One of the interesting themes for that emerged for me at AACR this year was the amount of effort that is being expended on strategies to overcome drug resistance. This was particularly noticeable in metastatic melanoma and non-small cell lung cancer (NSCLC).  More on lung cancer in another post, as today I want to focus on melanoma.

In the advanced melanoma, vemurafenib is given to patients with the BRAFV600E mutation, which occurs in approximately 50% of patients. This oncogene drives activity of the tumour, but inhibition with vemurafenib (Zelboraf) has shown some remarkable effects, as the stunning before and after photos from Levi Garraway’s group demonstrate.

The challenge, however, is that adaptive or acquired resistance can occur in response to treatment and patients sadly find their melanoma returning after approximately 6-9 months on continuous daily therapy.

At last year’s ASCO, we saw that adding a MEK inhibitor such as trametinib to a BRAF inhibitor such as dabrafenib added around an extra 3 months over single agent BRAF therapy before the resistance set in and the disease returned, sometimes with a deadly vengeance.

I’ve written here on this blog about numerous mechanisms of resistance in advanced melanoma from MEK to COT and others (see related posts below for background reading).

The big question at this AACR was how is the field progressing with new research?

Sometimes, we have to go back to the lab to study animal models of resistance before returning to the clinic with new ideas.

Screen Shot 2013 04 15 at 2.54.50 PM e1366052173940 Overcoming resistance to vemurafenib in metastatic melanomaThat’s what a young Novartis Postdoctoral fellow from NIBR, Meghna Das Thakur, did. She asked critical questions and attempted to answer them in a series of elegant experiments with mice as well as retrospectively test the concept in patient data. The cool thing is that while many of the oral sessions were taken up by the Major League researchers is that it’s also nice to see up and coming young scientists present some nicely done research.

What Dr Thakur did was really interesting…

Her hypothesis was simple – that resistant tumours are ‘less fit’ than sensitive cells and have a selective disadvantage over sensitive cells in the absence of drug.

If this were true then we would expect to see dependence on drug for growth of resistant tumours in xenografts, much as we do in humans, with vemurafenib. The data clearly showed that vemurafenib resistant tumours were dependent on drug for growth. They also observed that:

1) p-ERK levels increased following withdrawal of vemurafenib in resistant tumours
2) There was a great deal of heterogeneity in the mechanisms of resistance

The key question then becomes how can we use this information to prevent resistance?

One way to explore this is to look at selective pressure, since vemurafenib is usually given continuously…

  • Treating continuously means that selective pressure enriches resistant cells
  • However, withdrawing the drug means that resistant cells suffer a fitness deficit

Essentially, the researchers noted that, “alternating the selective pressure prevents the emergence of a resistant population.”

In comparing continuous vs intermittent dosing, two things could be concluded from the model:

1) Resistant tumours emerge more rapidly under continuous dosing with vemurafenib
2) Intermittent dosing in multiple tumor xenograft models forestalled resistance

What can we learn from retrospective patient data?

What they did next was to look at computed tomography (CT) scans analysed for evidence of vemurafenib-dependence in patients treated with vemurafenib in the BRIM-3 and vemurafenib safety study, which were identified from the clinical trials database at the Royal Marsden Hospital. In particular, they focused on patients who stopped treatment because of progressive disease (PD).

Of 42 patients identified, 19 of these had CT scans performed after cessation of vemurafenib available for review, while 23 patients did not have a CT available for review and in 16 patients this was because of rapid PD.

For each of those 19 patients with a post-vemurafenib CT, the total tumour volume on three consecutive CT scans was recorded:

  • The CT performed prior to stopping vemurafenib
  • The CT performed when progressive disease was diagnosed and vemurafenib stopped
  • The CT performed after vemurafenib was stopped and prior to the initiation of further therapy

They found that 14 of the 19 patients experienced decreased tumour growth rate following cessation of vemurafenib, supporting the hypothesis that resistant tumours emerge more rapidly under continuous dosing with vemurafenib.

In this model, it is clear that intermittent dosing prolongs survival, but what is the underlying mechanism, and what does this mean for future treatment of patients and also clinical trial designs?

From this initial work it was clear that the MOA is not yet fully understood and further bench work will be needed to elucidate the mechanisms involved.  We don’t yet know, as the researchers point out, whether:

“Does resistance come from a clonal population or is it an adaptation or re-wiring of a selected few cells?”

What was clearer though, is that new clinical research will be needed to evaluate the potential for intermittent vs continuous dosing in patients, particularly in combination:

  • Will there be greater selective pressure from BRAF + MEK inhibitor combinations vs BRAF alone?
  • Identify combination partners that could be used during BRAF inhibitor holiday.

Overall…

I thought this was a very nice piece of well thought out research, perhaps one of my favourites from the AACR meeting this year.  Critically, we saw that the preclinical mouse xenograft model predicted a clinically-relevant resistance mechanism. Removal of drug from resistant cells leads to MAPK pathway hyper-activation and resistant cells experience a fitness deficit. Cycling the mice on and off therapy led to better outcomes than if they were dosed continuously, thereby giving us a new strategy to consider in melanoma patients.

The main impact of this preclinical study is that future clinical research in advanced melanoma should investigate the value of intermittent dosing strategies to improve patient outcomes.

The work turns the old concept of continuous dosing 365/24 on its head – suppressing the BRAFV600E oncogene continuously in melanoma may not necessarily be the best strategy in terms of superior outcomes.

This this does NOT mean that ALL tumours will behave in a similar fashion and intermittent dosing should be tested first in clinical trials where there is sufficient scientific evidence to warrant it.  If I were a patient, considering drug holidays without any evidence of effectiveness would NOT be a good idea.

I’m really looking forward to seeing the results of future combination trials with intermittent dosing to see if outcomes are indeed improved beyond would we currently see with continuous dosing either alone or in combination.