The SCLC immune microenvironment
The immune microenvironment will be an integral part of that journey, according to Dr. Liu.
“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.
“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.
Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.
Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.
Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.
“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.
Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.
“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).
Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.
“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.
“All of these will need to be accounted for in various patients.”
These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.
In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.
“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.
Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.
“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.
But many questions remain, he said.
For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?
And importantly, “how will we choose between these various molecules we have?” he asked.
“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”
It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.
However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.
“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.
Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.
“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”
As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.
“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”
Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.