A 60 percent response rate in melanoma would have sounded fanciful a generation ago. In a phase 2 study called CheckMate-069, the combination of Bristol-Myers Squibb’s Opdivo and Yervoy produced an objective response rate of 60 percent, against 11 percent for Yervoy by itself, among patients whose tumours lacked a BRAF mutation. Regulators in the United States granted accelerated approval, a first for any immunotherapy pairing in cancer.
How the drugs work
These are checkpoint inhibitors. The immune system carries its own brakes, and tumours learn to lean on them. Keytruda (pembrolizumab), from Merck, targets a protein called PD-1 on immune cells. That protein stops T cells from recognising and attacking cancer cells. ScienceDaily described the drug as one that, in effect, “cuts the brake lines.”
The FDA approved Keytruda for advanced melanoma on 4 September 2014 after testing on more than 600 patients whose cancer had spread. It had breakthrough therapy status, which allowed it to be fast-tracked. Dr. Antoni Ribas of UCLA, who led the study, said: “This drug is a game changer.” Opdivo (nivolumab), another PD-1 inhibitor, joined the market in the same year.
Yervoy came first
The older drug in this group blocks a different brake. Yervoy (ipilimumab) is a CTLA-4 inhibitor, and pharmaphorum reported that it reached the market in 2011, the first checkpoint inhibitor to do so. By the first half of the year in which the combination was cleared, Yervoy had sales of $621 million, while Opdivo had brought in $162 million.
The pairing worked better than either drug alone. Without progression, patients on Yervoy alone lasted a median of 2.9 months, those on Opdivo 6.9, and those on both drugs 11.5. CURE reported a 60 percent lower risk of the disease progressing or the patient dying, set against Yervoy by itself, in that phase 2 trial.
There was a cost, in two senses. A third of patients on the two drugs stopped treatment because of serious side effects, among them colitis, diarrhoea and rash. And the price: around $250,000 for the first full year and $150,000 thereafter. Leonard Saltz of Memorial Sloan Kettering warned at the American Society of Clinical Oncology meeting that combinations could eventually push treatment costs towards $1 million a year. Express Scripts called the rising trend unsustainable.
A second target
Roche’s Tecentriq (atezolizumab) took a different route. It targets PD-L1, a protein on tumour cells that can restrain the immune response. The FDA approved it on May 18, 2016 for some patients with urothelial carcinoma, the most common type of bladder cancer, the first new treatment for that disease in two decades.
The record also carries a caution. On March 8, 2021, Roche voluntarily withdrew the indication for previously treated metastatic bladder cancer in the United States, after confirmatory trials did not meet their primary endpoints of improved overall survival. Consult your doctor about treatment options.
Sources
- FDA approves new game changing drug to fight melanoma | ScienceDaily
- BMS gets green light in US for Opdivo/Yervoy combination | pharmaphorum
- FDA Approves Opdivo-Yervoy Combination for Melanoma | CURE
- Atezolizumab for Bladder Cancer – NCI
