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BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

Combination immunotherapy is necessary.
Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
PD-1 blockade should continue.
Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”

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.

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The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

Combination immunotherapy is necessary.
Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
PD-1 blockade should continue.
Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”

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.

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

Combination immunotherapy is necessary.
Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
PD-1 blockade should continue.
Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”

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.