I want to look at the RET driven NSCLC trial again. This is going to be a long winded post that due to Y’s limitations will have to be done in multiple segments. We all know that drug approval is a two headed monster, requiring satisfaction on 2 fronts, scientific and regulatory. Cabo utilization in this indication is still in its infancy with only four treated patients to date, 3 in the MSKCC trial and 1 in Japan. Despite the small numbers, this is a very promising opportunity for EXEL and Cabo. To understand the rationale for my enthusiasm, we need to revisit Pfizer’s Crizotinib (Xalkori) program. Criz inhibits the oncogenes ALK, MET, and ROS1. It started clinical development in 2005. In 2007, it was first reported that a subgroup of NSCLC was driven by a transfection of the ALK gene. Prior to that discovery it was known that that the majority of NSCLC cases were EGFR and KRAS mediated. Pfizer had already optimized dosing for Criz and had a ph 1 NSCLC trial underway. A single ALK positive patient was identified and treated in 2008. A partial response led to the opportunistic expansion of the phase one trial to recruit more ALK positive patients. Another single arm ORR primary endpoint trial was quickly initiated and the results of the 2 trials are below:
“One hundred thirty-six patients with locally advanced or metastatic ALK-positive NSCLC from Study A were analyzed at the time of data cutoff. The median duration of treatment was 22 weeks. Based on investigator assessments, there was 1 complete and 67 partial responses for an ORR of 50% (95% CI: 42%, 59%). Seventy-nine percent of objective tumor responses were achieved during the first 8 weeks of treatment. The median response duration was 41.9 weeks.
One hundred nineteen patients with locally advanced or metastatic ALK-positive NSCLC were enrolled into Study B at the time of data cutoff. The median duration of treatment was 32 weeks. Based on investigator assessments, there were 2 complete and 69 partial responses for an ORR of 61% (95% CI: 52%, 70%). Fifty-five percent of objective tumor responses were achieved during the first 8 weeks of treatment. The median response duration was 48.1 weeks.”
I just now listened to the conf call and was gratified to hear the discussion on a RET mutation NSCLC trial. I posted under this thread to make it easier to see some of my prior discussion on the topic. The beauty of this indication is how cheaply and quickly a pivotal trial can be completed. The indication size is small, but still magnitudes larger than MTC (2-3,000 U.S.) and it would not be a refractory population making for much longer treatment duration. This is an ideal indication for the FDA's new breakthrough therapy designation and an approval in this indication could actually happen before CRPC.
Nice points Ernie. EXEL had better not shuffle its feet for too long, Ponatinib is hot on the heels of Cabo in RET driven indications; it has a superior IC50 number for RET than Cabo although clinical results will still have to bear this out. It's also possible however that there are benefits of Cabo from something other than the theorized driver.
I haven't had a chance to listen again and I'm not willing to register with Seeking Alpha to read a transcript. I thought in the question and answer period that Gisella had , more or less, conceded that off label use in this indication would be another potential benefit to the trial disregarding the RET element. In other words that Cabo had more potential in NSCLC than just RET driven tumors. Maybe not. I'll try to listen again tonight.
As for the guy complaining about your raining on his parade...put him on Ignore, I have, and please know that your insights, judgment, and the work you put in are greatly appreciated by those of us less scientifically oriented. It's a Mitzvah on your part even if he's too dull to realize it.
"The indication size is small, but still magnitudes larger than MTC (2-3,000 U.S.) and it would not be a refractory population making for much longer treatment duration. "
And, as indicated in the CC ( I think?) it may well open up the wide, wonderful world of off label use in a disease that could use alternatives to many of the current therapies that either don't work at all or work for short periods of time.
Criz was approved by the FDA in Aug 2011, only 3 years from first patient treated and based on 2 small, short, and cheap ORR endpoint trials. ORR endpoint trials are short and easy to enroll. ORR endpoint approvals used to represent the majority of FDA drug approvals, but are becoming increasingly less common and now require high response rates in unserved indications for consideration. For a large pharma, Pfizer was uncharacteristically opportunistic in jumping on the newly discovered subgroup indication. To further sweeten the opportunity, ROS1 was discovered to be another NSCLC pathogenesis cause and Criz effectively treats this subgroup also. FDA does include ROS1 mutation positive patients as part of its approved use, but NCCN guidelines do. ALK mutations represent approx 5% and ROS1 1% of all newly diagnosed NSCLC cases
Now fast forward to 2011 at which time three groups nearly simultaneously discovered a new subset of NSCLC cases driven by aberrant RET fusions. In Sep 2012, the following was published:
“As of 1 June 2012, 14 pts were enrolled including 5 pts with non-small cell lung adenocarcinoma. Pts have been treated at 3 dose levels: 40, 60 and 80 mg. The NSCLC pts had a median of 4 prior regimens (range, 2 – 6). Four of the 5 NSCLC pts had a confirmed partial response (cPR) including a 51 yo female whose pre-treatment tumor sample lacked an EGFR activating mutation Analysis of tumor obtained pre-treatment and at progression demonstrated a KIF5B-RET fusion.”
Here is the rest of Ernie's post:
"In July 2012, MSKCC was granted an IND to conduct “Cabozantinib in Patients With KIF5B/RET Positive Advanced Non-Small Cell Lung Cancer.” At first I speculated that the decision to move into this trial began with a search for plausible indications for Cabo. The truth is that it started with the indication and a search of the literature for likely treatments. Based on the publication “The Effects of Four Different Tyrosine Kinase Inhibitors on Medullary and Papillary Thyroid Cancer Cells,” the trial coordinators chose cabo over vandetinib, axitinib, and sunitinib based on its in vitro ability to better inhibit RET in four different cell lines of thyroid cancer.
So here we are at present with ¾ PR’s and a single prolonged SD. Although admittedly anecdotal, this data combined with the theoretical basis for this targeted treatment augurs well for a positive outcome. FDA approved Criz on a 50% ORR in 200+ patients and NCCN added ROS 1 positive patients based on early phase 1 data that is largely anecdotal in nature. FISH tests are already available to test for the ROS 1 gene transfection and its rate of incidence is similar to the RET fusion. I hope EXEL does not sit on its heels. Cabo is the only drug being tested in this indication, but that could change quickly. From a regulatory perspective being first is often better than being best. A single arm open label 200 patient trial can get Cabo’s second indication in a meaningful niche market with an early NCCN listing before FDA approval. MSKCC has done the heavy lifting so far with minimal effort from EXEL. The MSKCC group also participated in the Criz program, so they understand the significance of what they are doing and the speed with which this has moved is breathtaking by pharma standards. There is little question of efficacy and a low risk $50-$100 million per year revenue opportunity is available for minimal expense."