Over the last couple of years, I’ve attended and spoken at a lung cancer conference that I find to be particularly gratifying. Each fall, the Annual Personalized Therapies in Lung Cancer conference is held at a location in southern California. I wanted to provide a summary of what was covered at the last one, back in November, since it covered a broad range of the topics I think are most interesting here, using an interactive, case-based format integrated into the presentations.
The first session focused on existing targets, specifically the HER/EGFR family and ALK, though the discussions were more forward-looking than reviews of information we already know. Dr. Paul Bunn, former ASCO President and President and then Executive Director of the International Association of the Study of Lung Cancer, started the day with a summary of “game changers” in lung cancer in 2013, a whirlwind tour of the emerging landscape of acquired resistance and discussion of rare variants of mutations. Dr. Phil Mack from the University of California at Davis then described the shifting world of lower costs and wider availability of whole genome sequencing for lung cancer, though he noted that this is still creating a haystack of data in which we’re still looking for needles. Of course, this field will be changing rapidly, and we should expect our practices to follow as the price and turnaround time decrease as the number of clinically useful targets increases.
Dr. Ron Natale from Cedars-Sinai in Los Angeles provided a great summary of the data comparing first and second generation oral EGFR inhibitors. Specifically, he covered the very consistent evidence that Iressa (gefitinib), Tarceva (erlotinib) and Gilotrif (afatinib) all handily demonstrate overwhelmingly greater activity than standard chemo as first line therapy for patients with an activating EGFR mutation, but we don’t have any direct comparisons of these agents to say that one is clearly superior to another. With regard to less common mutations, those not on exons 19 or 21, work with Gilotrif demonstrated that it isn’t particularly effective outside of those classic, activating mutations. And looking at the efficacy and side effect profiles of Gilotrif and Tarceva in different trials side by side, it appears that they are very similarly active, with greater diarrhea and probably rash and mouth sores with Gilotrif.
Dr. Fred Hirsch from the University of Colorado then looked at the potential role of IV antibodies to EGFR, such as Erbitux (cetuximab), in advanced NSCLC. He recapped the questions around the FLEX trial, marginally positive for a survival benefit, but with so little absolute difference between the arms that Erbitux hasn’t really entered into routine use. He noted that a related antibody, necitumumab, was actually positive for a survival benefit in the SQUIRE trial, as related in a press release, though we haven’t seen the actual results yet and don’t know if it will become a new, routinely used agent or another near miss like Erbitux.
Dr. Karen Kelly from the University of California at Davis then covered irreversible EGFR inhibitors like afatinib and highlighted the unknowns about whether it is an improvement beyond the reversible EGFR TKIs Iressa and Tarceva. She reviewed the encouraging phase II research work with dacomitinib (which has just been reported to demonstrate no improvement in efficacy compared with Tarceva in EGFR TKI-naïve patients, and no improvement compared with placebo in EGFR TKI-treated patients with acquired resistance), as well as offering her commentary on Gilotrif – noting that we really won’t know whether it is superior to other options until the outcome of a couple of randomized phase III trials being conducted now are completed – one against Tarceva, and another against Iressa.
Turning to ALK, Dr. Alice Shaw from Massachusetts General Hospital then reviewed established data with XALKORI (crizotinib) and then cataloged exciting new work with second generation ALK inhibitors LDK-378 (now ceritinib, from Novartis), alectinib (from Chugai/Roche), and AP26113 (from Ariad) – all with significant activity in XALKORI-resistant patients, and all with activity against brain metastases, unlike XALKORI. She also noted that several heat shock protein inhibitors (HSP90) have also demonstrated activity in ALK-positive patients and are now beginning to be studied in this setting as well.
I closed the session with a discussion of approaches for acquired resistance for EGFR mutation-positive patients. Starting with the concept that limited progression is appropriate to consider for local treatment like surgery or radiation, and slow, multifocal progression may also not require any change in treatment, I then spoke about options in patients who have more significant progression that warrants a change in systemic therapy. I spoke about the potential value of continuing the same targeted therapy with concurrent chemotherapy, vs. discontinuing it when switching to chemotherapy. I also touched on the early work with CO-1646 from Clovis, AZ9791 from Astrazeneca, the combination of Gilotrif and Erbitux, and the HSP90 inhibitor AUY922.
The next session covered more general topics, personalizing therapy outside of molecularly targeted therapies. GRACE’s own Dr. Jared Weiss from the University of North Carolina, Chapel Hill discussed the growing collection of data supporting use of doublet chemotherapy for elderly patients and those with a marginal performance status. He also summarized the work with Abraxane (nab-paclitaxel) that revealed a very promising efficacy in patients over 70, and which is leading to a subsequent study specifically in the elderly.
The morning ended with a presentation by Dr. Daniel Morgensztern, from Yale, who reviewed the full range of evidence and options in maintenance therapy. This summary highlighted that there is no single approach of choice, but a choice of approaches.
All of that was just what we did before lunch! I’ll summarize the afternoon’s presentations in part II.