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Immunotherapy for Small Cell Lung Cancer

GRACE Cancer Video Library - Lung



Dr. Cathy Pietanza from Memorial Sloan Kettering Cancer Center reviews early trial data of immunotherapy agents for treatment of small cell lung cancer (SCLC).


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There has been a lot of excitement with immunotherapy in non-small cell lung cancer — nivolumab was recently approved for the treatment, in the third line setting, for squamous cell lung cancer, and has received NCCN designation to be used in adenocarcinoma. These treatments, as I said, target the immune system, and the way that I like to explain it is that, currently, the cancer is able to decrease the amount that the immune system works against it, and by using immune therapy inhibitors, the proteins and the two systems become disconnected, so that way the immune system can really attack the cancer.

In June of 2015, at our annual clinical oncology conference, we saw data for two agents – one was nivolumab, and that clinical trial was very early phase, it was only a phase one, it was really only looking to see if there was safety. There were two arms to that study — one arm received nivolumab by itself, which is one inhibitor against the immune system, and the other used nivolumab with ipilimumab. Ipilimumab is another type of inhibitor against the immune system. It’s believed that, maybe, two inhibitors may work better than one alone, and both arms showed that there was a very nice response rate to these drugs in small cell lung cancer, and that the patients who did respond had a long-term response duration. And, so, these are being evaluated in newer trials. In fact, there’s a maintenance trial that’s planned to start opening in January 2016 or so, that will be looking at immune therapies in the maintenance setting, which is something that’s never really been explored in small cell lung cancer — that’s if we use a drug after first line chemotherapy. The trial is going to be a placebo controlled trial, so patients will be on one of three arms: either placebo, or nivolumab, or nivolumab with ipilimumab.

In June of 2015, also at our large clinical oncology conference, pembrolizumab, another immune therapy inhibitor, was also shown to be beneficial in patients with small cell lung cancer. There are several trials planned with this drug, also, in the maintenance setting, and in the second line setting. So, second line would be, again, after first line chemotherapy, when the disease recurs; the trial that’s expected to open there is a trial of pembrolizumab, versus the standard, topotecan.


Is It Feasible and Clearly Beneficial to Combine Immunotherapy Approaches?




Drs. Leora Horn, Ben Solomon, & Jack West review the potential rationale and possible limitations of combining different immuntherapy strategies with one another.

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Dr. West:  I would say, one of the other really hot concepts at World Lung and various other meetings, is combinations with immunotherapy. And that can be two different immunotherapy agents, perhaps a drug like Yervoy (ipilimumab), which is a CTLA-4 inhibitor, that really targets a different part of the immune system, in combination with these immune checkpoint inhibitors, like PD-L1, PD-1 — or, as we have alluded a bit to, chemotherapy in combination with immunotherapy or targeted therapy. How excited are you by some of the combinations, starting with, say, the different immune therapies combined together — is this incrementally far better than any one of these drugs, and is it financially possible to do this in the world we live in?

Dr. Solomon: So, I think in melanoma, the combination data looks super exciting. I think the combination of ipilimumab and nivolumab looks really impressive, particularly in PD-L1 negative patients, and it has to be a said, even that data are relatively early data. We know that it improves progression-free survival, where we’re yet to find out whether this changes overall survival. In lung cancer, I think Leora probably has been involved in some of the studies, but I’m not sure that we’re at that stage with the data — we’re relatively early, and the early studies were hampered by a lot of toxicity in the patients, and I think at this meeting we saw some slightly different schedules that might have improved the toxicity. Leora?

Dr. West:  Of course, we do need to be mindful that melanoma patients are often quite a bit younger and healthier than your average lung cancer patient. So, what is your thought on this matter?

Dr. Horn:  I agree that the data is very early — the MedImmune with tremelimumab combinations, and the nivolumab and ipilimumab combinations, but the toxicity, I do think, is going to be a big issue for lung cancer patients. They are older, they’re just not as hardy, and the toxicities are not inconsequential when they do happen.

Dr. West:  Yeah, I think that it’s appealing to think that, maybe, combinations will work in a broader range of patients, in whom a single agent may not be enough, and that, hopefully in a few years, we will be able to predict, reliably, which patients are best served by a single drug, versus a combination, if we can find combinations that are tolerable.

Dr West

PD-L1 Expression for Immunotherapy Agents in Lung Cancer? Vital or “Don’t Ask, Don’t Tell”?


In the span of a week, we’ve just had new FDA approvals of Keytruda (pembrolizumab) for previously treated advanced non-small cell lung cancer (NSCLC) patients with tumors that express PD-L1, followed by a broadened approval for Opdivo (nivolumab) for previously treated patients with advanced non-squamous NSCLC, without a requirement for PD-L1 expression testing. This second approval for Opdivo complements the prior lung cancer approval for Opdivo, for patients with advanced squamous NSCLC, without restriction by PD-L1 expression.

So now what? Do we test for PD-L1 and use that to decide between Keytruda and Opdivo? Do we use PD-L1 testing to determine when to give an immune checkpoint inhibitor, or even if we should give it at all? Or do we just decide that if we can give one checkpoint inhibitor without restriction by PD-L1 expression, it’s not worth the time, cost, or effort of doing a test to make things more restrictive?

This is a controversial question, and my own views have been evolving as I carefully consider the treatment landscape. I’ll present why I think we SHOULD be doing PD-L1 expression testing, why it doesn’t necessarily matter which of these treatments you give, and how I see this debate shifting as new data emerge and our treatment approaches are likely to change in the next few years.

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Dr Pennell

Real Hope for Small Cell Lung Cancer Treatments from ASCO 2015


Guest post by Dr. Nate Pennell, a board certified medical oncologist at the Taussig Cancer Center at the Cleveland Clinic. He specializes in the treatment of thoracic malignancies with a focus on lung cancer. Dr. Pennell’s research interests include clinical trials using novel therapies, with a goal of facilitating the movement of new treatments from the laboratory to the clinic. Follow him on Twitter at @n8pennell.

As the dust settles from a very exciting ASCO meeting in Chicago, it is time to reflect on some of the developments in the field of small cell lung cancer (SCLC). The SCLC session is historically the session at ASCO that no one wants to attend, where failed phase 3 trials are the rule and we are constantly reminded that treatments for SCLC haven’t changed in three decades. But 2015 was different for a welcome change, and as Dr. Cathy Pietanza noted in her pre-ASCO post on this topic, we did indeed hear exciting data.

Oh sure, we got our fair share of failed trials. Dr. Alessandro Morabito presented the Italian phase 3 STAD-3 trial comparing usual dose cisplatin and etoposide chemotherapy to “toxicity-adjusted” chemotherapy in extensive stage SCLC patients, which escalated the dose of chemotherapy in patients who did not have significant side effects in the hope that more is better. More was not better, and higher doses of chemotherapy only resulted in more side effects without any differences in survival. The only positive from this trial may be that we can finally put to rest the idea that higher doses of chemotherapy make a difference in this disease and move on.

However, progress was made in both translational and clinical research. Dr. Afshin Dowlati’s group in Cleveland identified a significant potential new target in SCLC called RICTOR which was amplified in 17% of SCLC patients, which may predict for benefit from drugs targeting mTORC1/2. Such drugs are available and trials are planned for this group of patients. Other studies continued to help shape our understanding of the genetics of SCLC, although simple targets are much less common than in non-small cell lung cancer.

The most exciting development was in immunotherapy, which I must admit I was skeptical about prior to the meeting. Two trials were presented, one testing the PD-1 inhibitor Keytruda (pembrolizumab) in patients with PDL-1-positive extensive SCLC, and one testing both the PD-1 inhibitor Opdivo (nivolumab) alone and in combination with Yervoy (ipilumumab) in SCLC not selected by PDL-1 positivity. In the KEYNOTE-028 trial, Dr. Patrick Ott showed that pretreated PDL-1+ SCLC had a 35% response rate with pembrolizumab! Of course, only 28% of patients screened were PDL-1+ so this was a select group, but as Dr. Orr pointed out, this was a “proof of concept” trial to show that the drug worked at all, not intended to restrict the drug in the future to only a small group of patients. The median duration of responses was longer than 6 months and many patients continued to respond well past that point.

The Checkmate-032 study presented by Dr. Scott Antonia was even more exciting, showing that pretreated SCLC patients, a notoriously hard group to help, had a 15% response rate to nivolumab alone and a 33% response rate to the combination of nivo and ipilumumab, with most of the responses ongoing at the time of the presentation. This was NOT restricted to PDL-1+ patients, opening the door to a potentially very effective combination for these patients. One note of caution was a low incidence of serious autoimmune disorders including one fatal case of myasthenia gravis which may have been induced by the immunotherapy.

Now that we know these drugs can work, larger trials testing them in SCLC patients should be the top priority for the field in my opinion. Hopefully this is just the start of a more hopeful era for SCLC patients, and in coming years we will continue to see more trials like the latter two and fewer like the STAD-3 trial.


Immunotherapy Combinations: Best Balance of Activity and Tolerability?


ASCO 2015 Highlights 04


As more immunotherapeutics become available to treat lung cancer, research must determine how to balance efficacy, toxicities, and cost. That means finding which patients who will benefit from which drugs while maintaining good quality of life.

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