As expected, Incyte yesterday announced positive top-line results for their lead drug candidate in myelofibrosis (MF). COMFORT-I, the pivotal Phase III clinical trial of INCB18424 (also known as ‘424) in MF patients was conducted under an FDA Special Protocol Assessment (SPA) agreement. The double-blind, placebo controlled Phase III trial enrolled 309 patients with a primary endpoint measuring the response rate defined as the percentage of patients achieving a 35% or greater reduction in spleen volume at 24 weeks as measured by MRI, or computerized tomography. The response rate was 42% in patients randomized to ‘424 versus less than 1% of patients randomized to placebo, leading to a very high level of statistical significance (p < 0.0001). This data is consistent with the Phase II data and the company plans to present the full results at ASCO 2011. To preserve the integrity of the data, we will not see any more details until then. So, we were happy to see that secondary endpoints based on symptomatic improvement were all met, but we did not get any details.
One question on the conference call regarding the secondary endpoints was about the durability of response. The company said response was sustainable and that many Phase II patients have seen durable responses for multiple years. The durability of response question was asked as analysts are trying to predict the results for COMFORT-II, INCY’s second Phase III trial being conducted by their partner, Novartis, in Europe. It is a randomized (2:1), controlled, open-label study designed to evaluate the efficacy, safety and tolerability of INCB18424 as compared to the best-available therapy in patients with MF. We expect COMFORT-II to also be positive as all signs from this trial and from Phase II show that ‘424 provides a durable response in MF patients. Results of COMFORT-II are expected early next year and will supplement the NDA that will be filed with the FDA next year. However, the NDA will not be held up while we wait for that data because the FDA considers COMFORT-I to be sufficient for a potential approval.
INCY has done an incredible job moving ‘424 swiftly past regulatory hurdles as the clinical program only started in May 2007 with the commencement of Phase I trials. Speed is not usually an asset when enrolling clinical trials, yet INCY has managed to be both fast and very good. Because MF is an unmet medical need, we can expect a relatively fast FDA review and ‘424 could be on the market before the end of 2011. We have always been impressed with INCY’s management and their vision. That said, we are now even more impressed by their execution. Completing a full clinical program in less than four years is basically unheard of in drug development. INCY’s stock price was up over 5% in after hours trading as the market is pleased with this excellent data set. We will not chase INCY at current prices as it was strongly recommended as a buy under $12 earlier this year. For now, just sit back and enjoy the ride.
By John McCamant
Some highs, and a big low from the annual San Antonio Breast Cancer conference.
As detailed during an oral session on the afternoon of December 10th, the AZURE trial, Adjuvant treatment with Zoledronic Acid in stage II/III breast cancer, unexpectedly bombed – having failed its primary endpoint of preventing cancer recurrence after neoadjuvant, or adjuvant chemotherapy, and/or hormonal therapy, with the bisphosphonate, Zometa, as compared to placebo. This result was in defiance of numerous smaller studies, which previously had suggested that bisphosphonates, in particular, Zometa, used in conjunction with chemotherapy was effective in treating solid tumor bone metastasis.
In reporting the results, the principle investigator, Robert Coleman, MD, admitted that the primary outcome was a big disappointment, but went on to highlight data from a secondary endpoint for a subset of patients – some 30% – who were five years post-menopausal; this population demonstrated a 29% improvement in overall survival.
Though seemingly positive, this drilldown analysis did nothing to dull the point of the take-home message, as stated by Julie Gralow, MD, an expert in investigational breast cancer treatments at the Fred Hutchinson Cancer Research Center. “For the group as a whole, for the primary endpoint, the result is dead negative.” As for the subset analysis, “If you’re going to pull out a post-menopausal group that’s positive, you have to look at the other end of it and say that it actually looks detrimental in two thirds of the patients – detrimental – more recurrences.” Dr. Gralow further elaborated that the definition of post-menopausal in the analysis, as if there were a defined biological cutoff, seemed unfounded. “Dr. Coleman is convinced it’s about a low estrogen state… it’s more complicated than that.”
That said, Dr. Gralow is not ready to abandon the use of bisphosphonates in this setting, and is heading up SWOG-SO307: A Phase III Randomized Study of Adjuvant Zoledronate Versus Clodronate Versus Ibandronate in Women With Resected Primary Stage I-III Adenocarcinoma of the Breast, an investigation that will report its interim data in the spring of 2011. “Based on these results from AZURE, before we do any analysis subsetting, we will build in a method to look at the pre, and post-menopausal status, and it’s relation to the use of chemotherapy.”
A Beat of Three
In contrast to the AZURE deflation, the morning of December 10th saw the rise of great promise for the use of targeted therapy in the neoadjuvant setting. Three large clinical trials were reported, the last two of which used a combination of biologics.
The first to be reported, GEPARQUINTO, a German study, compared chemotherapy plus either one of the two approved HER2-targeting agents, the antibody, Herceptin, or the small molecule, Tykerb; results showed a clear superiority in response to Herceptin.
More exciting, however, were the data sets that immediately followed, that of NeoSphere, and NeoALTTO. In NeoALTTO, the combination of Herceptin and Tykerb was compared to separate use of these agents (all with the addition of paclitaxel). Results here showed a much higher response – nearly a doubling – with the combination as compared to either agent used alone.
A similar design was used in NeoSphere, but with Tykerb being replaced by the investigative antibody compound, pertuzumab. Again, a near doubling of response was seen for the combination in this neoadjuvant setting.
It was hard to see a downside in the immediate atmosphere following these presentations, however, as these silver linings were later being considered, there came to mind several clouds. According to Dr. Gralow, it was debated whether NeoALTTO results should have been released before accrual to its companion trial, ALTTO, an adjuvant trial, was completed. Unlike NeoALTTO, ALTTO is powered to gauge a statistically significant disease-free survival endpoint, a result critical to the FDA’s approval of the biologics combination (and where there is approval, there is reimbursement).
Sandra Swain, MD, a leading authority in the treatment of early breast cancer at the Washington Cancer Institute understood that concern. “I think ALTTO is going to have difficulty recruiting now [more than 200 additional patients are needed]”. In NeoALTTO, the pCR (pathological complete response) rate was clearly much higher with the combination, and in GEPARQUINTO it was 10% lower with Tykerb alone, and ALTTO has this Tykerb/chemo arm…” Further complicating matters, since ALTTO is an open-label trial, Swain thinks that some patients may drop out of treatment arms that are now suggested to be suboptimal.
Neil Spector, MD, who once headed up the development of Tykerb, and is now the co-director of the Experimental Therapeutics Program at Duke University, was more concerned with the cost of the combination, reasoning that the approach will be effective in all stages of HER2+ disease. “I know Duke is advocating that this [combination] be the standard of care with HER2 + advanced breast cancer. It will be very interesting to see how insurers and the government deal with the costs of combining Tykerb and Herceptin in the early stage setting.” Adding that, “It will be a screaming match.” [Estimated cost: $150k and up.].
The results of NeoSphere and NeoALTTO could have even a greater financial impact when considered together, strongly suggesting the future advent of an all-biologic, non-chemotherapeutic treatment for HER2+ patients. “There’s talk of an Herceptin/Pertuzumab/Tykerb combination,” said Spector, and the scientific basis is sound, “but this will run $300k for every woman with early stage disease (such as the neoadjuvant setting). Late stage approval would be tested first, then early stage – and I can’t see any way that the healthcare system can sustain that.”
By Neil Canavan