Anticancer agent – nivolumab

Published: 6-Nov-2014

Although new drugs have reached patients with melanoma recently, when treatment fails few options remain


Melanoma is a particularly challenging cancer to treat, particularly after it has progressed. Although new drugs have reached patients recently, notably two BRAF inhibitors and a CTLA-4 inhibitor, when treatment fails few options remain. A new antibody that may have potential in pre-treated melanoma patients, nivolumab, is being developed by Bristol-Myers Squibb.

The drug is a fully human IgG4 monoclonal antibody that blocks the programmed cell death 1, or PD-1, receptor. The immune checkpoint inhibitor antibody releases the ‘brake’ the tumour places on the immune system, allowing it to attack cancerous cells once more, leading to tumour shrinkage.1

Several clinical trials have been carried out. In one, it was investigated in combination with a multipeptide vaccine.2 In the Phase I study, 90 patients with unresectable stage III or IV melanoma who had progressed after at least one prior therapy but who had not been treated with ipilimumab, or who had progressed after imilimumab were given 1, 3 or 10mg/kg every two weeks for 24 weeks and then every 12 weeks for up to two years, either with or without a multipeptide vaccine. The response rate for both groups was 25%, and higher pretreatment was associated with disease progression. Nivolumab was well tolerated at 3mg/kg, either with or without the peptide vaccine, and the responses induced lasted up to 140 weeks. The trial results support either concurrent or sequential dosing of the two antibodies.

In another trial, 53 patients with advanced melanoma were given concurrent therapy with nivolumab and the CTLA-4 inhibitor ipilimumab, with patients being given the two antibodies every three weeks for four doses, and then nivolumab alone for a further four three-weekly doses. They then received the combined treatment every 12 weeks for up to eight doses.

Another 33 patients who had previously received ipilimumab treatment were given sequenced treatment, receiving nivolumab every two weeks for up to 48 doses. For patients in the group dosed concurrently, the objective response rate was 40%, and 65% achieved stable disease or a conventional, unconfirmed or immune-related response after six months. At the maximum tolerated dose of 1mg/kg for nivolumab and 3mg/kg for ipilimumab, 53% had an objective response, with tumour reduction of at least 80%.3

A further trial in 107 patients with advanced melanoma involved intravenous nivolumab dosing every two weeks for up to 96 weeks.4 The median overall survival was 17 months, with a one-year survival rate of 62% and two-year of 43%. The estimated median response duration in the 33 patients whose tumours receded was two years. Responses continued after therapy stopped, and the long-term safety was good.

Preliminary data on an open label Phase III trial were reported at this year’s ESMO meeting.5 A group of 405 patients with unresectable metastatic melanoma who had progressed after ipilimumab treatment were given 3mg/kg nivolumab, darcbazine or carboplatin plus paclitaxel until progression or unacceptable toxicity occurred. There was a 32% response rate in the group given the antibody, compared with 11% in the chemotherapy control arm.

The company plans to file for approval on the basis of these results. Trials are also underway in non-small cell lung cancer and renal cell carcinoma.

References

1. C. Wang et al. Cancer Immunol. Res. 2014, 2, 846

2. J.S. Weber et al. J. Clin. Oncol. 2013, 31, 4311

3. J.D. Wolchok et al. N. Engl. J. Med. 2013, 369, 122

4. S.L. Topalian et al. J. Clin. Oncol. 2014, 32, 1020

5. J.S. Weber et al. ESMO Congress (Madrid, Spain, September 2014), Abst. LBA3_PR

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