A fast-moving field replete with blockbuster potential
Immune checkpoint inhibitor therapies block the pathways that cancers use to evade destruction by the immune system. The development of this field continues to progress apace, with new agents entering development and existing drugs gaining new approvals and market entries. The most successful of these are attaining blockbuster status, often very soon after their market entry. Opdivo and Keytruda entered the market in 2014 and achieved blockbuster status (> $1 billion in annual sales) in 2016, Tecentriq entered in 2016 and is forecast to hit blockbuster status by 2018, and Imfinzi and Bavencio entered in 2017 with blockbuster status forecast for 2019 and 2021, respectively. The eight immune checkpoint inhibitors in the table below are forecast to bring in combined annual sales topping $34 billion by 2022 (Source: Thomson Reuters I/B/E/S).
|NAME||GENERIC NAME||TARGET||DEVELOPER||MARKET ENTRY||2022 FORECAST (US $ BILLIONS)|
|Yervoy||ipilimumab||CTLA-4||Bristol-Myers Squib / Ono||2011||2.271|
|Keytruda||pembrolizumab||PD-1||Merck & Co||2014||10.664|
|Opdivo||nivolumab||PD-1||Bristol-Myers Squib / Ono||2014||11.222|
|Imfinzi||durvalumab||PD-L1||AstraZeneca / Celgene||2017||2.778|
|Bavencio||avelumab||PD-L1||Merck KGaA / Pfizer||2017||0.590|
|MEDI-1123||tremelimumab||CTLA-4||Pfizer / AstraZeneca||Phase III||0.895|
Keytruda and Opdivo, which are each forecast to earn more than $10 billion in 2022, were both discussed in our 2015 Drugs to Watch report, which highlights potential blockbusters entering the market that year, while Imfinzi and Bavencio are two of the eight drugs to watch in 2017. (Download the “2017 Drugs to Watch” report here.) The wealth of new developments in the immune checkpoint inhibitor field since the publication of that report just a few months ago demonstrates how fast-paced this field is. May 2017 alone saw the approval of five new indications for these drugs, plus the acceptance for regulatory review of two further indication filings. The approvals included a ground-breaking first (the approval of a drug for the treatment of a solid tumor based on its genetic signature rather than tumor type) and a new drug entering the field.
Keytruda: the first approval based on genetic features rather than tumor location
Until this ground-breaking approval, cancer drugs were indicated for use based on tumor location, for example in the lung, or pancreas, or colon. May 2017 saw the first ever approval by the FDA of a drug to treat any solid tumor that has a given type of genetic signature – microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in this case. Tumor types with these biomarkers include colorectal, endometrial, pancreatic and gastrointestinal cancers.
Keytruda also approved in first-line NSCLC regardless of PD-L1 status
Keytruda entered the non-small-cell lung cancer (NSCLC) market in October 2015 with approval for the salvage treatment of metastatic NSCLC that expressed the biomarker PD-L1. A year later, approval was extended to first-line treatment of metastatic NSCLC with high PD-L1 expression. In May 2017, the approval was further extended, this time to allow first-line treatment in combination with chemotherapy of all metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression levels. To date, Keytruda is the only PD-1/PD-L1 checkpoint inhibitor approved in this setting.
Imfinzi, Keytruda and Bavencio join Tecentriq and Opdivo in the bladder cancer market
Also occurring in May 2017 were the approvals of three checkpoint inhibitors for urothelial carcinoma, joining the two already available for that indication. Imfinzi’s approval for the second-line treatment of urothelial carcinoma represented its first approval and launch onto the market. Both Keytruda and Bavencio were also approved for second-line use, and Keytruda was additionally approved for first-line use. Bladder cancer is the fifth most common cancer in the U.S., with an estimated 77,000 new diagnoses in 2016; urothelial carcinoma accounts for approximately 90% of diagnoses. The new entrants will compete for market share with Tecentriq, which in May 2016 became the first FDA-approved treatment for patients with a specific type of bladder cancer in more than 30 years, and in April 2017 the first immunotherapy in the first-line setting, and with Opdivo, which entered in the second-line setting in February 2017.
Opdivo accepted for U.S. review for second-line hepatocellular carcinoma
Opdivo, already on the market for a number of cancer indications, had its filing for approval for the second-line treatment of hepatocellular carcinoma (HCC) accepted for FDA review in May 2017, with a decision on approval expected in September 2017. HCC is the most common type of liver cancer; worldwide it affects more than 700,000 people annually and is the second most frequent cause of cancer death. Development of Opdivo in the first-line HCC setting is also ongoing.
Keytruda accepted for U.S. review for gastric or gastroesophageal junction adenocarcinoma
Keytruda had a particularly successful 2Q17, gaining not just the approvals described above, but also the acceptance for review of a filing for gastric or gastroesophageal junction adenocarcinoma. The FDA’s decision regarding approval is expected in September 2017. Worldwide, gastric cancer is the fifth most common cancer with about 950,000 patients diagnosed annually, and the third leading cause of cancer death with about 720,000 deaths reported worldwide every year.
Not all news is positive for Keytruda – myeloma deaths
Despite the raft of positive Keytruda news, not all of the recent updates have been so encouraging. In June 2017, Merck & Co announced that it had paused enrollment in two phase III trials for multiple myeloma, after more reports of death in the Keytruda groups. KEYNOTE-183 is assessing third-line use of Keytruda plus Pomalyst (pomalidamide) and dexamethasone, while KEYNOTE-185 is assessing Keytruda plus Revlimid (lenalidomide) and dexamethasone in the first-line setting. It remains to be seen what further analysis of the data will show.
ASCO sees positive mesothelioma data for Opdivo and Yervoy
Earlier in June 2017, Opdivo and Yervoy showed promise against malignant pleural mesothelioma, an incurable cancer with a 100% relapse rate for initial chemotherapy and a median life expectancy of just 13 to 15 months. Data from the phase II MAPS2 trial, reported at the 53rd annual meeting of the American Society of Clinical Oncology (ASCO), showed a 12-week disease control rate in the second- or third-line setting of 44% for Opdivo, and 50% for Opdivo plus Yervoy. This compares with a disease control rate of less than 30% for all previously tested treatments. The ongoing trial is expected to complete in December 2018, while the phase III CheckMate743 trial assessing the combination as a first-line mesothelioma treatment, which began in October 2016, is to run until August 2021.
Mixed data for INCB-24360 at ASCO
Incyte’s IDO checkpoint inhibitor INCB-24360 showed a mixed set of data at this year’s ASCO, with limited efficacy in some solid tumor types, but more promising results in the second-line treatment of NSCLC. Although the breast and ovarian cancer data from the phase I/II ECHO-202 trial of INCB-24360 in combination with Keytruda were marginal (development in these indications has been discontinued), the data from the NSCLC patients showed an overall response rate of 35% – a significant improvement over Keytruda monotherapy in that setting. Further, the combination appeared effective regardless of PD-L1 expression and was well tolerated. Positive effects had also been seen in melanoma and renal cell carcinoma.
These data highlight the possibility of combined PD-1/IDO inhibition as an alternative to less-well tolerated combined PD-1/CTLA-4 inhibition, which is the only immuno-oncology combination currently approved (as Opdivo plus Yervoy for melanoma). Phase III development of INCB-24360 plus Keytruda began in 2016, with the phase III ECHO-301 trial for melanoma, and further phase III studies are planned: for INCB-24360 plus Keytruda in first-line NSCLC, first- and second-line bladder cancer, first-line renal cell carcinoma and first-line squamous cell carcinoma of the head and neck; and for INCB-24360 plus Opdivo in first-line head and neck cancer and first-line NSCLC.
The checkpoint inhibitor field, and indeed the whole of immuno-oncology, is fast-paced and fascinating, with huge clinical and commercial potential. The challenge in the coming years will be to define the best type and combination of immuno-therapy, and the best target population to receive it. Keytruda’s groundbreaking approval for a biomarker-based rather than location-based indication is a solid step in this direction, and is likely to be followed by other such approvals. As the field develops, it is to be hoped that immuno-oncology therapeutics will continue to deliver the significant improvements in patient outcome that have been seen so far.