All the Talk About ALK, and Crizotinib (PF-02341066)

June 9, 2010 - 5:14 pm email to a friend

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Dr West

Probably the leading story in lung cancer at ASCO this year was about ALK inhibitor therapy and the Pfizer drug crizotinib (PF-02341066). Though we’ve covered it before, last year the promising story remained under the radar for a while after having the initial work presented in a session on developmental therapeutics. This year was the official coming out party for crizotinib, with the phase II study previously described in prior work re-presented with additional patients, but now in the most visible forum in the oncology world.

In fact, you could certainly hear some grumbling about whether this work merited being part of the ASCO Plenary Session, being a phase II study that is applicable to only a small minority of patients with an ALK rearrangement (about 4-5% of NSCLC overall, though disproportionately never-smokers and those with an adenocarcinoma, and especially younger patients) and a story that had already been broken. However, this information was largely known primarily to the lung cancer community and well-informed members of the patient/caregiver communities (especially GRACE participants). It hasn’t really penetrated throughout the oncology community.

So what did we learn this year? The Plenary Session presentation by Dr. Bang and colleagues began with a scientific review of the biology, largely covered in the very excellent GRACE webinar presentation by Dr. Ross Camidge. It also reviewed clinical data by Dr. Alice Shaw from Massachusetts General Hospital (MGH), which highlighted that patients with ALK rearrangements do not appear to do particularly well with standard chemo or EGFR inhibitors like Tarceva (erlotinib) or Iressa (gefitinib), in contrast with patients with EGFR activating mutations, who we know tend to have very high response rates and prolonged progression-free and overall survival to EGFR inhibitors (and also chemotherapy in some studies).

(click on image to enlarge)

The current data set of patients with an identified ALK mutation who received crizotinib includes results for 82 patients being followed through April of this year, a group of patients for whom several distinct features are notable. First, their median age is 51, nearly 20 years younger than the median age for a patient with a new diagnosis of NSCLC in the US today; the oldest patient with an ALK rearrangement is 78. They are predominantly (76%) never-smokers, and most of the remaining patients have a very limited prior smoking history of 10 pack-years (the product of average number of packs smoked per day x number of years smoking). While the vast majority (96%) have an adenocarcinoma, a single patient with a squamous cancer had an ALK rearrangement detected, and a couple were categorized as “other” (presumably so poorly differentiated a histology couldn’t be defined, or not enough tissue available). Importantly, the majority had received at least two prior lines of therapy, with 41% actually receiving three or more prior regimens.

With more patients and longer follow-up, the initial promise of crizotinib has held up, with a “waterfall plot” (in which bars extending down from the horizontal line represent tumor shrinkage) showing that nearly every patient demonstrated benefit as measured by some degree of tumor shrinkage:

These aren’t the kind of results we expect to see in NSCLC, especially for heavily pre-treated patients. The current rate of significant tumor shrinkage is 63% (including uncomfirmed responses), with 87% of patients demonstrating stable disease or better eight weeks into treatment. In addition, responses or non-progression was generally prolonged, with 72% of patients on this study showing no progression at six months, and median progression-free survival still not reached.

Importantly, there appear to be no new safety issues for this oral therapy, with mild nausea, vomiting, diarrhea, and mild visual symptoms being among the more commonly reported symptoms, along with a minority of patients experiencing moderate elevations in their liver function tests.

As was discussed in the podcast by Dr. Camidge, this agent is not currently available outside of clinical trials, of which there are two ongoing large efforts:

(details about trials here and here)

Another important issue is that there have been rare cases (though I’ve seen two in the last two months) in which patients have had ALK inhibitor testing come out positive at lab that isn’t the official central lab (University of Colorado, MGH, and University of Chicago are doing it, along with the official central lab that is a joint venture between Pfizer and Abbott), then have had testing at the official central lab that was reported as negative, rendering them ineligible for these trials. All of the researchers involved are working to determine the cause(s) for these rare discrepancies. In the meantime, Pfizer is changing the eligibility for the single arm trial to permit patients who test positive at one of their broader range of approved labs, so that they would be defined as ALK rearrangement positive but ineligible for the randomized phase III trial.

Another interesting result was presented by Dr. Lecia Sequist, also at MGH, who went back and tested a limited number of tissue samples from her study of the heat shock protein inhibitor IPI-504 that showed very limited activity. Three of the 14 samples tested had an ALK rearrangement, and two of those three had responded to IPI-504, with the third also demonstrating tumor shrinkage. Though we obviously can’t draw any firm conclusions from results in three patients, it is a lead suggesting that once we have identified distinct subgroups, we may be able to demonstrate that they show sensitivity to other agents, whether standard chemotherapy are targeted biologics, that can continue to define new treatment options for limited populations.

Though this is still a small population, the evidence is very convincing that ALK inhibitors can have a major impact for these patients, with the potential that we may also identify agents that can offer additional benefit to patients with an ALK rearrangement.

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