The American Association for Cancer Research annual meeting is always a source of major news and discussion on the oncology research front, and the 2017 meeting held earlier this month was no exception.
One area of particular interest was the encouraging data on long-term survival that is emerging for some patients treated with immuno-oncology approaches. Bristol-Myers Squibb presented the first long-term survival data in patients with previously treated metastatic non-small cell lung cancer (NSCLC) from a small, early Phase 1b study of Opdivo (nivolumab). Follow-up data showed that 16% of the treated patients remained alive after 5 years, a major advance over the historic 5-year survival rate for the disease of less than 5%.
BMS also presented Phase 3 data showing that a combination of Opdivo and BMS’s CTLA4 inhibitor, Yervoy (ipilimumab), could deliver durable long-term benefits in the treatment of advanced melanoma. Sixty-four percent of patients receiving the combination therapy were alive after two years, while 59% of those receiving Opdivo alone, and 45% for Yervoy alone achieved that milestone. After at least 28 months of follow-up, median overall survival had not be reached with either the combination or Opdivo alone; median OS in the study for Yervoy alone was 20 months. There were trade-offs however: the combination therapy was much more toxic than either antibody alone, with 59% of patients experiencing Grade 3 or 4 adverse events.
Another area worth noting was the growing activity around IDO1 inhibitors, which focus on the tumor microenvironment. Incyte revealed plans to initiate eight new Phase 3 studies with its IDO1 inhibitor, epacadostat — six with Merck’s PD1-inhibitor Keytruda (pembrolizumab) and two with BMS’s Opdivo, putting the company at forefront of IO development. The planned studies span a range of solid tumors including advanced melanoma, NSCLC, and renal, bladder, and squamous head and neck cancers. All of the studies will be 50:50 cost-shared and run with Incyte’s big pharma partners.
NewLink Genetics also had news regarding its own IDO1 inhibitor, indoximod, at AACR, where the company presented data from a trial pairing its drug with Keytruda in advanced melanoma. The company reported a response rate of 52% in 66 evaluable patients, including hard to treat ocular melanoma patients, compared to a historical response rate in the low 30s% for Keytruda alone. The company said that the safety profile for the combination was similar to that associated with Keytruda alone, suggesting it may be safer to combine IDO1 and PD-1/PD-L1 inhibitors — compared to what has been seen with Yervoy (ipilimumab), BMS’s anti-CTLA4 antibody.
BMS is also developing its own IDO1 inhibitor in earlier stages of development, acquired through the company’s acquisition of Flexus Biosciences.
Clearly, the emerging long term survival data reinforces the very encouraging gains that IO drugs and combinations are making for a wide range of tumor types, including some of the most difficult to treat cancers. But the issue of limited response rates — and how to identify the most likely responders — still looms. Moreover, the therapeutic benefits of some combinations are tempered by high rates of adverse events, often severe. Also casting a shadow over the field are recent reports that in a small subset of patients, IO therapy has led not to an anticancer response, but instead to rapid tumor growth and disease progression. Clearly more work is needed to better understand and be able to identify who will benefit — and from what combinations — as well as who may be a risky candidate for IO treatment.
Also the growing activity around IDO1 inhibitors and their combination with checkpoint inhibitors and other anticancer agents only reinforces the importance for drug developers to stake a broad position for their agents in combination with other IO therapies. From a commercial perspective, the IO landscape is subject to rapid change where being first is not a guarantee of success, as new agents and/or new combinations, along with faster paths to approval, drive changes in standards at a previously unseen pace. Drug developers will need to constantly monitor market changes and adjust strategy in response, so considering the field and how it affects one’s own therapeutic programs and assets from the earliest days of the development process through to commercialization will be essential.