[Some more text attributed to Morgan Stanley's comment after Medarex ASCO data became available]
Key Data:
The response rate is nearly 10%, but is not fully reflective of efficacy; impressive stable disease will also likely weigh in. The response rate in the optimized 10mg dose (which is being used in the pivotal trials) is around 9% (see Exhibit 1). We believe this is a real response as the lower doses serve as an effective control (Exhibit 2 and 3).
Additionally, it is backed by the response we see by aggregating all the monotherapy doses across all the trials, which included suboptimal and single doses (Exhibit 4). We note that most thought leaders believed that response rate is not fully reflective of efficacy. Nearly 25% to 30% patients have stable disease in the overall data set, which is as durable as the response (both of which, in several cases, exceed expected life expectancy), likely resulting in extended survival.
Going forward, we expect PFS or OS to be the metric used in increasing efficacy of this drug. We note that PFS is the endpoint in the ongoing front line trials. The current data set disease to the correct evaluation of this drug’s potential, as these patients will have the potential to become formalized responders over a period of 2-16 months.
Responses Maintained with Various Combinations
In an aggregation of 6 studies, including various ipilimumab single and multiple doses as either monotherapy or in combination with an additional chemotherapeutic, immunotherapeutic, or vaccine (all in the relapsed melanoma setting), response rates were largely in the same range.
Durability of Stable Disease/Responses is Outstanding
As seen in the previous exhibits (1-4), the durability of stable disease and responses is uniformly unprecedented. One poster presenter even noted that these data are 4-6 months old at this point, and that most responders are still responding, implying that duration of responses could improve even further. From the more mature data set, nearly 25 patients (of all 356 across all trials and doses) have maintained responses greater than five years. To provide context, the natural history of this disease predicts a median survival in this setting of 7-10 months. We see this durability as pivotal towards the potential approval of the drug.
Responses Migrate Positively Over Time
Some patients appear to be migrating from stable disease to PR to CR as time moves on, regardless of whether they discontinued therapy or remain on some maintenance dosing. This migration will have major implications for the surveillance of these patients over time, as well as the evolution of data from the many trials. We fully expect that these data (highlighted below) could improve with periodic updates.
Toxicity is Manageable
At this point, most, if not all, physicians that we have spoken with are comfortable handling the side effects of the CTLA-4s via the various steroid and hormone algorithms that have been tested. Most of the more serious problems, including gastrointestinal perforations, have occurred in the earliest patient groups. While still not trivial, the balance of evidence, in our opinion, supports the use of these drugs. In addition, even the more severe side effects, such as uveitis and hypophysitis, are reversible. |
