COMMENTARY

ESMO: STIMULI Optimism Despite Trial Data Disappointment

Prof Sanjay Popat

Disclosures

September 23, 2020

Prof Sanjay Popat on potential future advances after the STIMULI trial's negative outcomes in limited stage small cell lung cancer.

This transcript has been edited for clarity.

Hello, my name is Sanjay Popat, consultant medical oncologist at the Royal Marsden Hospital in London and professor of thoracic oncology at the Institute of Cancer Research.

What were the headline results?

STIMULI was a randomised phase II study in the setting of limited stage small cell lung cancer.

It's an important study because it's one of the first studies to evaluate the role of immunotherapy in this very difficult to treat disease, and we know already that immunotherapy is active in metastatic small cell lung cancer when combined with chemotherapy.

This trial was designed a few years ago and took patients with limited stage disease and randomised them to receive either four cycles of concomitant chemoradiotherapy with either once or twice daily radiotherapy, consolidated with prophylactic cranial irradiation, and then were allocated in a random manner, either observation, which is our current standard of care, or consolidation with combination of nivolumab (Bristol-Myers Squibb) and ipilimumab (Bristol-Myers Squibb), four cycles, followed by nivolumab for up to 1 year.

The nivo-ipi schedule is one where the nivolumab dose was 1 mg/kg, and the ipilimumab dose was 3 mg/kg, based on previous data in small cell lung cancer, early data, demonstrating a potential benefit for that regime.

The study was a large study, an international study, and unfortunately had to close early because of reduced recruitment, mainly because limited stage small cell lung cancer isn't as common a disease, as we expect, and the large number of patients that didn't make the full amount of chemoradiotherapy, therefore eligible to be randomised at completion of the chemoradiotherapy.

The primary endpoint of the study was progression-free survival, but unfortunately there was no improvement in progression-free survival, for consolidation immunotherapy over observation.

In the forest plots of progression-free survival we see a potential signal for twice daily radiotherapy over once daily radiotherapy. And that I think is something worth investigating further in the future.

In terms of overall survival, there was no overall survival benefit. And again, a signal perhaps of benefit in the twice-daily radiotherapy arm.

So overall, there seem to be no clinical benefit for the consolidation of nivolumab-ipilimumab at the dose of nivo 1 / ipi 3 in patients with limited stage small cell lung cancer who have completed a full schedule of concomitant chemoradiotherapy, together with prophylactic cranial radiation.

Were you disappointed with the outcomes?

Of course, we're disappointed to see that there was no improvement in the primary endpoint of progression-free survival. But you know, this is the nature of clinical science.

And this is exactly why we do randomised trials to see what the science shows.

Nevertheless, this is an advance in the field because we've already demonstrated that this is not perhaps the best schedule of nivolumab-ipilimumab to be using because there was a relatively high rate of grade 3 and more adverse events really due to the scheduling of the nivo and ipi dosing.

That combined with the full schedule of concomitant chemoradiotherapy can be quite tough for patients. So I look forward to additional trials which are ongoing in this area.

Is there potential work in subgroups following the trial?

We need to look at the subgroups of the STIMULI data in more detail. And of course, we need to follow up these patients for a little bit longer.

There's some evidence of non-proportionality of hazards for the overall survival, as we've seen previously in trials of nivolumab and ipilimumab. And it may be that there is a small group that does show benefit, but that's not quite as apparent just yet. So with more time, we'll have a better understanding on the different subgroups that may or may not benefit.

The other key issue is translational analyses. We've collected a lot of specimens in this trial, and that will help us evaluate the role of biomarkers, trying to work out a group that might benefit from immune checkpoint inhibition in the limited stage setting further.

What's the anticipated role for immuno-oncologics in this space?

Personally I've no doubt that in the future we will be showing that checkpoint inhibitors are active in limited stage small cell lung cancer, we just don't have the data yet. And there are trials going on in this setting. We know that when we combine checkpoint inhibitors with chemotherapy in the metastatic setting there is a meaningful benefit from patients.

We have two randomised trials IMpower133 and CASPIAN, both demonstrating a similar magnitude of benefit for PDL-1 inhibitors.

There are a number of trials ongoing in the limited stage setting. But I guess one of the trials that many of us are looking forward to is the ADRIATIC trial in which patients that had completed concomitant chemotherapy for limited stage 4 cell lung cancer have been randomised to either durvalumab, or durvalumab-tremelimumab combination, or placebo, and this will really be an important trial when it reads out eventually.

Overall, are you still optimistic?

Overall, despite the fact that we didn't demonstrate a PFS or OS advantage in STIMULI, I do remain optimistic that there will be a proven role for checkpoint inhibitors in the future in limited stage small cell lung cancer. We just have to prove that benefit, and that's why it's absolutely important we continue to generate the evidence and ensure that our patients get access to clinical trials.

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