dose group (n=36) demonstrated objective response rates (ORR) of 92% in all pts, and 100% in pts who had received only 1 prior therapy (n=16). The higher response rate in pts with fewer prior lines of therapy provides a rationale for investigating this combination earlier in the disease course. This randomized, open-label, phase 3 trial will determine if the addition of Elo to Len/Dex improves progression-free survival (PFS) in pts with newly diagnosed, untreated MM. Methods: Pts (N=750) with newly diagnosed symptomatic MM ineligible for stem cell transplant will be randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 of cycles 3-18 followed by 20 mg/kg on day 1 of cycle 19 onward. Dex 8 mg IV + 28 mg PO is used during the weeks with Elo. Treatment will continue until disease progression, death, or withdrawal of consent. Pts will be followed up for response every 4 weeks until progressive disease and for survival every 16 weeks. The primary endpoint is PFS (90% power for a hazard ratio [experimental to control arm] of 0.74) and the secondary endpoints are ORR and overall survival. Exploratory endpoints are safety, time to response, duration of response, time to subsequent therapy, health-related quality of life, and pharmacokinetics and immunogenicity of Elo. Potential biomarkers will also be assessed. As of January 1, 2012, 13 pts were enrolled and 9 pts were treated. NCT01335399.

A phase 2, open-label, multicenter study to evaluate the efficacy, safety, and tolerability of KN046 in combination with chemotherapy in subjects with advanced non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9060-9060
Author(s):  
Yunpeng Yang ◽  
Wenfeng Fang ◽  
Yan Huang ◽  
Xingya Li ◽  
Siyuan Huang ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Pivotal Phase ◽  
Doublet Chemotherapy ◽  
Platinum Doublet

9060 Background: Dual blockade of PD-1 and CTLA-4 has shown improved overall survival (OS) in combination with a short course of chemotherapy. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86. We hypothesized that KN046 could be combined with a full course of chemotherapy and build more durable clinical benefit. Methods: This study enrolled systemic treatment naive, stage IV NSCLC patients (pts). Eligible pts received KN046 plus platinum doublet chemotherapy until progressive disease, unacceptable toxicity, withdrawal of informed consent or death. Efficacy evaluation was performed by investigators per RECIST 1.1. Safety and tolerability were assessed per NCI-CTCAE v5.0. Results: As of the Jan. 19, 2021, 87 pts [Cohort 1 (n = 51), Cohort 2 (n = 36)] have been enrolled with 83 pts having tumor PD-L1 expression data (PD-L1 ≥1%: 55.4%; PD-L1 < 1%: 44.6%). 33.3% pts remained on the study treatment and 66.7% pts discontinued treatment due to disease progression (27.6%), TEAE (13.8%), death (9.2%) and other reasons (16%). The median treatment duration of KN046 was 21 weeks (range: 1.6̃68.7 weeks). Treatment related TEAE (TRAE) occurred in 92% pts. 25.3% pts experienced Grade≥3 TRAE [diarrhoea (5.7%), alanine aminotransferase increased (4.6%), infusion related reaction (3.4%), rash (3.4%), aspartate aminotransferase increased, dermatitis allergic and immune-mediated pneumonitis (2.3%, respectively), anaphylactoid reaction, autoimmune hepatitis, back pain, bilirubin conjugated increased, hypertension, neutrophil count decreased, platelet count decreased, pneumonitis, rash maculo-papular, septic shock and white blood cell count decreased (1.1%, respectively). In 81 efficacy evaluable pts, the overall objective response rate (ORR) was 50.6% (95% CI: 39.3%,61.9%) and disease control rate (DCR) was 87.7% (95% CI: 78.5%-93.9%). The ORR and DCR in pts with non-squamous NSCLC (n = 48) were 45.8% (95% CI: 31.4%, 60.8%) and 89.6% (95% CI: 77.3%, 96.5%). The ORR and DCR in pts with squamous NSCLC (n = 33) were 57.6% (95% CI: 39.2%, 74.5%) and 84.8% (95% CI: 68.1%, 94.9). Progression free survival (PFS) and OS events have occurred in 53% and 18% patients. Median PFS was 5.9 (95%CI: 5.3, 8.7) months. Median OS was not reached. OS rate at 12 and 15 months were both 74.9%. Similar OS curves have been observed in PD-L1 ≥1% and PD-L1 < 1% pts. In PD-L1 ≥1% patients, median PFS was 6.7 months (10.8 months for PD-L1 ≥1% squamous NSCLC pts). Conclusions: KN046 combined with platinum doublet chemotherapy is tolerated and has shown promising clinical benefit as IL treatment for stage IV NSCLC particularly in PD-L1≥1% tumors and squamous histology. Pivotal Phase III trial in advanced unresectable or metastatic squamous NSCLC is currently ongoing. Clinical trial information: NCT04054531.

Randomized, open-label, phase III study of pemetrexed plus carboplatin (PemC) followed by maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab (PCB) followed by maintenance bevacizumab in patients with advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA8003-LBA8003 ◽  
Author(s):  
Ralph Zinner ◽  
Helen J. Ross ◽  
Robert Weaver ◽  
Ramaswamy Govindan ◽  
Viran R. Holden ◽  
...  
Keyword(s):  
Safety Data ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Drug Regimen ◽  
Primary Objective ◽  
Phase Iii ◽  
Rank Test ◽  
Type I ◽  
Open Label ◽  
Grade 3

LBA8003 Background: PemC and PCB are regimens used for first-line treatment of advanced NS-NSCLC. The primary objective was to compare progression-free survival without Grade 4 toxicity (G4PFS) between two vs three drug regimen arms. Methods: Patients ≥18 years, Stage IV NS NSCLC, AJCC (v7.0), and ECOG PS 0/1 were enrolled. Patients were randomized (1:1); received 4 cycles of induction (PemC: Pem, 500 mg/m2 and C, AUC = 6; PCB: P, 200 mg/m2, C, AUC = 6, and B, 15 mg/kg) followed by Pem (PemC Arm) or B (PCB Arm) maintenance therapy in the absence of progressive disease or discontinuation. Secondary endpoints were PFS, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The study was powered for G4PFS; assuming hazard ratio (HR) of 0.75; there was 80% power to detect superiority of PemC over PCB with a 2-sided type I error of 0.10. Efficacy data were analyzed by intent-to-treat principle using the log-rank test for time-to-event variables, and an exact test for ORR and DCR. Safety data were evaluated using CTCAE v3 for patients who received ≥1 dose of study treatment. Results: Patients were randomized to PemC (N = 182) or PCB (N = 179). Baseline factors were balanced between arms: median age 66/66 years; % female 42/42; % PS=0, 47/47; % stage IV M1a 29/30; for PemC vs PCB, median G4PFS (months) was 3.91/2.86 (HR = 0.85, 90% CI 0.7, 1.04, p = 0.176); PFS and OS had HR = 1.06 (95% CI 0.84, 1.35), p = 0.610, and HR = 1.07 (95% CI 0.83, 1.36), p = 0.616, respectively. The ORR (%) 23.6/ 27.4 and DCR (%) 59.9/57.0 were for PemC vs PCB, respectively. Significantly more drug-related grade 3/4 anemia (18.7% vs 5.4%), and thrombocytopenia (24.0% vs 9.6%) were seen on PemC; significantly more grade 3/4 neutropenia (48.8% vs 24.6%) and grade 1/2 alopecia (28.3 % vs 8.2%) were seen on PCB. Conclusions: PemC was not superior to PCB in G4PFS; no difference in PFS or OS was observed for the two- vs three-drug regimens. There were no unexpected toxicities; the toxicity profiles demonstrated distinctions by arm, and both regimens demonstrated tolerability. Clinical trial information: NCT00948675.

ALPINE: Phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7572-TPS7572 ◽  
Author(s):  
Peter Hillmen ◽  
Jennifer R. Brown ◽  
John C. Byrd ◽  
Barbara Eichhorst ◽  
Nicole Lamanna ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Geographic Region ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Open Label ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Independent Review ◽  
Ecog Ps

TPS7572 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.

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