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Opdivo + Yervoy as the first immunotherapy treatment for previously untreated unresectable malignant pleural mesothelioma, FDA approved


The U.S. Food and Drug Administration ( FDA ) has approved Opdivo ( Nivolumab ) 360 mg every three weeks plus Yervoy ( Ipilimumab ) 1 mg/kg every six weeks ( injections for intravenous use ) for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma ( MPM ).

This approval is based on a pre-specified interim analysis from the phase 3 CheckMate -743 trial in which the combination of Nivolumab and Ipilimumab ( n=303 ) has demonstrated superior overall survival ( OS ) versus the Platinum-based standard of care chemotherapy ( n=302 ) ( hazard ratio [ HR ]: 0.74 [ 95% confidence interval [ CI ]: 0.61 to 0.89 ]; P=0.002 ), with a median overall survival ( mOS ) of 18.1 months ( 95% CI: 16.8 to 21.5 ) versus 14.1 months ( 95% CI: 12.5 to 16.2 ), respectively.
These results were observed after 22.1 months of minimum follow-up.
At two years, 41% of patients treated with Nivolumab + Ipilimumab were alive and 27% with chemotherapy.

This approval was granted less than six weeks following the submission of a new supplemental Biologics License Application ( sBLA ), which was reviewed under the FDA’s Real-Time Oncology Review ( RTOR ) pilot program.
The RTOR program aims to ensure that safe and effective treatments are available to patients as early as possible.

CheckMate -743 is an open-label, multi-center, randomized phase 3 trial evaluating Nivolumab plus Ipilimumab compared to chemotherapy ( Pemetrexed and Cisplatin or Carboplatin ) in patients with histologically confirmed unresectable malignant pleural mesothelioma and no prior systemic therapy or palliative radiotherapy within 14 days of initiation of therapy ( n=605 ).
Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.
In the trial, 303 patients were randomized to receive Nivolumab 3 mg/kg every two weeks and Ipilimumab 1 mg/kg every six weeks; 302 patients were randomized to receive Cisplatin 75 mg/m2 or Carboplatin AUC 5 plus Pemetrexed 500 mg/m2 in 3-week cycles for six cycles.
Treatment in both arms continued until disease progression or unacceptable toxicity or, in the Nivolumab + Ipilimumab arm, up to 24 months.
The primary endpoint of the trial was overall survival in all randomized patients. Additional efficacy outcome measures included progression-free survival ( PFS ), objective response rate ( ORR ) and duration of response ( DOR ), as assessed by BICR utilizing modified RECIST criteria.

Treatment was permanently discontinued for adverse reactions in 23% of patients treated with Nivolumab + Ipilimumab, and 52% had at least one dose withheld for an adverse reaction.
An additional 4.7% of patients permanently discontinued Ipilimumab alone due to adverse reactions.

Serious adverse reactions occurred in 54% of patients receiving Nivolumab + Ipilimumab. The most frequent ( 2% or more ) serious adverse reactions in patients receiving Nivolumab + Ipilimumab were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism.
Fatal adverse reactions occurred in 4 ( 1.3% ) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.
The most common ( 20% or more ) adverse reactions were fatigue ( 43% ), musculoskeletal pain ( 38% ), rash ( 34% ), diarrhea ( 32% ), dyspnea ( 27% ), nausea ( 24% ), decreased appetite ( 24% ), cough ( 23% ) and pruritus ( 21% ).
The median number of doses was 12 for Nivolumab and 4 for Ipilimumab.

Nivolumab + Ipilimumab is a unique combination of two immune checkpoint inhibitors that features a potentially synergistic mechanism of action, targeting two different checkpoints ( PD-1 and CTLA-4 ) to help destroy tumor cells: Ipilimumab helps activate and proliferate T cells, while Nivolumab helps existing T cells discover the tumor.
Some of the T cells stimulated by Ipilimumab can become memory T cells, which may allow for a long-term immune response.
Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.

Mesothelioma is a rare but aggressive form of cancer that often forms in the lining of the lungs.
There are approximately 3,000 cases diagnosed in the United States each year.
Malignant pleural mesothelioma is the most common type of the disease. It is most frequently caused by exposure to asbestos and diagnosis is often delayed, with the majority of patients presenting with advanced disease.
Prognosis is generally poor: in patients with advanced malignant pleural mesothelioma, median survival is approximately one year and the five-year survival rate is approximately 10%. ( Xagena )

Source: Bristol Myers Squibb, 2020

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