Adjuvant nivolumab superior to ipilimumab in surgically resected stage III/IV melanoma

September 11, 2017

Adjuvant nivolumab is superior to standard of care ipilimumab in patients with surgically resected stage III/IV melanoma who are at high risk of relapse, according to late-breaking results from the CheckMate 238 trial presented today at the ESMO 2017 Congress in Madrid (1) and published in the New England Journal of Medicine (NEJM). (2) The anti-programmed death-1 (PD-1) antibody nivolumab led to better relapse-free survival, with fewer side effects than ipilimumab.

Adjuvant therapy is given after initial cancer treatment with the goal of preventing metastases. Drugs that are effective in metastatic disease may be given as to patients who have been surgically resected of their disease and are at high risk of relapse.

Nivolumab and ipilimumab are immune checkpoint inhibitors approved for metastatic . Ipilimumab is also the Food and Drug Administration (FDA)-approved standard of care therapy for resected stage III melanoma in the US. Nivolumab was well tolerated and showed promising survival results when investigated as adjuvant therapy in a pilot study of 33 patients with resected stage IIIC and IV melanoma. (3)

The benefit shown for in metastatic disease and those pilot data provided the impetus for CheckMate 238, a randomised, double-blind, phase III trial comparing adjuvant treatment with nivolumab versus standard of care ipilimumab. The trial included 906 patients with stages IIIB, IIIC, and IV resected melanoma who had a greater than 50% risk of relapse over five years. Patients were randomised 1:1 to either treatment.

The primary endpoint was relapse-free survival. Overall survival was a secondary endpoint which will be complicated by the anticipation that patients will cross over to the alternative drug upon relapse.

The trial was stopped early by the data safety monitoring committee due to clear evidence of benefit for nivolumab. The planned interim analysis which occurred at a minimum follow-up of 18 months, presented today, shows that the rate of relapse-free survival was significantly improved with nivolumab (66.4%) compared to ipilimumab (52.7%), with a hazard ratio of 0.65 (p < 0.0001). There were similar results across prespecified subgroups of patients.

There were fewer treatment-related, clinically relevant side effects (grade 3/4) in the group treated with nivolumab (14%) compared to those treated with ipilimumab (46%). Just 10% of patients taking nivolumab had to stop treatment due to side effects compared to 43% taking ipilimumab.

First author Dr Jeffrey Weber, deputy director, Perlmutter Cancer Center, NYU Langone Health, New York, USA, said: "The results clearly show that relapse-free survival is more favourable with nivolumab. The majority of patients had higher risk disease than in most prior adjuvant melanoma trials, which makes the findings even more encouraging."

"A previous trial found that ipilimumab had a significant relapse-free and overall survival advantage compared to placebo," continued Weber. (4) "CheckMate 238 shows that nivolumab is superior to ipilimumab, so extrapolating these results, nivolumab is far better than no adjuvant treatment for high-risk melanoma. It is also much less toxic than ipilimumab."

He concluded: "Nivolumab looks like a superior adjuvant melanoma regimen compared to ipilimumab from every angle. It leads to better relapse-free survival, has fewer side effects, and is well tolerated."

Professor John Haanen, head, Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands, said: "An adjuvant trial presented at the ESMO 2016 Congress showed that ipilimumab gave an overall survival advantage over placebo but it was highly toxic. In the US it has become standard of care but this is still being debated in Europe."

Commenting on the findings presented today, he said: "The results of CheckMate 238 are very exciting. They show for the first time that an anti-PD-1 drug is superior in the adjuvant setting and because of its lower toxicity nivolumab is much easier to give than ipilimumab. The same occurs in the metastatic setting where anti-PD-1 treatment is more efficacious and has a much better safety profile and has replaced as first line treatment."

Another anti-PD-1 drug, pembrolizumab, is being tested as adjuvant therapy against placebo in with resected stage III melanoma in a phase III European Organisation for Research and Treatment of Cancer (EORTC) trial. Haanen said: "If relapse-free survival is better with pembrolizumab, it is likely that adjuvant anti-PD-1 will become standard of care for high-risk melanoma in the near future, provided an overall survival benefit is also shown."

Explore further: Ipilimumab as adjuvant therapy improves overall survival in high risk stage III melanoma

More information: References:

1 Abstract LBA8_PR 'Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238)' will be presented by Dr Jeffrey Weber during Presidential Symposium III on Monday, 11 September, 16:30 to 17:45 (CEST), in Madrid Auditorium.

2 Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. DOI: 10.1056/NEJMoa1709030

3 Gibney GT, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res. 2015;21:712-720. DOI: 10.1158/1078-0432.CCR-14-2468.

4 Eggermont AM, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845-1855.

Related Stories

Ipilimumab as adjuvant therapy improves overall survival in high risk stage III melanoma

October 8, 2016
Ipilimumab as adjuvant therapy significantly improves overall survival in patients with high risk stage III melanoma, according to the EORTC 18071 phase III trial results presented for the first time today at the ESMO 2016 ...

Drug combination shows better tolerance and effectiveness in metastatic renal cell cancer

July 26, 2017
A new cooperative research study including Norris Cotton Cancer Center's Lionel Lewis, MB BCh, MD, finds that nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses ...

Adjuvant Ipilimumab effects survival after high risk lymph node and melanoma resection

April 20, 2015
Results of an EORTC trial appearing in The Lancet Oncology show that adjuvant Ipilimumab significantly improves recurrence-free survival in patients with completely resected stage III melanoma at high risk of disease recurrence, ...

FDA approves Adjuvant Yervoy in melanoma based on results of EORTC trial 18071

November 13, 2015
Based on the results of EORTC trial 18071, the FDA expanded the approval of Yervoy (ipilimumab) in melanoma to include adjuvant treatment of patients with stage 3 melanoma at high risk of recurrence following complete resection.

Early research suggests first immunotherapy for mesothelioma on the horizon

June 5, 2017
Malignant pleural mesothelioma or MPM is a rare cancer, but its incidence has been rising. This cancer is usually associated with asbestos exposure, and patients have a median life expectancy of only 13-15 months. All patients ...

Phase II trial of ipilimumab-nivolumab combo shows promise in advanced melanoma

April 21, 2015
Giving the two immunotherapies ipilimumab and nivolumab simultaneously yielded better treatment responses than ipilimumab alone in patients with advanced melanoma who received no prior treatment, according to phase II clinical ...

Recommended for you

Alternative splicing, an important mechanism for cancer

September 22, 2017
Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances ...

'Labyrinth' chip could help monitor aggressive cancer stem cells

September 21, 2017
Inspired by the Labyrinth of Greek mythology, a new chip etched with fluid channels sends blood samples through a hydrodynamic maze to separate out rare circulating cancer cells into a relatively clean stream for analysis. ...

Whole food diet may help prevent colon cancer, other chronic conditions

September 21, 2017
A diet that includes plenty of colorful vegetables and fruits may contain compounds that can stop colon cancer and inflammatory bowel diseases in pigs, according to an international team of researchers. Understanding how ...

Drug combination may improve impact of immunotherapy in head and neck cancer

September 21, 2017
Checkpoint inhibitor-based immunotherapy has been shown to be very effective in recurrent and metastatic head and neck cancer but only in a minority of patients. University of California San Diego School of Medicine researchers ...

New kinase detection method helps identify targets for developing cancer drugs

September 21, 2017
Purdue University researchers have developed a high-throughput method for matching kinases to the proteins they phosphorylate, speeding the ability to identify multiple potential cancer drug targets.

Brain cancer growth halted by absence of protein, study finds

September 20, 2017
The growth of certain aggressive brain tumors can be halted by cutting off their access to a signaling molecule produced by the brain's nerve cells, according to a new study by researchers at the Stanford University School ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.