GRACE :: Lung Cancer

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Should Small Cell Lung Cancer Patients Who Respond to Chemo Receive Consolidation Radiotherapy?

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Dr. Nasser Hanna outlines the possible benefits of consolidation chest radiation for small cell lung cancer patients who respond well to chemotherapy.

CREST Trial Design


What Went Wrong? The Failure of MetMab with Tarceva in Advanced Non-Small Cell Lung Cancer

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“Dead negative,” is how Dr. Nasser Hanna describes results of a phase 3 study that examined how patients with high MET expression did on the drug MetMab (onartuzumab).

OAM4971g: Overall Survival Results


Not all EGFR Activating Mutations are Created Equal: Time to Stop Pooling Them Together

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It’s been a decade since EGFR gene mutations were first identified as highly correlated with a high probability of response to EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) and Tarceva (erlotinib), and more recently Gilotrif (afatinib).   We’ve learned that there are an array of EGFR mutations, and that the two most common ones, an exon 19 deletion or an L858R substitution on exon 21 (an exon is a specific expressed portion of a gene), each somewhere around 40-45% of  the EGFR mutations seen, are actually the ones consistently associated with a dramatic and often long-lasting response to EGFR TKIs. In contrast, the other 10-12% of EGFR mutations, most commonly on exon 18 or exon 20, are a heterogeneous group with a less clear benefit from EGFR TKIs.  

For about the last 5 years, the lung cancer community has reached a pretty clear consensus that the exon 19 deletions and exon 21, L858R substitutions represent so-called “activating mutations”, and patients with these specific mutations in their tumors are the ones that have, in trial after trial, been shown to have a markedly higher response rate (RR) and longer progression-free survival (PFS) with EGFR TKIs than with standard chemotherapy.  Over that time, they have been pooled together and largely presumed to be very comparable. More recent research presented at ASCO 2014, however, rekindles questions that go back many years and cast doubt on whether we should really pool these two mutations together. 

Back in 2006, two different publications came out — one from Boston’s Dana Farber Cancer Institute (on the top of the figure below), and another from New York’s Memorial Sloan-Kettering Cancer Center (bottom of figure below) — each independently reported that while both mutations were associated with very good responses to Iressa or Tarceva, the exon 19 patients seemed to do better, potentially in terms of both PFS and overall survival (OS).  

Exon 19 vs. Exon 21 2006

(click on image to enlarge)

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Gilotrif (Afatinib) Reports Survival Benefit for EGFR Mutation-Positive Advanced NSCLC: Is it a Superior EGFR Inhibitor?

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One of the high profile presentations in the lung cancer track at ASCO 2014 was from Dr. James Yang of a pooled analysis of the LUX-Lung 3 and LUX-Lung 6 trials, each comparing Gilotrif (afatinib) to standard chemotherapy as first line treatment of EGFR mutation-positive advanced NSCLC, which for the first time demonstrated an actual survival benefit not seen in similarly designed trials with Iressa (gefitinib) or Tarceva (erlotinib). We should expect to see a huge marketing campaign built on this result, implying that Gilotrif is now the leading choice of oral EGFR inhibitors that would be considered for EGFR mutation-positive patients. But is this a fair claim?

The LUX-Lung 3 trial compared Gilotrif to cisplatin/Alimta (pemetrexed) in a global trial, while LUX-Lung 6 compared Gilotrif to cisplatin/gemcitabine in an Asian trial, each with over 300 EGFR mutation-positive patients. Both showed a highly significant improvement in response rate and progression-free survival that largely reproduced the same results seen in several preceding trials with Iressa (gefitinib) or Tarceva (erlotinib) vs. other chemo regimens over the past few years.  However, all of the preceding trials have failed to demonstrate a difference in overall survival (OS) from the EGFR tyrosine kinase inhibitor (TKI).  This has been presumed to have been because the vast majority of patients receiving initial chemotherapy have crossed over to an EGFR TKI at progression, with the presumption that these patients then demonstrate the same kind of dramatic and long-lasting response that we hope to see in EGFR mutation-positive patients starting on an EGFR TKI as initial treatment. In other words, we might presume that it doesn’t matter if you receive an EGFR TKI as first or subsequent treatment if you have an EGFR mutation, as long as you get it, so this “crossover” effect should negate any survival benefit from an EGFR TKI given as first line therapy.

The LUX-Lung trials did not demonstrate a significant improvement as individual studies, and in fact, the LUX-Lung 6 trial didn’t even show an improvement in median OS for the Gilotrif arm over chemotherapy. Overall, when we look at the absolute results of the two trials, at least in terms of median OS, we see that they did very comparably to preceding trials with other EGFR TKIs — in fact, the best median OS was seen in a Japanese trial with Iressa.

Is OS superior to other EGFR TKIs

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Does Adding Avastin to Tarceva Help EGFR Positive Lung Cancer Patients?

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Drs. Nasser Hanna, Melissa Johnson and Jack West discuss results of a phase 2 trial presented at ASCO 2014 that studied if adding Avastin (bevicizumab) to Tarceva helped EGFR positive lung cancer patients increase progression-free survival. June 2014.

Primary endpoint: PFS by independent review


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