NEW YORK – While patients with non-small cell lung cancer have myriad biomarker-targeted therapy options, precision oncology has yet to benefit those with the more aggressive small cell subtype.
Still, drugmakers and academic researchers aren't giving up on personalizing treatment for small cell lung cancer patients with new biomarker strategies. For example, Boehringer Ingelheim is exploring the activity of a DLL3 inhibitor in patients with DLL3-expressing SCLC, while others are hoping to home in on best responders to immunotherapies with the help of biomarkers. Still others are assessing if circulating tumor DNA testing can be used to quickly figure out whether SCLC patients are responding to a treatment they're on.
But given the aggressive nature of SCLC and the dearth of efficacious treatment options, especially for those with extensive-stage disease, drugmakers are also motivated to develop agents that aren't limited by biomarkers and are broadly efficacious. The five-year survival rate among patients with heavily pretreated extensive-stage SCLC is 3 percent. Recognizing the unmet need, Amgen, for one, has decided to forgo a biomarker strategy for its DLL3 inhibitor and is hoping to commercialize it for all SCLC patients.
"Small cell is actually quite different than non-small cell lung cancer," said Sumita Bhatta, Amgen's VP of global medical affairs and head of oncology. "There are very few effective therapies approved [for SCLC], and the reason is because it's extremely aggressive. Often, by the time you've seen a patient and diagnosed them with small cell, they're at a very aggressive point in their disease."
Although like non-small cell lung cancer and melanoma patients, those with SCLC tend to have a high mutation burden and genomic abnormalities in their tumors, and they don't respond as well to immunotherapy. In addition, there aren't any approved treatments for genomically defined SCLC subgroups. Currently, there are two immunotherapies available in the US for first-line treatment of extensive-stage SCLC — AstraZeneca's Imfinzi (durvalumab) and Genentech's Tecentriq (atezolizumab) — which are both given with chemo. In the second-line metastatic SCLC setting, there is Jazz Pharma's DNA-damaging chemotherapy Zepzelca (lurbinectedin), which garnered accelerated approval from the US Food and Drug Administration in 2020.
But once SCLC patients have exhausted these options in the first- and second-line settings, more chemo or hospice are typically all that's left. For patients in their third line of treatment, for example, there are no approved drugs, and the median overall survival is about 4.4 months, Bhatta noted. "The incremental benefit of recent treatment advancements has been quite small," she said. "Responses are short-lived and most patients still experience rapid and aggressive recurrences."
For all comers or DLL3 expressers only?
One of the most active areas for new drug development in SCLC is DLL3-targeted therapies. Both Amgen, where Bhatta works, and Boehringer Ingelheim are evaluating their DLL3 drugs in heavily pretreated SCLC patients who are out of treatment options.
Amgen's tarlatamab, a DLL3/CD3 bispecific T-cell engager, is undergoing testing in several SCLC studies: a Phase III trial comparing tarlatamab to standard-of-care chemo in second-line SCLC; a potentially registrational Phase II trial of tarlatamab in the third-line or later setting of extensive-stage SCLC; and multiple Phase I trials exploring tarlatamab in combination with other agents including in earlier lines of therapy.
Boehringer Ingelheim's BI 764532, another DLL3/CD3 bispecific T-cell engager, is in earlier stages of development. The firm presented data in June from the first-in-human Phase I trial of BI 764532 in patients with advanced or metastatic DLL3-positive SCLC and neuroendocrine carcinoma.
Where these two DLL3-targeted drugs differ is in their use of biomarkers. Amgen is pushing ahead in an all-comer population with tarlatamab, while Boehringer Ingelheim is studying BI 764532 only in SCLC patients whose tumors express DLL3.
More than 80 percent of SCLC patients tend to have DLL3-expressing tumors, but they don't express DLL3 in normal tissues. Bhatta noted that early studies of tarlatamab showed efficacy across all patients, likely due to the high level of DLL3 expression seen in SCLC.
Exploratory analysis within a Phase I trial of tarlatamab suggested that patients with DLL3-expressing tumors may have a higher magnitude of clinical benefit on Amgen's drug, but some patients who didn't have the tumor biomarker also responded.
Based on the clinical activity seen in clinical trials of tarlatamab, Bhatta said Amgen doesn't see a need to select patients for treatment by DLL3 expression but noted that researchers are continuing to collect DLL3 data and perform biomarker analysis in ongoing studies of the drug.
"Especially in the late-line setting, there are no good standard-of-care options because nothing really performs well there, and we believe that a therapy in this setting should be available to all comers," she said. Amgen is expecting a data readout from the potentially registrational Phase II study of tarlatamab in the second half of this year. The firm did not disclose a timeline to file for approval of tarlatamab if the Phase II data is positive.
Boehringer Ingelheim, meanwhile, is sticking to a biomarker-informed strategy based on BI 764532's mechanism of action and efficacy signals from preclinical research. "What we're trying to achieve here is to bring a molecule that will target in one arm the T-cell receptor CD3, and then on the other arm a protein expressed on cancer cells, DLL3," said Lamine Mbow, global head of cancer immunology and immune modulation at Boehringer Ingelheim.
"In order to improve and maximize the therapeutic benefit of this, we believe that we ought to be going into a population that has at least some levels of DLL3 expression," Mbow added, "because that would make this drug more effective in our opinion."
In a Phase I study of the DLL3/CD3 bispecific drug in patients expressing DLL3, the response rate was 26 percent among 39 SCLC patients who received the recommended or a higher dose of BI 764532. Median duration of response was not reached at the time of this data readout, but some patients on BI 764532 responded for more than a year.
This Phase I dose-escalation study of BI 764532 is ongoing. Earlier this year, Boehringer Ingelheim began a larger Phase II study of two doses of the drug in the same heavily pretreated SCLC patient population. Mbow said the company hopes to progress into the Phase II trial in DLL3-positive SCLC by the end of this year.
"The late-symptom presentation, the rapid growth, greater progression, and the limited efficacy of available treatment options make this subset of patients quite challenging," Mbow acknowledged. "But it is in line with our core focus to really go after areas with high medical need to provide solutions to patients."
Optimism despite mixed results
Beyond DLL3, researchers exploring other targets and biomarker strategies have had mixed results. At the American Society of Clinical Oncology's annual meeting this year, researchers presented biomarker analyses from studies of various checkpoint inhibitors, such as Merck's Keytruda (pembrolizumab) and Genentech's Tecentriq (atezolizumab) combined with Pfizer's PARP inhibitor Talzenna (talazoparib).
Within the KEYNOTE-604 trial of Keytruda plus chemo, researchers evaluated extensive-stage SCLC patients' survival according to several biomarkers including tumor mutational burden (TMB), an 18-gene T cell-inflamed gene-expression profile, or SCLC transcriptional subtypes.
They found that high TMB and the SCLC transcriptional subtypes were not associated with overall survival in the Keytruda arm compared to the placebo arm. And while the T cell-inflamed profile was associated with higher survival in both treatment arms, the biomarker did not identify best responders to Keytruda specifically.
A Phase II study of maintenance treatment with Tecentriq-Talzenna versus Tecentriq alone in patients with SLFN11-expressing SCLC, meanwhile, showed that the addition of the PARP inhibitor improved outcomes in this subset of patients. Median progression-free survival in the Tecentriq-Talzenna arm was 4.2 months versus 2.8 months on Tecentriq alone in SLFN11-expressing patients, but the benefit did not extend to overall survival.
In a discussion of the data from these biomarker-defined SCLC trials at ASCO this year, Alberto Chiappori, a senior member within the oncology and medicine group at Moffitt Cancer Center's thoracic oncology program, reflected that the research community has reason to be "hopeful and optimistic" about using biomarkers in SCLC but also "recognizes that there is a lot of work to be done and that we need to continue looking at these biomarkers." He added that in order to keep exploring precision oncology approaches in SCLC, researchers need to overcome challenges to obtaining tumor tissue from these patients for biomarker testing.
Precision oncology in liquid biopsy era
Historically, SCLC drug trials that involve biomarker screening have relied on tissue-based testing. In Amgen and Boehringer Ingelheim's trials, for example, researchers used Roche's Ventana SP347 tissue-based assay to screen for DLL3 expression.
However, blood-based testing is an emerging, non-invasive option that may not only circumvent the challenges of obtaining tumor tissue for biomarker analysis from advanced SCLC patients but also help usher in a new generation of precision treatments. For example, Menarini Silicon Biosystems in July launched the CELLSEARCH Circulating Tumor Cell liquid biopsy test that can detect DLL3-expressing tumor cells in the blood of SCLC patients. The test is currently available for research use to drugmakers interested in testing for the biomarker to track treatment response in clinical trials.
A study published in Clinical Cancer Research in June also suggested that circulating tumor DNA monitoring could improve treatment management for SCLC patients, according to Valsamo Anagnostou, senior author of the paper and an assistant professor of oncology at Johns Hopkins' Sidney Kimmel Cancer Center.
In the ctDNA study, Anagnostou and colleagues found that SCLC patients who had a molecular response on chemotherapy or immunotherapy-based treatment, defined as a decrease in cell-free tumor load rather than in a specific mutation, had longer overall and progression-free survival. The correlation between molecular response and survival outcomes existed across SCLC patients in first-, second- and third-line treatment settings.
"Despite the presence of putatively actionable mutations in small cell lung cancer, molecularly targeted therapies have not been as effective," Anagnostou said. In the absence of SCLC drugs targeted to specific tumor markers, ctDNA monitoring could be a helpful precision oncology tool that informs treatment decisions for SCLC patients and allows physicians to quickly pivot to new treatments if testing indicated patients weren't having a molecular response.
While the study published in Clinical Cancer Research included only 33 SCLC patients, Anagnostou's team is already working on a study to validate these findings in a larger cohort of patients, which they hope will ultimately establish ctDNA as a clinical trial endpoint that provides an early indicator of response for metastatic SCLC patients receiving investigational drugs. In this way, "liquid biopsies can also be used for drug development targeting small cell lung cancer, where drug efficacy is captured … and [testing] informs go or no-go decisions in drug development," she suggested.
Anagnostou noted that procuring tumor tissue samples for biomarker testing can be challenging for SCLC patients if they have extensive-stage disease, at which point cancers have spread to other parts of the body and there is an urgent need to begin treatment. "To this end, liquid biopsies offer a complementary approach to understanding the genetic make-up of cancer cells and capturing tumor burden dynamics in real-time during therapy and again at the time of progression, opening a window of opportunity for therapeutic intervention," she said.