I do want to start off with the patients here and really, so I don’t forget, really thank. This study, due to the rarity of these TRK fusions, really required patients to travel from around the world. It really was a heroic effort on the part of the patients, many of whom flew trans-continentally monthly to participate in this study. I really am in awe of these patients and I just wanted to take a moment to thank them.

TRK fusions may be a new genetic alteration to many of you and what TRK fusions are defined by is one of the TRK genes becoming abnormally connected to another gene. Whereas TRK has a very limited role in function of normal biology after birth this fusion event causes the TRK protein to be turned on and the cancer to grow and the cancer becomes addicted to this event. One of the defining features of TRK fusions is the fact that they are not just found in one cancer type but can be found in dozens of different cancer types, not only in adults but in both children and adult, really spanning the entire lifetime of a person. Some of the cancer types you see here and it really follows two patterns: some cancers which are common but the TRK fusions occur rarely in and others which are uncommon diseases which are pretty much defined by the presence of a TRK fusion, and that’s illustrated here.

The drug that I’m going to be talking to you about is called larotrectinib and it is the only selective pan-TRK inhibitor currently in clinical development. This is a unique effort because it is really potentially the first novel targeted therapy that was developed and may eventually be used in a truly tumour agnostic manner. Also, to our knowledge, it may be the first cancer therapy ever developed simultaneously in adults and children. In total, to give you a sense of the frequency here, we estimate that upwards of 5,000 patients are diagnosed with TRK fusion positive cancers in the United States each year although this may truly significantly underestimate the rate due to inadequate ascertainment by many of the existing profiling technologies.

What you see here is what I believe to be a very efficient and focussed drug development plan for larotrectinib. I’ll be discussing 55 TRK fusion patients enrolled to two phase I studies, one in children and one in adults, and then another global phase II study in TRK fusion positive cancers.

Another point I want to emphasise is that these patients were identified based on local testing. We did not perform central screening to find the TRK fusions and, in fact, fifteen different laboratories identified the 55 patients that I’ll be presenting today, sharing with you. This, in a sense, really represents the real world identification of these patients as a result.

The key endpoints for this study were overall response rate and I’ll be presenting investigator assessed response as well as duration of response and progression free survival. I find this to be a striking slide: among 55 patients enrolled in the study there were 17 unique cancer types enrolled including, again, both common cancer types as well as a variety of rare and orphan diseases.

These are the results of the study. This is a waterfall plot, the colour of the bars encodes the cancer types that each patient had. The overall response rate in patients with confirmatory response data available, which was 50 of the 55 patients was 76% which, to me, was really striking, more than three out of every four patients responded to therapy. You would be hard pressed to find a targeted therapy even within a single disease context that has results like this. 12% of these patients had complete responses. The additional five patients were on study but were too early to have had their confirmatory scan but all five of those incremental patients had at least a partial response and remain on study and are awaiting their confirmatory scan.

I want to point out several aspects of this figure. One is that not only this dotted line here represents the bar for calling a partial response or better. What you can see here is that most of these patients were not just meeting criteria for partial response but had very deep tumour regressions. In fact, two of these patients had such deep regressions that they actually were able to be down-staged and then taken forward to potentially curative surgery, which previously would have not been possible, and had pathologic complete responses, meaning once they had surgery there was no microscopic cancer left in their resection specimen. The other point here is the diversity of bar colours and you can generally agree with me that there is no trend of one tumour type responding better than another.

This swimmer plot shows the duration of larotrectinib therapy in each individual patient with all 55 represented. I want to point out a couple of key points. First, 93% of all responding patients remain on therapy or have undergone surgery with curative intent due to down-staging. Second, these yellow dots indicate the time of first response in each patient. As you can see, responses occurred a median of 1.8 months into therapy which is actually just a reflection of when the first scan was obtained but in the clinic patients report dramatic improvement of their symptoms within days of beginning therapy. Actually the patient who has been on treatment for the longest, out at 25 months, was the first TRK fusion positive patient treated with larotrectinib.

In conclusion, I believe these data demonstrate that larotrectinib is consistently and durably effective in TRK fusion positive cancers regardless of tumour type with an overall response rate of 76% including 12% of patients achieving complete response and 91% of responding patients remaining progression free at six months of therapy. What I didn’t cover in detail is that this is an extremely well-tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events. Notable elements of this programme include its tumour and age agnostic paradigm and its very rapid path from the very first patient with a TRK fusion positive cancer dosed with larotrectinib to the final was just 24 months. Loxo has announced that they intend to submit a new drug application later this year or early next year. I believe these data support larotrectinib as a potential new standard of care for these patients. However, I want to emphasise that really recognising this benefit in the community will require that we test patients more universally for the presence of TRK fusions or other tumour agnostic biomarkers such as microsatellite instability. To really enjoy these benefits we will have to change the paradigm by which we test these patients. Thank you very much.