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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Might Alimta be Particularly Effective for NSCLC Patients with an ALK Rearrangement?
Sat, 02/26/2011 - 23:14
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

A new article just coming out in the Journal of Thoracic Oncology by our friend Dr. Ross Camidge and colleagues from the University of Colorado suggests that patients who have an ALK rearrangement appear to often have a particularly long progression-free survival (PFS) with Alimta (pemetrexed). Though it comes from a single institution and is the first time such an idea is being presented, it's a very interesting report.

The University of Colorado is on the very short list of cancer centers that are more or less routinely ordering EGFR and KRAS mutation testing, as well as looking for an ALK rearrangement, in the vast majority of their patients with NSCLC. Last year, Dr. Camidge mentioned to me that he and colleagues were noticing that many of their patients who were found to have an ALK rearrangement also seemed to do unusually well with Alimta, so they reviewed their center's experience to assess this more carefully. Specifically, they retrospectively reviewed the clinical results for 89 of their patients who had received Alimta with or without another chemotherapy and who had also been tested for these three mutations. They then reviewed the PFS of patients on an Alimta-containing regimen depending on whether patients had an EGFR mutation, KRAS mutation, ALK rearrangement, or was "triple negative".

What they found was that the 12 patients with an EGFR mutation had a median PFS of 5.5 months, 21 patients with a KRAS mutation had a median PFS of 7 months, the 19 with an ALK rearrangement had a median PFS of 9 months, and 37 with a triple negative profile (no mutations) of 4 months. Please note that these are all pretty small groups, so the numbers shouldn't be taken to the bank, especially when thinking about median numbers for very small groups. To get a little more information, it may help to look at the range of results in the form of a waterfall-type plot, in which the horizontal lengths of the individual bars reflects the duration of treatment on Alimta without progression:

ALK and Alimta PFS (click on image to enlarge)

You can see that there is really a lot of variability in how people did in all of the groups, but Dr. Camidge and his colleagues raise the question and also provided a possible mechanism for the effect, based on the concept that ALK overexpression may lead to high levels of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (ATIC), a folate pathway enzyme inhibited by Alimta. Don't worry -- that's not on the test! Besides, it's really just a hypothesis right now.

Still, in the figure above you can see that there are some patients with very long periods of PFS on Alimta-based chemo, especially with an ALK rearrangement, but also notable in a few patients with a KRAS mutation. Speaking with Dr. Camidge directly, he noted thathis impression is indeed that a subset of patients with a KRAS mutation do extremely well with Alimta.

The authors make the point that the observations need to be validated and that it's not clear whether the finding, even if it's real, is specific to Alimta: it could be the case, for example, that patients with an ALK rearrangement are more responsive to several types of chemotherapy. Still, I can say that my limited experience with patients with an ALK rearrangement includes a couple of patients who have been on maintenance Alimta for very prolonged periods of more than a year without progression as they have been known to have an ALK rearrangement but have needed to wait for progression to qualify for the randomized trial of crizotinib vs. second line chemotherapy. Meanwhile, the authors raise the point that if many of the patients in the randomized trial receive Alimta (since they can receive either Alimta or Taxotere (docetaxel)), crizotinib may not appear overwhelmingly better than chemotherapy -- if only because chemotherapy outperforms what we'd have expected.

I've also seen a few patients with a KRAS mutation who have done very well on platinum/Alimta combinations. It may or may not be the case that many KRAS mutation-positive patients do especially well with Alimta, but such cases at least underscore that a patient with advanced NSCLC having a KRAS mutation doesn't mean that there isn't effective therapy out there.

This type of molecularly-defined population research is early, but it highlights the potential value of defining new subsets within lung cancer that may well lead us to recognize new patterns and identify more or less effective treatments for them, even if sometimes from unsuspected angles.

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