MDX-1106 Phase 1 Trial in Several Cancer Types Including RCC
Mario Sznol from Yale University School of Medicine delivered an oral presentation on the safety and efficacy of administering bi-weekly doses of the immunotherapy agent MDX-1106, a monoclonal antibody, to patients having advanced solid tumor malignancies. MDX-1106 is a PD-1 inhibitor. PD-1 is a protein which itself inhibits anti-tumor T-cell activity. In vitro (in the test tube), anti-PD1 agents caused increased cytokine production (T-cells, etc. that fight tumors) and suppression of T-reg cells, which reduces T-cell effectiveness. A previous 39-patient Phase I trial for MDX-1106 in four solid tumor cancers showed low toxicity and partial response in three patients including a 15+ months one in a renal cell patient.
The current trial, conducted at 10 cancer centers, is a Phase I, dose-escalated trial in melanoma, renal cell, prostate, non-small cell lung cancer (NSCLC), and colorectal cancer. Doses of 1, 3, or 10 mg/kg infusions were administered every other week with evaluation every 8 weeks. Some patients who had progression were kept on the trial and subsequently had a response to the therapy. All patients had to have had prior therapy, and Sznol reported on 106 patients, who had an average of 2½ prior therapies. Note that these 106 patients, who were reported on, were all accrued to the trial before the analysis cut-off date in May. Additional patients were accrued after the May cut-off.
MDX-1106 was very well tolerated with 23 grade 3/4 adverse events out of 106 patients including five patients who were fatigued. The incidence of “only drug-related” adverse events is given by the following table.
The response to the therapy is given in the following chart – taken from Dr. Sznol’s talk.
As can be seen from the table, no colorectal or prostate cancer patient responded. One out of ten lung cancer patients responded.
The above table is rather busy. Following is a simplified breakdown of response.
None of the 21 responders for all cancer types on the trial have progressed (as of the presentation date in June)! For the five responders who have RCC, the duration of treatment is: 17+ months (mos), 10+ mos, 8+ mos, 8+ mos, and 7+ mos.
Since this was a trial which included five different cancers, no statistics were presented stratifying just RCC patients by previous therapies or pathology, although Sznol mentioned that some patients who responded to MDX-1106 had previously failed High-Dose IL-2. This well-tolerated drug (the maximum tolerated dose (MTD) was not reached) showed significant response in kidney cancer and melanoma. There was activity at both dose levels, and some patients progressed at first and then responded after continuing the therapy.
So what about the future? No Phase II trial is currently planned. The drug’s developer, Medarex, was purchased by Bristol-Myers Squibb (BMS) in September, 2009. It looks as though BMS may have a winner here, especially with respect to melanoma and RCC. They should be encouraged to continue testing the drug in RCC.
There was no one from BMS who has a leadership role over MDX-1106 present at ASCO. We contacted the BMS rep for MDX-1106 but were unable to extract any definitive information from him about BMS’s plans for future development of this drug in RCC. Based on conversations with BMS and investigators, the current Phase I trial will be opened for additional patients in mid-January or later. Unconfirmed rumors indicate that there may be 15-30 additional kidney cancer patients recruited for the trial, over 30 melanoma patients, and possibly 50-60 lung cancer (NSCLC) cancer patients. Although the trial results reported at ASCO showed very favorable results for RCC patients, having only 16 patients on the trial is not sufficient to get an accurate portrait of MDX-1106’s effectiveness in RCC. Without that evidence, BMS’s decision to embark on a Phase II trial would be problematic. Testing over 50 additional lung cancer patients in the drug, if true, would indicate that BMS would like to develop it for NSCLC even though its preliminary results for that disease were not as encouraging as those for melanoma and RCC. Maybe BMS sees a bigger market in lung cancer that for RCC? A little pressure from the RCC community might be helpful here.
Update: January 2010