The two phase I studies differed only in the dosing schedule.  In the first trial, T-DM1 was administered every 3 weeks whereas in the second trial, it was administered on a weekly basis. In the case of the three-weekly study, most of the data was already disclosed in previous conferences, including objective responses (significant reduction in tumor burden) in six out of 15 patients who received the maximal tolerated dose (3.6 mg/kg). One piece of new data was the median progression-free survival (PFS) of those fifteen patients, which was 9.6 months, substantially higher than patients who received lower doses of T-DM1. These results led to the initiation of a phase II trial that will evaluate T-DM1 in the same dosing schedule in 100 patients.

Data from the second phase I trial, with the weekly dosage of T-DM1, is still very preliminary. Nevertheless, this trial has the potential to demonstrate even better results because this dosing schedule may be more appropriate for ADCs. While naked antibodies stay in the bloodstream for weeks, most ADCs are cleared out the body within a week after administration. In the case of Herceptin, for instance, substantial amounts of the antibody remain in the bloodstream for over a month. Arming Herceptin with a toxic payload of DM1 dramatically reduces the circulation time to less than a week. Therefore, the patients who received T-DM1 every three weeks actually spend two weeks of every cycle without significant levels of the T-DM1 in their bloodstream. Using a weekly administration schedule, it may be possible to maintain stable levels of the ADC in patients’ bloodstream, if, of course, sufficient doses can be given every week without leading to severe side effects. If so, patients could receive higher cumulative doses of the drug.  Because there is not a lot of experience and knowledge about the safety profile of ADCs, all initial evaluations were done at a three-weekly schedule. Now that Genentech showed that T-DM1 can be administered at a relatively high dose (3.6 mg/kg every three weeks) with a good safety profile, the move to a more frequent dosing regimen was obvious.

The weekly trial was a typical dose escalation study, with the aim of finding  the highest dose that can be given to patients. So far, Genentech disclosed data only for 7 patients who received escalating doses of T-DM1. The lowest dose was 1.2 mg/kg per week, which is equivalent to the MTD from the first phase I trial (3.6 mg/kg). The next cohort of 3 patients received a dose of 1.6 mg/kg per week without any signs of substantial toxicity. Of note, the equivalent dose in the three-weekly trial was found to be too toxic. Therefore, even if the MTD is eventually set at 1.6 mg/kg per week, this trial already enables the evaluation of higher cumulative doses. It does not mean that this regimen will necessarily be more efficacious, but it certainly increases the probability for a stronger effect. The seventh patient was given a dose of 2 mg/kg per week, the same dose at which Herceptin is given. If this dose level is proven safe, that would serve as a great sign with regard to T-DM1’s  safety profile. On the efficacy side, of the seven patients, 4 (57%) achieved a partial response. This response rate is encouraging, but in order to show some sort of an advantage over the three-weekly regimen, there must be data on more patients. Nevertheless, seeing that number of responses before establishing an MTD is quite encouraging. Because these results were submitted more than four months ago, it is reasonable to assume that Genentech will present more data with respect to the MTD and the response rate from the trial, so it looks like there is a lot to look forward to.

SGN-35

Seattle Genetics will report results from a dose escalation phase I trial of its wholly-owned ADC, SGN-35, in heavily pretreated Hodgkin’s Lymphoma patients. Preliminary data from this trial was already reported last year, and included multiple partial responses. Since then, the company recruited additional patients at higher dose levels (up to 2.7 mg/kg), but still did not reach MTD. The fact that even at a dose of 2.7 mg/kg every three weeks, there were no severe side effects, implies that Seattle Genetics is capable of creating very safe ADCs as well. According to the data submitted to ASCO in the beginning of the year, 9 out of 28(32%) evaluable patients achieved a partial response. In addition, there was a clear dose dependent response, as at dose levels of 1.2 mg/kg or higher, 7 (54%) of 13 patients had a PR. This compares favorably to only two cases of PR among the 15 patients receiving doses lower than 1.2 mg/kg. Since submitting the data, Seattle Genetics has recruited patients at higher doses and expects to present more responses at the conference.  The company initiated a trial for evaluating weekly doses SGN-35 and plans to evaluate this schedule in combination with chemotherapy (gemcitabine) going forward. This is the place to point out that Hodgkin’s Lymphoma represents a limited opportunity, with only 8200 new cases expected this year in the US, the vast majority of whom will be cured with available treatments. Including additional patient populations who may be suitable for SGN-35 treatment, the worldwide potential market for SGN-35 is still less than 10 thousand per year. Therefore, SGN-35 is more of a technology “validator” rather than a substantial commercial opportunity.

Results from another ADC powered by Seattle Genetics’ technology, CR011-vcMMAE, will be presented by Curagen. Curagen is expected to report updated results from a phase I dose escalation trial among 27 melanoma patients. It has previously disclosed data from 23 patients, so the new data is only for the last five patients. I wrote about this drug candidate in the past and gave my somewhat skeptical point of view on this trial. My skepticism stemmed from the poor historical success rate in metastatic melanoma and the limited activity the ADC demonstrated (although there was an apparent dose dependent response). The updated results include data from higher doses of CR011-vcMMAE and show a clear dose dependent response, as CR011-vcMMAE managed to achieve one (11%) partial response and led to disease stabilization in 7 (78%) of the 9 patients who received the 3 highest doses.  Among the remaining 18 patients who received the lower doses, there was a SD rate of only 39%. These results triggered a phase II trial in additional 32 patients for the evaluation of CR011-vcMMAE given at the MTD.

Bearing in mind that in its naked form, CR011 did not have an effect even on cell cultures, this study can be seen as yet another validation for Seattle Genetics’ ADC technology. The response rate may appear low compared to other oncology programs, but metastatic melanoma is notorious for being resistant to most chemo drugs, which usually demonstrate even worse results. Nevertheless, I am still not a big fan of this clinical program because metastatic melanoma is characterized by the worst ever success rates and the overall market is quite limited. By default, investors should stay away from any drug candidate for metastatic melanoma , with one exception to the above rule: Synta Pharmaceuticals’ (SNTA) elesclomol.    

On a more encouraging note, Curagen recently announced plans to initiate another phase II trial in metastatic breast cancer, one of the largest oncology markets. The presence of CR011-vcMMAE’s target, GPNMB, has been observed in many cases of advanced breast cancer. More interestingly, this target has been suggested to play an important role in disease progression and the development of metastases. It is also reasonable to assume that CR011-vcMMAE was found to be active against breast cancer tumors in preclinical systems before the expensive phase II trial was announced. There is still a great deal of uncertainty as to the merits of this study, as GPNMB is not a validated target for breast cancer.