In September a study presented at the European Cancer Congress showed that some patients, who took Yervoy, a drug made by Bristol-Myers Squibb (NYSE:BMY) and Ono Pharma, lived for 10 years with melanoma.
In the pre-Yervoy era, patients with advanced metastatic melanoma survived 10 to 11 months on the average.
The data showed a plateau in overall survival with 21 percent of patients alive at 3 years, 17 percent still alive after 7 years, and no deaths after that. The longest follow-up in the database was 9.9 years.
The long-term numbers came from a pooled analysis of patient data collected from 12 clinical trials during development of the drug (1861 patients), and from an expanded access program in which patients were treated before it was approved ( 2985 patients).
Yervoy was given every 3 weeks in a total of 4 doses, and most studies included the option for patients to receive a maintenance therapy.
For the length of life expectancy none of the variables seem to have mattered. The plateau, which started at 3 years and continued through to 10 years, was observed regardless of dose given (3 or 10 mg/kg), whether the patients had received previous treatment or not, and whether or not they had been kept on a maintenance dose of the drug. It should be emphasized that this was not a randomized comparison, so direct conclusions cannot be drawn.
During clinical trials, Yervoy, on average, added only about four months of life, but around 20 percent of patients had an amazing durable response to the drug.
In some of those patients the disease goes away, and they go into remission, and in others there is still tumor showing on the computed tomography scan, but it does not change, which means that the deadly cancer has turned into a chronic disease.
Stephen Hodi, MD, assistant professor of medicine at the Dana-Farber Cancer Institute, who presented the data, was cautious about using the term "cure", but described recent advances as a "paradigm shift".
Alexander Eggermont of the Institut Gustave Roussy Comprehensive Cancer Center in France, who specialises in the treatment of melanoma, said the results suggested some patients could be effectively cured of their cancer, with the drug helping the immune system to keep the disease in check.
Eggermont said, at the site linked to above:
"Patients apparently can keep residual tumors under control for a long time when the immune system is properly 'reset', and the concept of 'clinical cures' becomes a reality."
He predicted that these survival results will improve further with the anti-PD1/PDL1 monoclonal antibodies that are in development.
Yervoy has been approved in 2011 in the U.S. and in Europe.
It has a novel mechanism of action, interfering with the immune system instead of acting directly on the cancer. It targets CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), a protein found on the surface of T cells (the immune fighters of the body) that acts like a brake. The drug removes the brake, allowing the T cell to go into attack mode and kill cancer cells. The drug is typically given as a course of 4 injections during a period of 3 months, and some patients also receive retreatment or maintenance therapy.
For a small group of the patients, it seems that this short treatment is enough to reset the immune system and reach a new balance.
The cost of Yervoy in the U.S. varies widely by hospitals and insurance companies. The wholesale price of Yervoy in the U.S. is $29,232 per infusion of a 200 mg vial. The actual price at pharmacies and hospitals may be much higher.
Yervoy is part of a new generation of very expensive cancer drugs. The mounting price tags have payers and health officials concerned about society's ability to pay, and patients' ability to foot their share of the bill, which can be substantial.
In spite of all the excitement surrounding the long-term survival, the overall response rate to Yervoy is low: only about 10 to 15 percent of all patients respond.
Also, immunotherapy in melanoma is not competitive with targeted therapies, such as BRAF inhibitors (like Roche's Zelboraf) for the 50 percent or so of patients whose tumors are BRAF-positive.
Next generation of drugs
Bristol-Myers Squibb is conducting late stage trials of its next-generation drug, nivolumab, in advanced melanoma, while rival Merck (NYSE:MRK) is developing a competitor, MK-3475, which in early-stage trials helped shrink tumors in 38 percent of advanced melanoma patients.
Roche (OTC:RCHBF) also has a contender, MPDL3280A in this class.
Nivolumab: Long-term data from nivolumab's Phase 1 trial were presented during the 2013 American Society of Clinical Oncology Annual Meeting in Chicago in June by Suzanne L. Topalian, MD.
Benefits in overall response rates and survival were evident in patients with three different cancers: advanced melanoma, NSCLC (non-small cell lung cancer) and RCC (renal cell carcinoma), with the most dramatic results seen in melanoma.
The overall response rates were 31 percent for patients with melanoma, 29 percent for those with RCC, and 17 percent for participants with NSCLC.
The results represent long-term efficacy data involving 306 patients who received nivolumab from 2008-2012, with at least 14 months' follow-up. The participants had a median age of 63 years and nearly half had received three or more prior therapies.
Intravenous doses of nivolumab and Yervoy were administered in every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses. The combined treatment was subsequently administered every 12 weeks for up to 8 doses.
In a sequenced regimen, a group of patients previously treated with Yervoy received nivolumab every 2 weeks for up to 48 doses.
A total of 53 patients received concurrent therapy with nivolumab and Yervoy, and 33 received sequenced treatment.
The objective-response rate, as defined by World Health Organization criteria, for all patients in the concurrent-regimen group was 40 percent. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for 24 weeks) was observed in 65 percent of patients.
At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and Yervoy at a dose of 3 mg per kilogram), 53 percent of patients had an objective response, all with tumor reduction of 80 percent or more.
Nivolumab is an anti-PD-1 drug.
The PD-1 (programmed death 1) protein and its signaling molecule PD-L1 prevent the body's immune system from attacking and killing cancer cells and this allows the cancer to spread. Anti-PD1/PDL1 monoclonal antibodies work by blocking the interaction between PD-L1 and the immune system, thereby boosting a patient's anti-cancer immune response.
Yervoy's survival results could double or even triple with the new anti-PD1/PDL1 monoclonal antibodies, and metastatic melanoma could become a curable disease for perhaps more than half of all patients over the coming 5-10 years.
Bristol-Myers Squibb posted second quarter sales of $4.0 billion, a decline of 9 percent from same period a year ago, due to the U.S. patent expiration of Avapro and Plavix in May 2012. Excluding Plavix and Avapro, sales grew by 10 percent.
The company reported net earnings of $536 million, or $0.32 per share, in the quarter compared to $645 million, or $0.38 per share, a year ago.
As of June 30, cash and cash equivalents were $6.0 billion, with a net debt position of $1.2 billion.
Bristol-Myers Squibb's sales in the second quarter were driven by Yervoy, which grew 44 percent, Onglyza, which grew 40 percent, Sprycel, which grew 28 percent, and Orencia, which grew 21 percent.
Yervoy's worldwide sales for the 6 months ending June 30 were $462 million, up 46 percent year-over-year. Eliquis and the diabetes franchise did not get the results the company expected and improvements are needed.
The company revises its full year non-GAAP earnings per share guidance to a range of $1.70 - $1.78. 2013 sales are expected to be between $16.0 to $16.5 billion.
Cancer immunotherapy is now a major new direction for Bristol. The company aggressively invests in its cancer immunotherapy program that started out with Yervoy and in which Bristol now has a leadership position.
CEO Lamberto Andreotti said this at the July earnings call:
Yervoy is performing well in all markets and we continue to develop it in new indications. We have seven potential registrational trials underway on Nivolumab in three separate cancer types, renal, lungs, and melanoma. And we are considering additional tumors, and we have other products at an earlier stage of development.
Significance is the fact that we are developing our immuno-oncology assets in both monotherapy and combination and at ASCO we presented the results ... combining Nivolumab and Yervoy in patients with advanced melanoma in the first such clinical trial... Simply stated the results of this Phase 1 trial were striking.
We will continue as I said to devote significant resources to our exciting immuno-oncology program.