Monday, June 3, 2013

More Progress on Melanoma Therapeutics

There seems to be an increasing competition between pathway inhibitors and immune system enhancers in the treatment of melanoma. Two papers, one by Wolchok et al and the other by Hamid et al have shown significant progress in the immune portion.

CTLA-4 and PD-1 can be inhibited and such inhibition allows T cells to function by attacking the malignant cells. In effect we have re-activated the immune system to go after the cancer cells.

As NEJM states:

Wolchok et al. and Hamid et al. report in the Journal the results of phase 1 clinical trials showing that the combination of PD-1 and CTLA-4 antibody blockers leads to improved treatment outcomes in patients with melanoma, without an escalation of toxic effects. 

The results of these trials are striking and complementary. In the trial by Hamid et al., a PD-1 monoclonal antibody was administered in patients who had had a relapse after CTLA-4 antibody monotherapy (ipilimumab); the authors found that durable and clinically significant responses were as common and robust as were those observed in patients who had not received ipilimumab therapy previously. Thus, progression of melanoma after anti-CTLA-4 therapy does not preclude a response to anti-PD-1 therapy. 

Wolchok et al., who in part report similar data for sequential CTLA-4 and PD-1 antibody therapy, also tested concomitant administration and found that at the maximum tolerated dose, 53% of patients with advanced, treatment-resistant melanoma had objective tumor responses, with tumor regression of at least 80% in every patient who had a response. 

Surprisingly and importantly, the use of ipilimumab and either one of two PD-1 monoclonal antibodies — whether the PD-1 and CTLA-4 antibodies were given sequentially or together — resulted in a rate and severity of adverse events that were no higher than those observed with the individual drugs alone.

 It is expected that from these trials we can eventually see a combination therapy and then a selected genetic individual therapy.

Finally as NEJM so properly puts it:

The clinical successes of CTLA-4 and PD-1 antibody immunotherapy in cancer are the outcomes of the correct recognition of the therapeutic potential of the molecules at the time of discovery, preclinical studies that showed high therapeutic potential, and well-designed and well-executed clinical trials. This partnership of basic science, translational science, and clinical medicine should be celebrated.

These two papers focus on the immune system approach. We have seen that if we can combine this approach with the pathway blocking approach that perhaps there may be some added efficacy, yet the results are not yet in.