Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma.
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ABSTRACT:
SUBMITTER: Homicsko K
PROVIDER: S-EPMC9103038 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma.
Homicsko Krisztian K Dummer Reinhard R Hoeller Christoph C Wolchok Jedd D JD Hodi F Stephen FS Larkin James J Ascierto Paolo A PA Atkinson Victoria V Robert Caroline C Postow Michael A MA Re Sandra S Paulucci David D Dobler Darin D Michielin Olivier O
Cancers 20220505 9
The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use ≤ 30 days before initiating study treatment were included in the PPI-use subgroup. Pos ...[more]
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Project description:BackgroundIn patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.MethodsWe administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.ResultsA total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.ConclusionsConcurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).
| S-EPMC5698004 | biostudies-literature
Project description:PurposeIn the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes.Patients and methodsPatients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated.ResultsMedian OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF-wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed.ConclusionThese 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.
| S-EPMC8718224 | biostudies-literature
Project description:ImportanceTreatment-free survival (TFS) represents an alternative time-to-event end point, accurately characterizing time spent free of systemic therapy, providing a more patient-centric view of immune checkpoint inhibitor (ICI) therapy regimens. There remains a lack of studies evaluating TFS outcomes among patients with advanced melanoma who are receiving immunotherapy, especially outside of the clinical trial setting.ObjectiveTo evaluate TFS outcomes for patients with advanced melanoma receiving first-line ICI therapy outside of a clinical trial setting.Design, setting, and participantsThis multicenter cohort study of patients with advanced melanoma receiving first-line ICI therapy between August 1, 2013, and May 31, 2020, was conducted in Alberta, Canada. Data analysis was performed in August 2022.ExposuresPatients received standard-of-care, first-line ICI therapy treatment regimens including single-agent nivolumab, single-agent pembrolizumab, or ipilimumab-nivolumab.Main outcomes and measuresTreatment-free survival was defined as the difference in the 36-month restricted mean survival time between 2 conventional survival end points: (1) time from treatment initiation to ICI cessation, death, or censoring at last follow-up and (2) time from treatment initiation to subsequent systemic anticancer therapy, death, or censoring at last follow-up.ResultsA total of 316 patients with advanced melanoma receiving first-line nivolumab (n = 51; median age, 66 years [IQR, 56-78 years]; 31 men [60.8%]), pembrolizumab (n = 158; median age, 69 years [IQR, 60-78 years]; 112 men [70.9%]), or combination nivolumab-ipilimumab (n = 107; median age, 53 years [IQR, 42-60 years]; 72 men [67.3%]) were included. Treatment groups were similar with regard to sex, primary tumor location, and presence of metastasis, although patients receiving combination nivolumab-ipilimumab had a lower Eastern Cooperative Oncology Group status, were younger, and were more likely to be BRAF V600E positive than those receiving anti-programmed cell death protein 1 (anti-PD-1) monotherapy. The restricted mean TFS was longer for nivolumab-ipilimumab (12.4 months [95% CI, 8.8-16.0 months]) compared with nivolumab (8.9 months [95% CI, 4.4-13.5 months]) and pembrolizumab (11.1 months [95% CI, 8.5-13.8 months]). During the 36-month follow-up interval, patients treated with nivolumab-ipilimumab spent 34.4% of their time (12.4 of 36 months) not receiving systemic anticancer treatments compared with 30.8% (11.1 of 36 months) and 24.7% (8.9 of 36 months) of the time for the pembrolizumab and nivolumab treatment groups, respectively.Conclusions and relevanceThis cohort study of patients with advanced melanoma receiving first-line ICI therapy suggests that TFS represents a patient-centric, informative end point. Patients treated with combination nivolumab-ipilimumab spent more time alive and free from systemic anticancer therapy than those treated with anti-PD-1 monotherapy alone.
| S-EPMC10290253 | biostudies-literature
Project description:BackgroundNivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial.MethodsWe randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group.ResultsAt a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group.ConclusionsAmong patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).
| S-EPMC5706778 | biostudies-literature
Project description:BackgroundMonoclonal antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) (e.g., ipilimumab [IPI]) and the programmed cell death-1 (PD1) receptor (e.g., nivolumab [NIVO]) represent significant breakthroughs in the treatment of advanced melanoma. A combination of the 2 agents has demonstrated efficacy and survival benefits over NIVO or IPI monotherapy in treating advanced melanoma. We compared melanoma-specific costs following treatment with NIVO + IPI, NIVO monotherapy, or IPI monotherapy from the UK and German perspectives to ascertain whether these clinical benefits resulted in a cost advantage.MethodsPatient-level resource utilization data for the three treatment cohorts were obtained from the CheckMate 067 trial (NCT01844505). All melanoma-specific resources, including drugs (index, concomitant and subsequent melanoma medications), office visits, emergency room visits, hospitalizations, lab tests, procedures and surgeries, utilized over a 48-month evaluation period after start of index treatment were included. Unit costs specific to each geography were applied from external sources. Mean costs per surviving patients were calculated for each successive 30-day period from treatment start and aggregated over the evaluation period.ResultsThe total per-patient costs incurred by advanced melanoma patients over the 48-month period following treatment initiation with NIVO + IPI were 9% lower than NIVO monotherapy (£226k vs £248k) and 3% lower compared to IPI monotherapy (£226k vs. £233k) in the UK. In Germany, the total costs incurred by NIVO + IPI cohort were 5% lower than NIVO monotherapy (€258k vs €271k) and 4% lower compared to IPI monotherapy (€258k vs. €268k). Drug costs accounted for > 85% of total costs. Non-drug costs were slightly higher for NIVO + IPI and IPI monotherapy because of higher hospitalization rates. Costs incurred on subsequent drugs post progression were about 45% and 65% lower in NIVO + IPI cohort compared with NIVO and IPI monotherapy cohorts respectively.ConclusionsThe total costs incurred by a patient over a 48-month period following treatment initiation with NIVO + IPI are lower when compared with patients initiating monotherapies; further, the cost advantage is seen to be increasing over time. The clinical benefits offered by the regimen are thus supplemented by a cost advantage, as patients receiving either monotherapy treatment experience faster progression and, consequently, higher subsequent treatment costs. (Note: The cost results reported here are specific to the UK, and Germany, and may not be generalizable to other geographies).
| S-EPMC6610852 | biostudies-literature
Project description:ImportanceAlthough the combination of nivolumab plus ipilimumab has unquestionable benefit over nivolumab monotherapy in advanced melanoma, currently no summative analyses have compared the combination with nivolumab monotherapy for advanced cancers other than melanoma.ObjectiveTo examine whether the addition of ipilimumab to standard-dose nivolumab safely improves clinical outcomes in patients with advanced cancers other than melanoma.Data sourcesElectronic databases (PubMed, EBSCO Information Services, Embase, and Cochrane Library) were systematically searched for studies of standard-dose nivolumab plus ipilimumab vs nivolumab alone in the treatment of advanced cancers other than melanoma published from database inception to October 31, 2022.Study selectionEight studies (total patients, 1727; nivolumab plus ipilimumab group, 854; nivolumab monotherapy group, 873) met the selection criteria. Patients had squamous cell lung cancer, non-small cell lung cancer with programmed death ligand 1 level of 1% or higher, small cell lung cancer, pleural mesothelioma, urothelial carcinoma, esophagogastric carcinoma, sarcoma, or glioblastoma multiforme.Data extraction and synthesisFor comparison of overall survival (OS) and progression-free survival (PFS) outcomes, estimation of log(hazard ratios [HRs]) and SEs was initially performed for OS and PFS of each included study based on summary statistics extracted from individual Kaplan-Meier curves. Inverse-variance weighting was then used to compute pooled HRs (95% CIs). For comparison of dichotomous data (treatment-related grade 3 to 4 adverse events and discontinuations), odds ratios (ORs) were used, and the Mantel-Haenszel method was used to estimate pooled ORs (95% CIs).ResultsTreatment with nivolumab plus ipilimumab was not associated with improvement in OS over treatment with nivolumab alone (pooled HR, 0.95; 95% CI, 0.85-1.06; P = .36), with 4 of the 8 studies having numerically lower median OS with the combination. Nivolumab plus ipilimumab combination therapy was associated with marginal, but not clinically meaningful, improvement in PFS over nivolumab alone (pooled HR, 0.88; 95% CI, 0.79-0.98; P = .02). The combination was associated with substantially higher treatment-related grade 3 to 4 adverse events (pooled OR, 1.84; 95% CI, 1.47-2.31; P < .001) and treatment-related discontinuations (pooled OR, 1.96; 95% CI, 1.44-2.65; P < .001). This finding was recapitulated in meta-analyses of individual grade 3 to 4 adverse events of hepatotoxicity, gastrointestinal toxicity, pneumonitis, endocrine dysfunction, dermatitis, fatigue.Conclusions and relevanceIn this meta-analysis of 8 advanced cancers other than melanoma, the differences detected in OS and PFS between nivolumab plus ipilimumab and nivolumab were not clinically meaningful (even though statistical significance was detected in PFS). Treatment-related higher-grade toxicity and discontinuations were substantially higher with the combination therapy. The data indicate that investigations of anti-programmed death 1 (PD1) plus anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies in any nonmelanoma advanced cancer should be conducted along with anti-PD1 monotherapy to ensure that the net effect of the addition of anti-CTLA-4 to anti-PD1 can be clearly established for that cancer and setting and that unnecessary CTLA-4 inhibition with related toxic effects (both clinical and financial) can be avoided.
| S-EPMC10472261 | biostudies-literature
Project description:BackgroundIn a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.MethodsIn this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors.ResultsAmong patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication.ConclusionsThe objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).
| S-EPMC5744258 | biostudies-literature
Project description:BackgroundThe combination of nivolumab and ipilimumab is approved in several jurisdictions (United States, European Union, Canada) for the first-line treatment of patients with advanced melanoma. CheckMate 218 is a North American expanded-access program (eap) of nivolumab plus ipilimumab in patients with advanced melanoma. Here, we report safety and survival outcomes for the Canadian cohort in the eap.MethodsEligible patients were those 18 years of age or older with unresectable stage iii or iv melanoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior anti-PD-1 or anti-ctla-4 therapy. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction phase); they then continued with nivolumab 3 mg/kg every 2 weeks (maintenance phase) until progression, unacceptable toxicity, or a maximum of 48 weeks, whichever occurred first. Safety and overall survival (os) data were collected.ResultsOf 194 patients enrolled, 174 were treated, and 51% continued on nivolumab maintenance. Median follow-up was 12.9 months. All-grade and grades 3-4 treatment-related adverse events were reported in 98% and 60% of patients respectively and led to treatment discontinuation in 40% and 28% of patients. Two treatment-related deaths were reported. The 12- and 18-month os rates were 80% [95% confidence interval (ci): 73% to 86%] and 76% (95% ci: 67% to 82%) respectively.ConclusionsIn this Canadian population, nivolumab plus ipilimumab demonstrated a safety profile and survival outcomes consistent with phase ii and iii clinical trial data.
| S-EPMC7467793 | biostudies-literature
Project description:BackgroundStandard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma followed by nivolumab single-agent maintenance therapy. While many patients receive less than 4 doses due to immune-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and assess if fewer doses of I/N can lead to similar survival outcomes.MethodsWe performed a retrospective analysis on a cohort of patients with advanced melanoma who w0ere treated with standard I/N. Cox regression of progression-free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 1 or 2 vs 3 or 4 doses of I/N adjusted by known prognostic variables in advanced melanoma.Results199 patients were evaluated. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.16, 95% CI 0.08-0.33; p<0.001) and OS (HR: 0.12, 0.05-0.32; p<0.001) compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.09, 0.05-0.16; p<0.001) and OS (HR: 0.07, 0.03-0.14; p<0.001). There was no survival risk difference comparing 1 or 2 vs 3 or 4 doses of I/N for PFS (HR: 0.95, 0.37-2.48; p=0.921) and OS (HR: 1.04, 0.22-4.78; p=0.965).ConclusionsEarly interval imaging with response during induction with I/N may be predictive of long-term survival in advanced stage melanoma. CBR after 1 or 2 doses of I/N is associated with favorable survival outcomes, even in the setting of fewer I/N doses received. Further studies are warranted to evaluate if electively administering fewer combination I/N doses despite tolerance in select patients may balance the benefits of therapy while decreasing toxicities.
| S-EPMC9296775 | biostudies-literature
Project description:Proton pump inhibitors (PPIs) are commonly used as a supplement to cancer therapy. Yet, their effect on cancer mortality is largely unknown. Using data from Danish nationwide registries and Cox models regressing of both propensity scores and drug use, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer-specific and noncancer death among PPI users (≥2 prescriptions within six months after diagnosis; n = 36,066) compared with nonusers (<2 prescriptions, n = 311,853) or users of histamine H2 -receptor antagonists (H2 RA; n = 5,152). Adjusted HRs for cancer-specific mortality among postdiagnostic PPI users as compared with nonusers or H2 RA users were 1.29 (95% CI, 1.27-1.32) and 1.15 (95% CI, 1.10-1.20), respectively. HRs for cancer mortality associated with PPI use were highest for ovarian (1.35; 95% CI, 1.20-1.52) and lowest for esophageal cancer (0.91; 95% CI, 0.81-1.04). The associations were stronger among new PPI users after cancer diagnosis, indicating potential confounding. To test the effect of PPIs on tumor growth in a model system free for confounding factors, we investigated the effect of pantoprazole on tumor growth in mice. Pantoprazole (5 mg/kg/day) enhanced tumor growth (p = 0.033) and reduced the antitumor activity of gemcitabine (p = 0.008) in fibrosarcoma-bearing Balb/c mice, but not in immunodeficient Balb/c nude mice. In breast carcinoma-bearing FVB/N mice, pantoprazole had no effect on tumor growth alone but it reduced the life-prolonging effect of doxorubicin significantly (p = 0.007). Taken together, these data raise concerns about the increasing use of PPIs and calls for further studies addressing their safety among cancer patients.
| S-EPMC7611279 | biostudies-literature