Paul A. Bunn Jr, MD

Insights From the ESMO 2017 Congress: Lung Cancer

Question

Does any research presented at the European Society of Medical Oncology (ESMO) 2017 Congress inform clinicians how and when to administer PD-1 or PD-L1 therapies?

Answer

There were a couple of abstracts that addressed that. Of course, one of those abstracts was giving durvalumab, a PD-L1 inhibitor, after chemoradiation for stage III, unresectable non-small cell lung cancer (NSCLC). Progression-free survival (PFS) was statistically in favor of the durvalumab, and that now has been published in The New England Journal of Medicine.¹

Such treatment has not yet been approved by the US Food and Drug Administration (FDA) or any guideline committee, though it likely will be practice-changing. The major issue is that the coprimary endpoint of [overall] survival has not yet been presented. Most people presume that the OS coprimary will look like PFS, and will be statistically better. But some physicians may wish to await OS results before adopting this therapy as routine for all patients.

With respect to timing, for the PACIFIC trial, they allowed you to start durvalumab any time after the chemoradiation was over, up to 7 weeks (42 days) afterwards. It was better for PFS to give it within 14 days, as compared to more than 14 days, but that was a subset that was not planned. So, you could start anytime up to 42 days after chemoradiation.

There are trials ongoing looking at giving checkpoint inhibitors before or during chemoradiation. There are also ongoing trials looking at giving checkpoint inhibitors in resectable patients either before surgery, after surgery, or both. Some preliminary results for nivolumab before surgery have been presented, although not at this ESMO Congress.

There was an updated survival from KEYNOTE-021 cohort G, which randomly assigned previously untreated stage IV non-squamous cell carcinoma patients to get pemetrexed/carboplatin and pembrolizumab vs just chemotherapy.³ In the original presentation there was really no apparent difference in survival. In this presentation, there was some survival advantage for the people getting the combination of chemotherapy with pembrolizumab (this was for stage IV patients).

There was also a study looking at whether it mattered if you gave nivolumab beyond a year or stopped, and it appeared that continuing the treatment beyond a year was helpful.²

Question

Some data presented at ESMO suggest that CDK4/6 inhibition may be effective in late-stage lung cancer. Do you agree with this? Would CDK4/6 inhibition be supplemented effectively with pembrolizumab or another checkpoint inhibitor?

Answer

There was an abstract presented that looked at the CDK4/6 inhibitor, abemaciclib. That study combined it with a PI3K inhibitor; another group got [abemaciclib] with pembrolizumab. There weren’t any responders in either group.⁴

The group that got pembrolizumab had a stable disease rate of 65% and a progressive disease rate of 5%. Those seemed better than the group that got abemaciclib plus the PI3K inhibitor. There, the stable disease rate was 30%, compared with 65%, and the progressive disease rate was 12% compared with 5%, so clearly that combination didn’t seem to be as good.

It would appear that giving abemaciclib with pembrolizumab is better, but what we don’t know is whether the combination would have been better than pembrolizumab by itself. While the trial did suggest that that particular combination was better than the other, but it really doesn’t give us much indication that that combination would be better than pembrolizumab by itself. Certainly it might be enough to continue to study, but no one is going to reach any clinical conclusion about that other than maybe that the combination should be studied more.

Question

Do results from the phase 3 IFCT-0302 trial change your recommendation about how to follow up with patients with resected lung cancer?

Answer

This was a trial looking at follow-up of patients who might have been cured by their original surgical treatment or surgery with chemotherapy or radiation.⁵ There’s no guideline for how often those patients should receive follow-up CT scans or follow up scans of any kind.

In this trial patients were randomly assigned to receive a clinical examination and chest X-ray or clinical examination and chest X-ray with CT scans and/or bronchoscopy every 6 months for 2 years and then yearly.

There were a large number of patients on this trial (1775) and it was not clear that there was a survival advantage in patients who received CT scans every 6 months and then once a year. On the other hand, the overall survival was a bit better in the people that got the CT scans than in the group that didn’t, but the differences were not statistically significant; the study has not met the endpoint of benefit in terms of survival.

The researchers concluded that they need longer follow-up to make sure there’s not an overall benefit, because recurrences and second primaries can occur much later. And so, in my opinion, it’s not a practice-changing abstract at this time.

Another reason to give CT scans yearly, however, is to find second cancers early, although that could affect survival. But the results of that are going to take years to know for sure.

I don’t think, personally, there’s any advantage of getting an abdominal CT; I don’t think there’s any advantage of giving contrast with the CT scans, I don’t think there’s any known value of doing PET scans, and I don’t think there’s any known value of doing chest X-rays.

At our institution, the practice of getting a chest CT scan every 6 months for 2 years and then yearly won’t change based on this abstract.

Question

Do any particular study results suggest to you that EGFR-mutated NSCLC is best treated first-line with an EGFR-TKI?

Answer

There was a trial called FLAURA in which patients were randomly assigned to get gefitinib or erlotinib — first-generation EGFR-TKIs — or osimertinib, a third-generation EGFR-TKI, as their first treatment for stage IV, EGFR-mutant adenocarcinoma of the lung.⁶ The primary endpoint of the trial was PFS, which was basically much longer with osimertinib compared with gefitinib or erlotinib (19 months vs 9 months), so the study met its primary endpoint.

Of course, there are other factors to consider. One is toxicity: osimertinib has less skin toxicity and diarrhea than erlotinib or gefitinib, and osimertinib crosses the blood-brain barrier, so there are fewer central nervous system (CNS) metastases.

So on the basis of fewer side effects, longer first PFS, and fewer brain metastases, certainly many people will choose to proceed with osimertinib first.

The question is, is it better to give osimertinib first or erlotinib and gefitinib followed by osimertinib? It’s not totally resolved by the data that have been presented. The overall survival data haven’t been presented either — it’s not likely that there’s going to be a survival difference, but there could be.

In my opinion, in the United States, that study will lead many people to give osimertinib first, because it has a longer PFS, fewer side effects, and fewer brain metastases. I think that the conclusion of the authors — that this is a treatment option — is correct, but it doesn’t necessarily mean that it’s the only treatment option, especially in countries where cost is a huge issue; I don’t think it’s required that everyone get osimertinib first. But in my own practice the majority of patients would get osimertinib first.

Question

What would you say are the most important “takeaways” from this year’s ESMO meeting for thoracic oncologists?

Answer

In my opinion, the most important data from the ESMO 2017 Congress for thoracic oncologists to be aware of are the PACIFIC trial, which showed that adding immunotherapy after chemoradiation prolonged PFS — that is a practice-changing abstract. It is also important for thoracic oncologists to be aware of the FLAURA trial results, which, as I explained, evaluated first line osimertinib compared with erlotinib and gefitinib. Lastly, the finding that there were survival differences in KEYNOTE-021 cohort G — pembrolizumab with chemotherapy compared with chemotherapy in the first-line setting — is also important to be aware of.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Sep 8. doi: 10.1056/NEJMoa1709937 [Epub ahead of print]

2. Spigel DR, McLeod M, Hussein MA, et al. Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC). Presented at: ESMO 2017 Congress; Madrid, Spain: September 8-12, 2017. Abstract 1297O.

3. Borghaei H, Langer CJ, Gadgeel S, et al. Updated results from KEYNOTE-021 cohort G: a randomized, phase 2 study of pemetrexed and carboplatin (PC) with or without pembrolizumab (pembro) as first-line therapy for advanced nonsquamous NSCLC. Presented at: ESMO 2017 Congress; Madrid, Spain: September 8-12, 2017. Abstract LBA49.

4. Garrido Lopez P, Goldman J, Kelly K, et al. Efficacy and safety of abemaciclib combined with either LY3023414 or pembrolizumab in stage IV NSCLC. Presented at: ESMO 2017 Congress; Madrid, Spain: September 8-12, 2017. Abstract 1363P.

5. Westeel V, Barlesi F, Foucher P, et al. Results of the phase III IFCT-0302 trial assessing minimal vs CT-scan-based follow-up for completely resected non-small cell lung cancer (NSCLC). Presented at: ESMO 2017 Congress; Madrid, Spain: September 8-12, 2017. Abstract 1273O.

6. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: ESMO 2017 Congress; Madrid, Spain: September 8-12, 2017. Abstract LBA2_PR.