Pharma Strategy Blog

Continuing our mini series on molecular targets and lung cancer this week, today I’m going to focus on MET amplications for this post.

A few years ago, Jeffrey Engelman’s group at Mass General (see Reference section below) reported that MET amplication leads to resistance with EGFR inhibitors such as gefitinib (Iressa) by activating ERBB3 signalling:

“MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.”

Others have shown similar results in non-small cell lung cancer (NSCLC) with erlotinib.

Subsequent to this, a number of MET inhibitors have entered the clinic looking at the impact of combining a MET inhibitor with erlotinib in adenocarcinomas that are EGFR mutation positive.

Two of the leading compounds in phase II/III development are described below:

1. ARQ-197 (ArQule/Daiichi Sankyo) a small molecule inhibitor of c-MET
2. METMab (Roche/Genentech) a monoclonal antibody to c-MET

ArQule currently has two phase III trials both in the refractory setting looking at non-squamous NSCLC in combination with erlotinib versus erlotinib alone – one is currently enrolling while the other will soon be open to recruitment.

Of course, there are other MET inhibitors in earlier development (eg crizotinib is a weak inhibitor of c-MET, but is being evaluated in ALK translocated NSCLC).

What was interesting at ESMO last September was the phase II data that was presented on both agents in the same session.  The ARQ-197 data grouped all the patients together as one group and showed a trend in favour of the combination arm vs erlotinib plus placebo (7.3 vs 3.6 months) in terms of time to new metastases.

Since then, the ArQule phase III trials have been set up and appear to be looking at:

“The status of the following biomarkers will be collected in this study: EGFR and KRAS mutation status prior to randomization, and MET status post randomization.”

I think that is a good approach, because the METMab data at that conference clearly showed that MET High and MET Low patients had very different outcomes, based on the limited phase II data I saw at ESMO.

Meanwhile, the final METMab phase II data was presented from the OAM4458g study at ASCO this month, with no major change from the interim data presented last Fall ie MET High patients appear to have superior responses with the combination than erlotinib monotherapy.  The results clearly illustrate the importance of accurate biomarker analysis in these types of studies because while some patients did well on the combination, others did not, some did worse and the unselected group overall showed no difference.

Which begs the all important question – which patients did well on METMab plus erlotinib?

Those who had high MET expression, confirming the theory that resistance can be attenuated, at least for a while, with a dual combination approach of MET plus EGFR inhibitors but only in a very select subgroup of patients.

To illustrate this we can see that the addition of METMAb to erlotinib almost doubled the median time that those who were MET High (positive) were free of disease from 1.5 months to 2.9 months (HR 0.53; P=0.04) as you can see in the table from the ASCO abstract.  The combination also tripled median OS from 3.8 months to 12.6 months (HR 0.37; P=0.002):

I would imagine that a phase III trial in NSCLC will evolve very soon and it will be most interesting to see how the design and patient selection criteria for the trial will evolve, based on the known findings to date.  These factors may determine whether a successful difference can be seen with the combination based on biomarkers to define a more homogenous group.

Interestingly, a phase II study is currently enrolling with METMab in triple negative breast cancer.  This is a complex three arms design looking at the impact of:

• MetMAb + bevacizumab + paclitaxel
• MetMAb + placebo + paclitaxel
• Placebo + bevacizumab + paclitaxel

In theory, this should tell us whether eith METMab or bevacizumab have any advantage over paclitaxel chemotherapy.

What does the data with MET inhibitors mean?

The trials with both ARQ-197 and METMab teach us some important lessons in NSCLC:

1. Catch-all studies of homogenous groups are a recipe for the dreaded words, “there was no significant difference in survival between the two groups”
2. The importance of biomarkers in teasing out those most likely to respond
3. The importance of careful patient selection in achieving those aims

When we think about this year’s ASCO conference theme of “Patients. Pathways. Progress,” we should be mindful of the fact that in order to match the therapy to the patient’s mutations, we need to continue to devise studies that seek to do exactly that – sometimes good drugs fail, not because they didn’t work, but because the relevant biomarker wasn’t found to illustrate which patients did respond.  When that happens, it’s a failure of R&D, not the drug itself.

Going back to the quote above from the Engelman et al., (2007) paper, I do wonder if MET plus erlotinib is the ideal combination in the relapsed/refractory setting with adenocarcinomas, even allowing for MET-High status?  Would a pan-EGFR inhibitor that also inhibits HER3 be a better partner with MET inhibitors than erlotinib in these patients?  Who knows, but hopefully someone will test that hypothesis out in a phase II trial at some point.

References:

Engelman, J., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J., Lindeman, N., Gale, C., Zhao, X., Christensen, J., Kosaka, T., Holmes, A., Rogers, A., Cappuzzo, F., Mok, T., Lee, C., Johnson, B., Cantley, L., & Janne, P. (2007). MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling Science, 316 (5827), 1039-1043 DOI: 10.1126/science.1141478