ASCO: Dispatches from the frontline against cancer
pharmafile | July 22, 2013 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | ASCO, McConaghie
The growing promise of pharma’s immunotherapy pipeline for cancer was undoubtedly the hottest topic at this year’s ASCO conference. |
The class of compounds generating the most anticipation is the PD-1 inhibitor drugs. As in most immunotherapy treatments, these new compounds work by helping the body’s own immune system to identify and fight the cancer itself.
However, where many immunotherapies have so far produced limited efficacy and sometimes severe side effects, the PD-1s look set to overcome these obstacles.
Researchers have discovered that several tumour types can use a kind of ‘molecular camouflage’ which conceals them from the body’s immune system, which would otherwise identify and destroy them.
PD-1 (Programmed Death 1) is an ‘immune checkpoint receptor’ and by disrupting its action, the drugs allow the cancer cells to be ‘revealed’ to the T-cells, which then attack the cancer.
Three major pharma companies have a PD-1 inhibitor in development – BMS, Merck and Roche. Bristol-Myers Squibb’s nivolumab and Merck’s lambrolizumab (MK-3475) are both being studied in advanced melanoma, while Roche’s MPDL3280A about to enter pivotal studies in NSCLC.
Building on Yervoy’s advance
The first indication both Merck and BMS are aiming for is the advanced melanoma market, a field where BMS’s own Yervoy has helped transform treatment options for patients since its launch in 2011.
Merck’s lambrolizumab is now in a Phase II study versus standard chemotherapy for patients with advanced melanoma whose disease has progressed after prior therapy.
A Phase I trial showed the drug helped some patients who had failed to respond to prior treatment, including Yervoy (ipilimumab). These early signs that lambrolizumab could help advance melanoma treatment beyond Yervoy helped it gain the new ‘Breakthrough Therapy’ designation from the FDA in April this year.
Further late-stage studies including a Phase III study evaluating lambrolizumab in ipilimumab-naïve patients with advanced melanoma, and a Phase II/III trial in non-small cell lung cancer (NSCLC) are scheduled to commence in the third quarter of 2013.
Additional trials in several haematological cancers and evaluation of lambrolizumab-containing combinations are scheduled to start this year.
Nivolumab – potential market leader
Despite Merck’s compound being the only one of three PD-1 inhibitors to be given ‘breakthrough’ status so far, BMS’ nivolumab is currently the candidate expected to do best on the market.
‘Truly remarkable’ data
The key trial presented by the firm at ASCO (and published in the New England Journal of Medicine) centred on nivolumab’s combination with ipilimumab in the Phase I study, Study 004. The results suggest the combination has broken new ground in metastatic melanoma, producing durable tumour shrinkage in about half of patients in the Phase I study.
This response rate is a significant advance on Yervoy alone, which has typically produced a response in just 11% of patients.
Study 004 is a dose-ranging Phase I trial of 86 patients, evaluating the safety and anti-tumour activity of the drug combined either concurrently (n=53) or sequentially (n=33) with Yervoy (ipilimumab) in patients with advanced melanoma.
In patients who received the higher dose used in the Phase III trial in the concurrent regimen, 53% (n=9 of 17) had confirmed objective responses (OR) by mWHO criteria.
In all nine of these responders, tumours shrank by at least 80% by the time of the first scheduled clinical treatment assessment (12 weeks), including three complete responses (CRs). In response-evaluable patients across all concurrent cohorts, 40% (n=21 of 52) had an OR.
Sixteen patients (31%) had tumour shrinkage of at least 80% by the time of the first clinical trial assessment, including five CRs. Responses were ongoing among 19 of 21 responders, with responses lasting from between 6.1+ to 72.1+ weeks at the time of data analysis.
Median overall survival has not been reached after approximately 13 months of median follow up in the concurrent cohorts. The estimated one-year survival rate across all concurrent cohorts was 82% (95% CI 69.0 – 94.4 per cent).
The objective response rate with the combination was higher than in earlier trials of the two drugs used alone, said lead investigator Jedd Wolchok, MD, from the Memorial Sloan-Kettering Cancer Center in New York City.
Sandra Swain, MD, outgoing president of ASCO, picked out the results as one of her highlights from the conference. “This is truly remarkable,” said Swain. “This kind of response has not been seen with immunotherapy before.”
A Phase III trial of nivolumab in combination with Yervoy in advanced melanoma is now underway, which analysts predict could eventually result in FDA approval by late 2014.
The FDA has granted nivolumab a fast-track designation for three tumour types: a form of lung cancer, renal cell carcinoma and advanced melanoma, and these are likely to be the key battlegrounds for the PD-1s.
The ASCO data prompted Goldman Sachs to predict peak sales of $7 billion for nivolumab across its numerous potential indications.
Non-small cell lung cancer
In the longer term, the biggest prize is likely not to be in melanoma, but in lung cancer. Non-small cell lung cancer (NSCLC) is far more common than melanoma, but similarly lacking in current effective treatment, making any genuine ‘breakthrough’ a major earner.
Roche and its biotech arm Genentech have chosen to prioritise NSCLC, and are initiating pivotal studies their MPDL3280A in these patients. The studies will incorporate an investigational companion diagnostic. MPDL3280A will also be studied in other cancer types, alone and in combination with other medicines, including Avastin (bevacizumab) and Zelboraf (vemurafenib).
Cornerstone of future cancer therapy?
The level of excitement about PD-1s among investors and analysts continues to rise, with some suggesting that these treatments and other immunotherapies will come to dominate the oncology market.
Citi senior analyst Andrew Baum released a note earlier this year predicting that immunotherapy will be the foundation for 60% of all cancer treatment regimens in the developed world within 10 years. This could translate into revenue of more than $35 billion for the industry by 2023.
“Rapidly accelerating advances in immunotherapy make it a potential tool to transform a significant percentage of cancers into something akin to a chronic disease,” wrote Baum.
While it seems certain that the age of immunotherapy is just around the corner, the frontrunners in the PD-1 still have much to prove in their Phase III trials, which will begin to produce results within 12 months.
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