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Ipilimumab: its potential in non-small cell lung cancer.

ABSTRACT: Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising results in a first-line NSCLC phase II study combining carboplatin/paclitaxel chemotherapy with concurrent or phased ipilimumab. The median immune-related progression-free survival was 5.68 months for the phased ipilimumab arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and 5.52 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). The main adverse events were immune related, such as hypophysitis, enterocolitis, and hyperthyroidism. These adverse events may be improved with high-dose glucocorticoids and may be correlated with tumor response. Phase III studies are ongoing. Future studies may investigate ipilimumab in the management of early stage lung cancer. Strategies for potential translational research studies are also discussed to identify prognostic and predictive biomarkers for the use of ipilimumab in the treatment of patients with NSCLC.

SUBMITTER: Tomasini P

PROVIDER: S-EPMC3296082 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Ipilimumab: its potential in non-small cell lung cancer.

Tomasini Pascale P Khobta Nataliya N Greillier Laurent L Barlesi Fabrice F

Therapeutic advances in medical oncology 20120301 2

Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising resu ...[more]

PMID: 22423263

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Project description:We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations. Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Project description:ImportanceTreatment with nivolumab-ipilimumab combination therapy was found to improve overall survival compared with chemotherapy among patients with advanced non-small cell lung cancer (NSCLC) in the CheckMate 227 clinical trial. However, these drugs are substantially more expensive than chemotherapy and, given the high incidence of advanced NSCLC, the incorporation of dual immune checkpoint inhibitors into the standard of care could have substantial economic consequences.ObjectiveTo assess whether nivolumab-ipilimumab combination therapy is a cost-effective first-line treatment for patients with advanced NSCLC.Design, setting, and participantsThis economic evaluation designed a Markov model to compare the cost-effectiveness of nivolumab-ipilimumab combination therapy with platinum-doublet chemotherapy as first-line treatment for patients with advanced NSCLC. The Markov model was created to simulate patients with advanced NSCLC who were receiving either nivolumab-ipilimumab combination therapy or platinum-doublet chemotherapy. Transition probabilities, including disease progression, survival, and treatment toxic effects, were derived using data from the CheckMate 227 clinical trial. Costs and health utilities were obtained from published literature. Data analyses were conducted from November 2019 to September 2020.ExposuresNivolumab-ipilimumab combination therapy.Main outcomes and measuresThe primary study outcomes were quality-adjusted life-years (QALYs) and cost in 2020 US dollars. Cost-effectiveness was measured using an incremental cost-effectiveness ratio (ICER), with an ICER less than $100 000 per QALY considered cost-effective. Model uncertainty was assessed with 1-way and probabilistic sensitivity analyses.ResultsTreatment with nivolumab-ipilimumab combination therapy was associated with an increase in overall cost of $201 900 and improved effectiveness of 0.50 QALYs compared with chemotherapy, yielding an ICER of $401 700 per QALY. The study model was sensitive to the cost and duration of immunotherapy. Treatment with nivolumab-ipilimumab combination therapy became cost-effective when monthly treatment costs were reduced from $26 425 to $5058 (80.9% reduction) or when the maximum duration of immunotherapy was reduced from 24.0 months to 1.4 months. The model was not sensitive to assumptions about survival or programmed cell death 1 ligand 1 status. A probabilistic sensitivity analysis indicated that, at a willingness-to-pay threshold of $100 000 per QALY, nivolumab-ipilimumab combination therapy was less cost-effective than chemotherapy 99.9% of the time.Conclusions and relevanceIn this study, first-line treatment with nivolumab-ipilimumab combination therapy was not found to be cost-effective at current prices despite clinical trial data indicating that this regimen increases overall survival among patients with advanced NSCLC.

Project description:BackgroundSurgical outcomes for non-small cell lung cancer after neoadjuvant immune checkpoint inhibitors continue to be debated. We assessed perioperative outcomes of patients treated with Nivolumab or Nivolumab plus Ipilimumab (NEOSTAR) and compared them with patients treated with chemotherapy or previously untreated patients with stage I-IIIA non-small cell lung cancer.MethodsForty-four patients with stage I to IIIA non-small cell lung cancer (American Joint Committee on Cancer Staging Manual, seventh edition) were randomized to nivolumab (N; 3 mg/kg intravenously on days 1, 15, and 29; n = 23) or nivolumab with ipilimumab (NI; I, 1 mg/kg intravenously on day 1; n = 21). Curative-intent operations were planned between 3 and 6 weeks after the last dose of neoadjuvant N. Patients who completed resection upfront or after chemotherapy from the same time period were used as comparison.ResultsIn the N arm, 21 (91%) were resected on-trial, 1 underwent surgery off-trial, and one was not resected (toxicity-related). In the NI arm, 16 (76%) resections were performed on-trial, one off-trial, and 4 were not resected (none toxicity-related). Median time to operation was 31 days, and consisted of 2 (5%) pneumonectomies, 33 (89%) lobectomies, and 1 (3%) each of segmentectomy and wedge resection. The approach was 27 (73%) thoracotomy, 7 (19%) thoracoscopy, and 3 (8%) robotic-assisted. Conversion occurred in 17% (n = 2/12) of minimally invasive cases. All 37 achieved R0 resection. Pulmonary, cardiac, enteric, neurologic, and wound complications occurred in 9 (24%), 4 (11%), 2 (5%), 1 (3%), and 1 (3%) patient, respectively. The 30- and 90-day mortality rate was 0% and 2.7% (n = 1), respectively. Postoperative complication rates were comparable with lung resection upfront or after chemotherapy.ConclusionsOperating after neoadjuvant N or NI is overall safe and effective and yields perioperative outcomes similar to those achieved after chemotherapy or upfront resection.

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Ipilimumab: its potential in non-small cell lung cancer.

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Ipilimumab: its potential in non-small cell lung cancer.

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