Anti-PD-1

If you have been to ASCO before you will be able to identify with the atypical ASCO-buzz around a promising early stage agent or target. Oral presentations featuring the emerging agent will have the planners wishing they had organized a bigger room, and featuring posters and their unwitting presenters will be treated like celebrities- an overflow of buzzing paparazzi snapping pictures of the posters from all angles.  The ASCO-buzz for me this year is undoubtedly centered upon PD-1 and its inhibitors. Indeed, spanning seven separate sessions, a total of seven oral presentations and several posters, anti-PD-1 has certainly kept us busy and well exercised.

Programmed death 1 (PD-1) suppresses antitumor immune responses through the binding of the PD-L1 ligand (also known as B7-H1). The PD-L1 ligand is overexpressed in many tumor types, and blockade of the PD-1/PD-L1 interaction through an anti-PD-1 inhibitor demonstrated antitumor effects in early preclinical studies. Bristol-Myers Squibb's anti-PD-1 monoclonal antibody BMS-936558 (also known as MDX-1106 and ONO-4538) is the most mature agent in development and it's Phase I data was presented across several presentations this meeting. Impressive response rates were seen in heavily pre-treated patients with advanced malignant melanoma (28%), non-small-cell lung cancer (18%), and renal-cell carcinoma (27%). Excitingly, responses were not only rapid, but were often durable, with approximately two thirds of responders maintaining responses for over a year and some patients continuing to respond until data cut-off. Furthermore, the agent was generally well-tolerated and the maximum tolerated dose has not yet been reached. The agent also demonstrated similar efficacy over a large dosing range.

So, how excited should we get about this targeted immunotherapy. The early clinical data is definitely compelling and appears superior in terms of response rate to ipilimumab (Bristol-Myers Squibb's Yervoy). Another advantage of the anti-PD-1 treatment is the possibility of predicting which patient will respond to the agentanalysis of pre-treatment tumor tissue indicated that none of the patients with PD-L1-negative tumors responded to anti-PD-1 treatment. Thus, the possibility of being able to stratify patients that will respond to this targeted immunotherapy is in stark contrast with ipilimumab, where the identification of a predictive biomarker is continuing to prove challenging. Potentially the most exciting indication for BMS-936558  is non-small-cell lung cancer, a disease that has often proven unresponsive to immunotherapies. We, and the many companies actively involved in anti-PD-1 development, eagerly await later-stage clinical data.

Dabrafenib and Trametinib

As with the ASCO meetings over the last two years, treatment for malignant melanoma (MM) again took center stage on Monday. Phase III results were reported separately for GlaxoSmithKline's BRAF inhibitor dabrafenib, and MEK inhibitor trametinib as monotherapies for the treatment of BRAF mutation-positive, unresectable and metastatic MM.

Dabrafenib met its primary end point by demonstrating PFS benefits over the comparator dacarbazine in the BREAK-3 trial. As expected due to the comparable profiles, the clinical data for dabrafenib were similar to that reported for vemurafenib (Roche/Genentech/Daiichi Sankyo/Chugai's Zelboraf)a currently widely used treatment option in the treatment of BRAF mutation-positive advanced MM. Though cross-over from comparator (dacarbazine) to dabrafenib was allowed in the trial protocol, it is expected that MOS will be similar to that demonstrated by vemurafenib in the BRIM-3 trial.

The METRIC study comparing the MEK1/2 inhibitor trametinib against chemotherapy (dacarbazine or paclitaxel) was described in the afternoon session. Trametinib demonstrated a PFS benefit (primary end point) over the comparator and a trend towards significant OS was demonstrated despite cross-over being allowed after progression on the chemotherapy arm. The response rate with trametinib treatment (24%) was lower than that observed with BRAF inhibition (approx. 50%) a possible reflection of the trial being in previously-treated patients although prior treatment with a BRAF inhibitor was not allowed.

How will these recently reported data affect the dynamics of the MM market. It is likely that both monotherapies will gain FDA approval; however, this will not necessarily result in new options for the patient. Studies suggest that using a MEK inhibitor after failure on BRAF inhibition does not provide benefit. Therefore, it is expected that both trametinib and dabrafenib will compete in the first-line BRAF mutation-positive setting with vemurafenib. Some interviewed physicians report that trametinib could be given to patients that have problems tolerating BRAF inhibitors, however, they acknowledge that MEK inhibition itself induces significant skin toxicity and this in turn could hinder uptake.

The icing on the ASCO cake for GlaxoSmithKline was the highly impressive updated data for Part B of the Phase I/II trial of the dabrafenib/trametinib combination in BRAF inhibitor treatment naive, BRAF mutation-positive metastatic MM patients. The combination, demonstrated a response rate of 63% and a remarkable duration of response of 11 months (interim data)a marked improvement over BRAF monotherapy (approx. 6 months), especially considering that over a third of patients are still receiving treatment on the trial and therefore the duration of response will ultimately be even higher. PFS in the optimal dose was a staggering 10.8 months. The combination also provided significant safety benefits with marked reductions in BRAF-inhibition secondary induced skin cancers and both BRAF and MEK inhibition induced skin toxicities. If these attributes are reproduced in a large randomized trial and the combination is approved by the regulatory authorities, it is difficult to imagine that BRAF or MEK monotherapy will continue to have a major role to play in the treatment of advanced MM.

Finally, as many presentations described, it is becoming clear that not only combinations of BRAF and MEK inhibitors, but also combinations of targeted small molecules and immunotherapies, could hold the key to future treatment of MM. As the science and clinical development picks up pace, and the requirement for a New England Journal of Melanoma becomes more necessary (as mentioned tongue-in-cheek by a session summarizer), it is clear that MM will not only continue to be a fast-moving indication, but also continue to be a dynamic market to forecast.

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