EADO Congress 2015

Metastatic melanoma: Patient-reported outcomes from the KEYNOTE-002 study

Prof Dirk Schadendorf - University of Duisburg-Essen, Essen, Germany

I want to ask you about patient reported outcomes in melanoma because we’ve got a few interesting trials here at the melanoma meeting in Marseilles. We’ve been hearing, of course, earlier in the year about KEYNOTE-002, could you review what the findings were on progression free survival in that study?

Yes, KEYNOTE-002 is a study in heavily pre-treated melanoma patients; more than two-thirds of the patients had two or three lines of previous treatment and the major message is that response rates using pembrolizumab, a PD1 blocking antibody, are increasing 20%, from 10% response rate chemotherapy to 35% with the pembro arms.

So you’ve justified adding pembrolizumab, then?

It’s not an addition, it’s a substitution of chemotherapy. That’s also the basis of registration of pembrolizumab for first and second line treatment in melanoma.

Now, you’ve also interestingly done health related outcomes, patient reported outcomes, from this study. What did you find?

That’s a very interesting finding. As I said, heavily pre-treated patients the benefit is still small but still we see an increase in quality of health parameters and scores. So the deterioration of health status with chemotherapy was significant and was slowed down using pembrolizumab.

And the rate of slowing was relatively modest, though, wasn’t it?

That’s true because since the response rate for the drug, for pembrolizumab, is only 35% only one-third of the patients benefitted clinically. So overall the benefit for the entire patient population is modest but still significant.

You started, then, with these patients who were pre-treated with pembrolizumab; had they had ipilimumab?

It was a requirement for this study that all patients had to see ipilimumab in a previous line of treatment and had failed ipilimumab. If a patient had a BRAF mutation status they in addition had a BRAF inhibitor and had failed this kind of treatment.

So in fact pembrolizumab was adding on top of all of those therapies.

Exactly, as a last line treatment option for those patients.

In view of the PFS findings and the quality of life findings, what is your recommendation to doctors about the use of pembrolizumab in this heavily pre-treated group of patients?

I think there is clear evidence that in heavily pre-treated patients pembrolizumab is working, it is giving clinical benefit and is also improving quality of life, definitely in those patients having also a clinical benefit. If we look at health related outcome measures, this is very much dependent on how many of the patient population treated are really having also a clinical benefit.

And is that a big number?

For the pembrolizumab KEYNOTE-002, as I said, it’s around one third of the patients who have a clinical benefit. If we now move in first line, for example, the response rate for pembrolizumab and PD1 antibodies is more than 40%, in the range of 40%, and in the targeted arena we have with BRAF inhibitor monotherapy a response rate of 50% or the combination which is now currently being approved, dabrafenib and trametinib, has response rates of 70%.

And indeed you are quoting at this meeting quality of life findings on that very combination, dabrafenib and trametinib, aren’t you?

Indeed, that’s true. We are seeing a comparison of the combination of dabrafenib and trametinib in comparison to either dabrafenib as a monotherapy in the COMBI-d study or in a second study in comparison to vemurafenib in the COMBI-v study. Both studies show also health related outcomes, a significant increase in patient related parameters including pain, including social functioning, in favour of the combination.

To a degree, the sequence in which you have used various drugs with these patients was dictated by the availability of these agents. What would you do in an ideal world right now?

That’s obviously a very interesting and challenging question. I think patients who have a BRAF mutation have at least two options: the dual blockade using dabrafenib and trametinib and a PD1 antibody which is currently available. Patients who are BRAF wildtype, the new standard for those patients is a PD1 antibody.

And that’s first line therapy?

That’s first line treatment option, yes.

So what should doctors briefly be taking home from all of this?

Compared to five years ago, we have increased survival times three times, from eight to ten months, now to more than two years. Progression free survival time has increased from DTIC around 2-3 months now to more than a year.

So big improvements, nowhere near the c word yet?

No, that’s true.

But prospect for more improvement?

I think combining and sequencing these new drugs will further increase overall survival times and definitely we need to identify the subgroups who are benefitting from these different kinds of modalities we have now in hand. Also to choose in patients where we have more than one option, BRAF inhibitors and immuno-oncology, what to do first because there is no clinical trial to inform us on the right sequence.