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  • 1
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    Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9504-9504
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9504-9504
    Abstract: 9504 Background: Initial results of the open-label, single-arm, phase 2 LEAP-004 study (NCT03776136) showed that len and pembro in combination had promising efficacy and manageable safety in pts with unresectable stage III-IV melanoma and confirmed PD on a PD-(L)1 inhibitor given alone or in combination. ORR was 21.4% with a 6.3-mo median DOR; ORR was 31.0% in patients with PD on prior anti–PD-1 + anti–CTLA-4. We present updated data from LEAP-004 and additional ORR subgroup analyses. Methods: Eligible pts with PD confirmed per iRECIST within 12 wk of the last dose of a PD-(L)1 inhibitor given alone or with anti–CTLA-4 or other therapies for ≥2 doses received len 20 mg/d once daily plus ≤35 doses of pembro 200 mg Q3W until PD or unacceptable toxicity. Primary end point is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. ORR was calculated for pts with PD on prior anti–PD-1 + anti–CTLA-4, pts whose only prior anti–PD-(L)1 was in the adjuvant setting, pts with primary resistance (ie, best response of SD or PD to prior anti–PD-(L)1 in the advanced setting) and pts with secondary resistance (ie, PD following best response of CR or PR on prior anti–PD-(L)1 in the advanced setting). Results: 103 pts were enrolled. Median age was 63 y, 68.0% of pts had stage M1c/M1d disease, 55.3% had LDH 〉 ULN (20.4% ≥2 × ULN), 58.3% received ≥2 prior treatments, 94.2% received therapy for advanced disease, and 32.0% received BRAF ± MEK inhibition. With median study follow-up of 15.3 mo (range 12.1-19.0), 17.5% of pts were still receiving study drug. ORR by BICR remained 21.4% (95% CI 13.9-30.5), although the number of CRs increased from 2 to 3. DCR was 66.0%. Median DOR increased to 8.2 mo, and the KM estimate of DOR ≥9 mo was 37.2%. ORR was 33.3% in pts with PD on prior anti–PD-1 + anti–CTLA-4 (n = 30), 18.2% in pts whose only prior anti–PD-1/L1 was in the adjuvant setting (n = 11), 22.6% in pts with primary resistance (n = 62), and 22.7% in pts with secondary resistance (n = 22). Median (95% CI) PFS and OS in the total population were 4.2 mo (3.8-7.1) and 14.0 mo (95% CI 10.8-NR); 12-mo PFS and OS estimates were 17.8% and 54.5%. Incidence of treatment-related AEs was as follows: 96.1% any grade, 45.6% grade 3-4, 1.0% grade 5 (decreased platelet count), 7.8% led to discontinuation of len and/or pembro, and 56.3% led to len dose reduction. Conclusions: The combination of len and pembro continues to show clinically meaningful, durable responses in pts with advanced MEL with confirmed progression on a prior PD-(L)1 inhibitor, including those with PD on anti–PD-1 + anti–CTLA-4 therapy, and regardless of primary or secondary resistance to prior anti–PD-(L)1 therapy. The safety profile was consistent with prior studies of len + pembro. These data support len + pembro as a potential regimen for this population of high unmet need. Clinical trial information: NCT03776136.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9504
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 2
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    The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 9531-9531
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 9531-9531
    Abstract: 9531 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in 〉 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With 〉 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.9531
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 5_suppl ( 2018-02-10), p. 189-189
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 5_suppl ( 2018-02-10), p. 189-189
    Abstract: 189 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with advanced BRAF V600–mutant melanoma; however, many still progress and die from this disease. Thus, new treatment strategies are needed. BRAF and MEK inhibitor combinations (eg, D+T) may reverse immunosuppressive phenotypes induced by oncogenic BRAF and improve sensitivity to checkpoint inhibitors by enhancing HLA and melanocytic antigen expression and tumor antigen–specific T-lymphocyte recognition. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating the anti–PD-1 antibody PDR001 in combination with D+T in treatment-naive pts with BRAF V600–mutant unresectable or metastatic melanoma in 3 parts: 1, safety run-in; 2, biomarker cohort; and 3, randomized, double-blind, placebo-controlled part. Here we report preliminary findings for 9 pts in part 1 dosed with PDR001 400 mg Q4W + D 150 mg BID + T 2 mg QD. Response was assessed at wk 12 and Q8W thereafter. Results: At data cutoff (16 Jul 2017; median follow-up, 2.7 mo), all 9 pts completed the 8-wk dose-limiting toxicity (DLT) period, during which 1 DLT (transaminitis [AST and ALT 〉 8 × ULN]; n = 1) occurred. Adverse events (AEs) of any grade occurring in 〉 3 pts included pyrexia (n = 9), headache (n = 6), chills (n = 4), and vomiting (n = 4). Grade 3/4 AEs reported in 〉 1 pt included hepatitis (n = 3), increased lipase (n = 2), and increased transaminases (n = 2). AEs leading to discontinuation occurred in 2 pts (22%; transaminitis, n = 1; grade 3 hepatitis, n = 1) who permanently discontinued PDR001 but were still receiving D+T at the data cutoff. All 9 pts responded: 3 (33%) achieved a complete response (confirmed, n = 1), and 6 (67%) had partial responses (confirmed, n = 1). Additional safety and efficacy results for these 9 pts, all ongoing at the data cutoff, will be presented. Conclusions: These preliminary results indicate that PDR001 can be combined with D+T with a manageable safety profile and demonstrate promising activity in pts with BRAF V600–mutant melanoma. Clinical trial information: NCT02967692.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.5_suppl.189
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy : Three-Year Follow-up of a Randomized Phase 3 Trial
    American Medical Association (AMA) ; 2019
    In:  JAMA Oncology Vol. 5, No. 2 ( 2019-02-01), p. 187-
    Details
    In: JAMA Oncology, American Medical Association (AMA), Vol. 5, No. 2 ( 2019-02-01), p. 187-
    Type of Medium: Online Resource
    ISSN: 2374-2437
    DOI: 10.1001/jamaoncol.2018.4514
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2019
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  • 5
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    Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. 8 ( 2021-08), p. e003188-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 8 ( 2021-08), p. e003188-
    Abstract: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial. Methods Patients with resected stage IIIB–C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from 〉 3–12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups. Results From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm. Conclusion Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident. Trial registration number NCT02388906 .
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-003188
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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  • 6
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    Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 17 ( 2023-09-01), p. 3352-3361
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 17 ( 2023-09-01), p. 3352-3361
    Abstract: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. Patients and Methods: Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. Results: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. Conclusions: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-3145
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
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    Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 33 ( 2020-11-20), p. 3937-3946
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 33 ( 2020-11-20), p. 3937-3946
    Abstract: The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein. PATIENTS AND METHODS In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m 2 every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report. CONCLUSION Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab mono-therapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.20.00995
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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