Growing treatment landscape in SCLC spurs excitement
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The treatment landscape for relapsed and refractory small cell lung cancer is an area ripe for investigation.
Although chemotherapy remains the standard treatment for small cell lung cancer in first- and second-line settings, notable progress in immunotherapy has recently taken place, begging the question of how these agents will be optimized in this tumor type.
“Small cell lung cancer is an aggressive form of lung cancer that is associated with rapid growth and quick metastatic spread,” Joshua M. Bauml, MD, assistant professor of medicine at University of Pennsylvania, told Healio.
Small cell lung cancer is divided into two groups — limited-stage and extensive-stage disease. In limited-stage disease, the cancer has not spread beyond the radiation portal and is potentially curable with a combination of chemotherapy and radiation. In extensive-stage disease — which accounts for most small cell lung cancers — the standard treatment regimen has changed significantly, according to Bauml.
“For the past 20 to 30 years, standard treatment for these patients has been chemotherapy combined with platinum etoposide,” Bauml said. “However, recently, there has been an approval for combination chemotherapy and immunotherapy, which was based upon the IMpower133 study.”
Key trials
IMpower133 is a double-blind study of PD-L1 inhibitor atezolizumab (Tecentriq, Genentech) among 403 treatment-naive patients with extensive-stage small cell lung cancer.
Researchers assigned patients to carboplatin and etoposide with atezolizumab (n = 201) or with placebo (n = 202) for 21-day cycles during the induction phase. During the maintenance phase, patients received atezolizumab or placebo until unacceptable toxicities, disease progression according to RECIST v1.1 or no additional clinical benefit was observed.
Results showed median OS was 12.3 months in the atezolizumab arm compared with 10.3 months in the placebo arm (HR for death = 0.7; 95% CI, 0.54-0.91). In addition, median PFS was 5.2 months with atezolizumab vs. 4.3 months with placebo (HR for disease progression or death = 0.77; 95% CI, 0.62-0.96).
“While the improvement observed was modest, it was the first study in more than 2 decades to show an improvement in OS in the first-line management of extensive-stage small cell lung cancer,” Bauml said. “We really need to dive down into the data and try to understand which patients truly benefit from this treatment, which will be done in future studies. For now, it is the standard of care combination for extensive-stage small cell lung cancer patients. This trial changed the standard of care for this population of patients overnight.”
More recently, the CASPIAN trial led to the approval of durvalumab in combination with etoposide.
The open-label, multicenter trial included 805 patients with extensive-stage small cell lung cancer. Researchers assigned patients to one of three regimens: durvalumab (Imfinzi, AstraZeneca) in combination with etoposide and either carboplatin or cisplatin chemotherapy; durvalumab and chemotherapy plus a second immunotherapy, the anti-CTLA-4 monoclonal antibody tremelimumab (MedImmune/AstraZeneca); or chemotherapy alone.
Results of an interim analysis showed the trial met one of its primary endpoints, as the addition of durvalumab to etoposide and either carboplatin or cisplatin conferred a significant improvement in OS. Results of the final analysis later confirmed the OS benefit.
“We now have two treatment options for the management of extensive-stage small cell lung cancer,” Bauml said.
Further, the CheckMate032 trial, which preceded both the IMpower133 and CASPIAN trials, showed an impressive response rate for the combination of nivolumab plus ipilimumab prior to chemo-immunotherapy for the management of extensive-stage small cell lung cancer.
“This was a bit of a complicated study that looked at recurrent small cell lung cancer that had progressed on platinum therapy. It is important to note that this was not a randomized study. Nevertheless, we saw an impressive response rate for the combination,” Bauml said. “However, in the modern era, this regimen does not have as much of a place because we do not know the effectiveness of the combination of nivolumab and ipilimumab in patients who have progressed on a PDL1 inhibitor — I hypothesize that it would not be very high. We would need prospective data before this regimen can be used in the modern era.”
Progress made, more needed
Many challenges exist for early detection of small cell lung cancer as it is a disease that grows rapidly, according to Bauml.
“Someone can have a clear scan one day and then a couple of months later they can be diagnosed with metastatic disease,” Bauml said. “This is also a disease that occurs nearly universally in patients with a history of tobacco use, as a result, there are frequent nodules that can be seen in these patients of which more than 90% of nodules identified on CT scan are false-positive. It is difficult to separate ‘the signal from the noise’ in a patient with a history of heavy tobacco use.”
Researchers are now examining the use of immunotherapy for patients with small cell lung cancer.
“There have been multiple efforts to try to incorporate immunotherapy into the management of small cell lung cancer, but none have moved the needle,” Bauml said. “Subsequent trials of nivolumab alone vs. nivolumab plus ipilimumab and similarly a study combining pembrolizumab with chemotherapy in the first-line setting were not able to show an improvement in survival among patients with this deadly disease. We really need to do better to improve outcomes for our patients.”
Biomarkers of response to treatment are also needed to better personalize care.
“Early data have identified subgroups of small cell lung cancer patients who appear to benefit the most from certain treatments, but they have not been validated in large prospective trials and so we still need to identify who would benefit from which treatment the most,” Bauml said.
Other promising data suggest DLL3 — a dipeptide linker expressed in approximately 80% of small cell lung cancers — is another target for treatment in small cell lung cancer.
“We were very excited about DLL3, which is overexpressed on small cell lung cancer and is a very appealing biomarker,” Bauml said. “The problem is that our most recent drug that targeted DLL3, rovalpituzumab tesirine [SC16LD6.5, Stemcentrx], had substantial toxicity in the early trials and despite excitement did not pan out in terms of efficacy. There are now multiple other drugs targeting DLL3 and I look forward to seeing those results.”
This past June, the RNA polymerase II inhibitor, lurbinectedin [Zepzelca, PharmaMar], was approved by the FDA for adults with metastatic small cell lung cancer that progressed on or following platinum-based chemotherapy, representing an exciting new treatment option, according to Bauml.
References
- Horn L, et al. N Eng J Med. 2018;doi:10.1056/NEJMoa1809064.
- Paz-Ares L, et al. Abstract PL02.11. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
- Antonia S, et al. Abstract OA 07.03a. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Oct. 15-18, 2017; Yokohama, Japan.
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