Expert Elaborates on Developments in SCLC and EGFR-Mutant NSCLC

Kathryn A. Gold, MD

Data from the phase III FLAURA study cemented osimertinib’s (Tagrisso) place as the frontline standard of care for patients with EGFR-mutation positive non—small cell lung cancer (NSCLC), said Kathryn A. Gold, MD.

In FLAURA, treatment with osimertinib nearly doubled the median progression-free survival (PFS) of first-generation tyrosine kinase inhibitor (TKI) therapy with erlotinib (Tarceva) or gefitinib (Iressa). The FDA approved osimertinib in this setting in April 2018 based on these data, followed by the European Commission making the same decision in June 2018.

Preclinical data suggest that patients who progress on osimertinib and harbor a C797S resistance mutation may derive benefit from first- or second-generation agents. However, Gold explained that combination trials will be the focus of research going forward.

The space of small cell lung cancer (SCLC) varies from that of EGFR-mutant NSCLC. Gold noted that although there have not been as many developments in SCLC as in NSCLC, the needle is beginning to move as a supplemental biologics license application for single-agent nivolumab (Opdivo) is currently under priority review by the FDA in the third-line setting.

The application is based on data from the phase I/II CheckMate-032 trial, in which single-agent nivolumab demonstrated a median overall survival (OS) of 4.4 months (95% CI, 3.0-9.3), as well as a 1-year OS rate of 33% (95% CI, 22-45) in patients with progressive SCLC following more than1 prior line of therapy.^1,2 The FDA is scheduled to make its decision by August 16, 2018 under the Prescription Drug User Fee Act.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Gold, associate professor of medicine, University of California, San Diego, discussed the evolving management of EGFR-mutant NSCLC and the latest developments in SCLC.Gold: As we all know, EGFR-mutant lung cancer is important to recognize clinically because these patients are treated differently. They benefit from TKIs rather than from standard chemotherapy. Until very recently, our standard treatment for patients was erlotinib, afatinib (Gilotrif), or gefitinib in the frontline setting.

Is the future of osimertinib in combination or as a single agent?

More recently, the FLAURA data have been presented. That looked at patients with previously untreated EGFR-mutant lung cancer. These patients were randomized to osimertinib versus the standard first-generation agents. The results were pretty impressive. Osimertinib clearly had improved PFS and [had] a trend toward improved overall survival [OS]. It’s also a very-well-tolerated drug. Our frontline standard of care has become osimertinib since those data were presented.Frontline osimertinib is here to stay for now. A 19-month PFS is pretty impressive for a very-well-tolerated drug. It’s tough to imagine frontline combinations coming in and beating [single-agent osimertinib], both in terms of tolerability and outcome.

How has osimertinib’s approval affected sequencing for patients who progress?

The combinations will come in the treatment of resistance to osimertinib. We’re going to see more patients who are progressing on these drugs. Right now, we don’t have any [other] standard option for people who progress on osimertinib except for cytotoxic chemotherapy, which many of our patients would like to avoid if possible.It’s to be determined. Normally, if patients get erlotinib, afatinib, or gefitinib in the frontline setting and osimertinib at resistance, I don’t go back to the TKIs following progression. I tend to go straight toward chemotherapy. With osimertinib, we’re learning more about the resistance mechanisms.

What is the rationale behind putting a MET inhibitor and osimertinib together?

Are there any patients who are ineligible to receive osimertinib in the frontline setting?

Are there different resistance mechanisms to osimertinib in the first-line versus the second-line setting?

There are some preclinical data showing that patients who have progressed with a C797S resistance mutation may maintain responsiveness to first- or second-generation agents. Clinically, we don’t have the data we need yet. That will be something to look for in the future. The combination trials are going to be very important in this setting. The TATTON trial, for example, is looking at a MET inhibitor in combination with osimertinib; that’s very promising.At least 30% of patients who progress on osimertinib will have MET amplification in their tumor. That suggests that it is an escape mechanism for osimertinib and leads to resistance. It makes sense to go after that pathway.The [patients with] more unusual EGFR mutations may be better candidates for afatinib. We know that G719 mutations are responsive to the first- and second-generation agents. However, those [patients] were excluded from the FLAURA trial. For those patients, it might be better to stick with a first- or second-generation agent. For most others, I’m going with osimertinib. There are some drug interactions that could make osimertinib tough to give that may not be a factor with the other drugs, but that’s the minority of patients.The differences in resistance to first- and second-line osimertinib are still to be determined. For erlotinib, we had many years of rebiopsy data and large case series telling us what the resistance mechanisms were. We have not had the time to build that up for patients progressing on osimertinib.

Where will dacomitinib fit into the landscape, if that is approved?

You also gave a lecture on SCLC. What did you highlight in this space?

That being said, we will see differences. Patients who receive osimertinib for T790M-positive disease tend to maintain that T790M mutation. That may have implications for subsequent therapy, whereas patients who progress on frontline osimertinib normally don’t have T790M, so it may make different options a possibility in the second-line setting.It is hard to know where it ts in. [Dacomitinib] didn’t go head-to-head against what is now our standard of care [osimertinib]. I find it’s tougher to tolerate, so I don’t know where that’s going to fit into the landscape.EGFR-mutant lung cancer is an area where we have had these rapid advances over the past 10 years that I’ve been [in this field]. We haven’t moved the needle as much as I would like in SCLC. In many cases, we are still using therapy that has been around for 20 years, which is platinum etoposide with the addition of radiation for limited-stage disease. That’s been a bit disappointing.

What are your thoughts on the priority review of nivolumab. Can you see it being moved to an earlier-line setting?

What about the latest results with rovalpituzumab tesirine (Rova-T)?

There [have] been a lot of exciting drugs that have died in the SCLC space. That said, we have a few advances. Immunotherapy, as is the case in many tumors, is becoming an important tool for SCLC. Recent trials using nivolumab either in combination with ipilimumab or as a single agent look promising. Nivolumab is under priority review right now for use as a single agent in the third-line setting. We’re nally starting to move the needle a bit.The drug is under priority review, but it’s been listed on the NCCN [National Comprehensive Cancer Network] guidelines for a while now. In SCLC, we don’t have many good options. It’s already being used off label for second- and third-line treatment. If it is FDA approved in the third-line setting, then that will hasten the adoption of [the agent]. Our other FDA-approved option is topotecan, and it doesn’t work very well. It’s not hard to persuade patients to switch from their standard of care to something new if it looks promising.Rova-T is an antibody-drug ligand targeting the DLL3 protein, which is expressed on most SCLCs but very few normal cells. It’s a promising and pretty unique target. The initial phase I trial showed pretty high response rates in a heavily pretreated group of patients.

Are there any other emerging strategies?

More recently, AbbVie [the manufacturer of Rova-T] announced that [it] had decided not to seek accelerated approval based on the results of their phase II trial. They’re still going ahead with a couple of large phase III trials—one in the maintenance setting after frontline chemotherapy and the other in the second-line setting after failure of a platinum-based doublet. We’ll see what those show. There might still be hope, but everyone was hoping the data would look better than they did from the phase II trial.The role of radiation is still being determined in extensive-stage [disease]. I’m not a radiation oncologist, but a few years ago we offered prophylactic cranial irradiation [PCI] to most patients with extensive-stage SCLC. Newer data suggest that it may not be needed and, in some cases, may be harmful.

I’m using less PCI, but more thoracic radiation. The data coming out [show] that even in extensive-stage [disease], there are groups of patients who can benefit from thoracic radiation; for example, those with limited extra-thoracic disease, those with a good response to frontline chemotherapy. My radiation [approach] has moved downward; no longer to the brain but more often to the thorax. I’ve seen some good results with that.

Are there any other immunotherapies besides ipilimumab and nivolumab that are being looked at?

There are not a lot of large-scale clinical trials. Rova-T and immunotherapy are lling up that space right now. There’s some interesting preclinical work coming out of The University of Texas MD Anderson Cancer Center and some other places looking at PARP inhibition. That’s not quite ready for prime time, but I’m interested to see the results of that.In SCLC, ipilimumab and nivolumab are really at the forefront. They were the first combination to go into this disease, and they’re definitely the furthest along. Some of the other drugs have had small cohorts in larger trials in SCLC, but I’m not aware of any other large-scale trials that are ongoing.

What is it about SCLC that has made it so much more difficult to make advances than NSCLC?

There was a very large-scale trial looking at the combination of chemotherapy with ipilimumab for frontline SCLC. I was a part of that trial, which enrolled about 1100 patients, the largest trial in SCLC. Newly diagnosed patients were randomized to either platinum etoposide with or without ipilimumab and followed for OS. Unfortunately, that trial was “stone cold” negative. There was no difference in OS between the arms, so it was a bit disappointing. I believe that paved the way for some of the immunotherapy trials that are coming along now.SCLC has not improved as rapidly as NSCLC. We have so many more treatment options for NSCLC than we do for SCLC now. Part of that is a numbers game. There are a lot more patients out there with NSCLC than SCLC, so it’s easier to rapidly enroll those patients on clinical trials.

Is there anything else you want to emphasize?

SCLC is also a very messy disease. It tends to have a very high mutation burden, and it tends to progress rapidly. It’s been hard to efficiently enroll patients before they get too sick to go on trial. There are so many mutations in this tumor, and a lot of them are in genes like p53 and RB. It’s tough to target those with therapies. We have not been successful at targeting them yet, which is another reason [progress has] really lagged behind.One of the most important things in cancer overall is to know that clinical trials are how we improve care, both for our current and future patients. Clinical trials are what I do; they’re what I love. The best treatment for many patients is on a clinical trial. For anyone facing this diagnosis, always ask your providers what clinical trials might be available and if they’d be a good fit for you.

References

1. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34 (suppl; abstr 100).
2. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial [published online June 4, 2016]. Lancet Oncol. doi: 10.1016/S1470- 2045(16)30098-5.