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Real Hope for Small Cell Lung Cancer Treatments from ASCO 2015
Dr Pennell

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.

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