Some comment from UBS' analyst Jeff Elliott to the ipilimumab-related abstracts released by ASCO last night. Boldening is Elliott's. Abstracts are available at www.asco.org
ASCO data much as expected
There were 17 abstracts relating to Medarex products released in advance of the 2008 American Society for Clinical Oncology (ASCO) Annual Meeting (May 30th - June 3rd, Chicago). In our view, the most meaningful of these are the 12 discussing studies of ipilimumab in the treatment of metastatic melanoma.
In general, the data released largely supported our expectations, based on the top-line data released in December 2007 and the recent disclosure that the company would not file a BLA for ipilimumab in the 2nd-line melanoma setting. Responses rates (BORR or OR) for the 10mg/kg dose of ipilimumab in the 3 trials which were included in the original 2nd-line SPA ranged from 5.8% to 15.8%, consistent with the company’s disclosure at the top-line data release of response rates ranging from ‘mid-single digits to mid-teens’. Disease control rates (objective responses + stable disease) ranged from 27.1% to 41.4%. These results are also essentially in-line with previous observed data for ipilimumab.
As we have previously outlined, we do not believe that absolute response rate is the key indicator of efficacy for ipilimumab; rather, the durability of response and the potential for survival benefit will ultimately be the measure of success. Included in the abstracts were a number of analyses of overall survival which suggested a potential benefit when compared to historical data. The utility of these analyses is limited however, reaffirming the importance of the ongoing 1st-line, placebo-controlled trial. Studies analyzing the durability and kinetics of response were supportive of previous results and highlight ipilimumab’s unique immunomodulatory mechanism of action. Below we summarize selected abstracts and provide commentary regarding our views on the results presented.
Ipilimumab in metastatic melanoma
Abstract 3018: An analysis of long-term survival from the Phase 1/2 MDX010-015 study which originally demonstrated an 8.7% ORR and 39.1% DCR in 24 patients receiving 10mg/kg ipilimumab. 30% of patients (7/23) are still alive at 24 months, with a median OS of approximately 14.4 months. Notably, 2 patients originally characterized with progressive disease 9PD) are alive at 24 months. OS of 14.4 months compares favourably with historical treatments for metastatic melanoma. Note that this data will be updated at ASCO 2008.
Abstract 3008: A study attempting to define new response criteria better suited to the unique mechanism of ipilimumab. Investigators defined novel immune-related response criteria (irRC), which differ from more standard World Health Organization (WHO) response criteria. Under WHO criteria response rates in the 3 2nd-line trials were 5.8%, 11.1% and 15.8%, while under the irRC, response rates were 25.8%, 15.3% and 30.9%. While we agree that the unique mechanism of action of ipilimumab relative to conventional chemotherapeutics makes standard definitions of response rates somewhat less accurate, the utility of these novel criteria is not well defined. Ultimately we believe ipilimumab has good potential to demonstrate an overall survival benefit, which will ultimately be the measure of success for the product.
Abstract 3020: An analysis of patients classified as having progressive disease (PD), demonstrating the potential for late developing responses. 27% of patients classified as having PD developed irCR/PR (15%) or irSD (12%) during follow-up. The investigators conclude that new lesions (PD) may not be indicative of treatment failure. This suggests that the previously observed result of ‘late developing’ responses is repeatable, however we note again that irRC (immune-related response criteria) is not a validated endpoint and therefore conclusions may be limited.
Abstract 3022: Analysis of the immune response in the -007 trial (+/- steroid treatment). As would be expected, the immune system is activated by treatment with ipilimumab.
Abstract 9010: Results from the prophylactic steroid trial (-007, +/- budesonide) trial. As previously disclosed, budesonide did not have a material impact on immune-related adverse events.
Abstract 9021: Results from the open label 2nd-line monotherapy trial (-008). Response rate of 5.8% was the lowest seen in the 3 registrational trials included in the 2nd-line SPA. We believe this may be disappointing to the market, despite the higher rates seen in the -007 and -022 trials, given this is at the low end of previously observed response rates.
Abstract 9022: Follow-up analysis of a 72 patient ipilimumab (3mg/kg) +/- DTIC trial which previously reported ORs of 5.4% (monotherapy) and 17.1% (combination). Median OS for monotherapy patients was 351 days, for combination median OS was 386 days. In the absence of a placebo-controlled group, OS benefit is difficult to assess, highlighting the importance of the 1st-line placebo-controlled trial currently ongoing.
Abstract 9025: Results from the dose ranging study (-022) in the 2nd-line setting. Response rates increase with increasing dose (0.3 mg/kg = 0.0%, 3 mg/kg = 4.2%, 10 mg/kg = 11.1%).
Abstract 9055: An analysis of the response rates to ipilimumab when used in 1st-line or 2nd-line setting (sub-group analysis of the -007 trial). There was no significant difference in response rate between the 1st- and 2nd-line setting. This results may cast some doubt on the 1st-line trial, however as we have previously outlined, OS will be the key efficacy measure.
Abstract 9063: Retrospective analysis of clinical trials to determine the effectiveness of treatment guidelines in reducing the rates of severe GI adverse event rates. The results from this analysis largely mitigate the negative results of the -007 trial, suggesting immune related adverse events can be minimized through treatment algorithms.
Abstract 9073: Retrospective analysis of previous trials to analyze dosing strategies. Confirms that 10 mg/kg dose is preferred to 0.3 and 3 mg/kg dose.
Abstract 20004: Analysis of overall survival in the -002, -008 and -015 trials. Median OS was determined to be 19.4 months (-002), 12.9 months (-008) and 10.0 months (-015). Not surprisingly, OS was significantly longer in the patients that achieved an OR (median not yet reached, 25th percentile = 21.7 months), than those who didn’t (median = 10.9 months). We believe this data is supportive of our view that ipilimumab has strong potential to generate an overall survival benefit. |
