Small cell lung cancer has such a high rate of attrition. The biggest impact will always be in the first-line setting. We’ll see empiric strategies that try to build on the chemoimmunotherapy approach validated by the IMpower133 and CASPIAN trials. The addition of thoracic radiation, alternate maintenance strategies, or incorporation of more immunomodulatory agents, like anti-TIGIT [T-cell immunoreceptor with immunoglobulin and ITIM domain] antibodies, will help build on those outcomes we see in extensive-stage small cell lung cancer. We’ll start to work on selective delivery of agents. We need to identify the unique subsets that exist within small cell lung cancer that can be treated differently. Empiric therapy is only going to take us so far. We desperately need predictive biomarkers that can guide therapy. There is a lot of enthusiasm for expression of transcriptional regulators as a guide. We still, however, need clinical data to validate this approach. Ultimately, we will need prospective data to see if this is an effective strategy going forward.

There are many active agents and combinations in development. Liposomal irinotecan was granted fast-track designation by the US FDA. In part 1, we saw a response rate of over 40%, which is exciting, but we need to wait for results from part 2, where patients are randomized to nal-IRI [nanoliposomal irinotecan] or topotecan. We need to reserve judgments for these agents until we see randomized data because we’ve seen responses before. A good example is amrubicin. In phase 2 studies, amrubicin showed high response rates, some over 50%, 60%. But in a randomized trial, those response rates didn’t translate to a survival benefit over standard topotecan. A similar example is the combination of lurbinectedin plus irinotecan. There was a high response rate, 62%, and 69% in chemotherapy-sensitive disease, but it’s not clear this is going to lead to any improvement in survival. In addition, that combination was fairly toxic, with 29% grade 3 diarrhea, 62% grade 3 neutropenia.

I am looking forward to seeing more data from AMG 757. This is a bispecific T-cell engager [BiTE] that targets DLL3. We know DLL3 is selectively expressed on small cell lung cancer and large cell neuroendocrine tumors. An antibody-drug conjugate, rovalpituzumab tesirine, was unfortunately too toxic, and not effective enough to demonstrate enough efficacy in DLL3-positive small cell lung cancer, but it doesn’t invalidate DLL3 as a target. The BiTE molecule, AMG 757, showed a response rate of 14%, which seems low, but 20% were ongoing at 6 months and some of these went out past a year. With more data, those numbers will increase. Primary toxicity of concern is cytokine release syndrome [CRS]. Those were low grade in the trial. As that study increases, as more patients go on, we can see if that toxicity demonstrates tolerability. There is also a DLL3 CAR [chimeric antigen receptor] T molecule that was in development. That trial is not accruing now, and we’ll wait to see the reason for that and early results from both of these studies, which are important approaches exploiting that selective expression of DLL3.

In the short run, meaning the next few years, small cell lung cancer is probably going to be more stable than dynamic. We have a number of trials coming down the pike that might change the standard of care in the period maybe just beyond that, and I’ll start with those. We just saw data at World Lung [the World Conference on Lung Cancer] on second-line liposomal irinotecan. There was a 20% rate of grade 3/4 diarrhea, 16% rate of grade 3/4 neutropenia. Efficacy data are limited. We only saw 25 patients treated at the recommended phase 2 dose. But in this limited sample, the response rate was promising at 44%. PFS [progression-free survival] there was 4 months and OS [overall survival] 8 months.

We also saw at World Lung data on apatinib plus chemotherapy. Here the chemotherapy is dealer’s choice of irinotecan or docetaxel; we saw a response rate of 25%, PFS of 7 months, and overall survival of 12.5 months. Again, only 31 patients here. There we saw some neutropenia, hypertension, and hand-foot syndrome. What was nice is we did get a dose out of that phase 1 study. We saw data at World Lung on AMG 757, which is a BiTE directed against DLL3. The CRS rate here was 44%, but most of them were low grade and easily managed, only 2% of them were high grade. The response rate was 14%, perhaps a bit higher as you got up to the higher doses, and the median duration of response was only 6 months.

Finally, we saw data on lurbinectedin in combination with irinotecan in relapsed small cell. There we saw data on 21 patients. The toxicity was perhaps acceptable but very real, 24% grade 3/4 fatigue, 29% high-grade diarrhea, 62% neutropenia. The response rate was good at 62%, 50% in those with a chemotherapy treatment-free interval of less than 90 days, 69% in those of at least 90 days. Frankly, for lurbinectedin, I’m much more excited about the single-dosing strategy that I already have access to, and I’m interested in strategies to optimize dose with single agent.

Looking past this immediate timeframe of a few years, I’m particularly excited about cellular therapeutics against extensive-stage small cell lung cancer. I would highlight as the 2 targets with most immediate promise, DLL3 and GD2. Looking further down the road than that, I’m impressed by thetranscription-based subtyping of extensive-stage small cell. I see very distinct biologic themes, and while these may have no impact on current treatment decisions and are not obtained as part of standard of care, the themes biologically are sufficiently distinct that I see high promise for these ultimately improving care and leading to novel therapeutics, and perhaps selection of patients for therapeutics.

Videos

Jared Weiss, MD, and Stephen V. Liu, MD discuss treatment of small cell lung cancer and therapies in the pipeline.

Emerging Agents and Future of Small Cell Lung Cancer

When we look at the survival curves for the IMpower133 and for CASPIAN studies, the separation really occurs after the completion of induction chemoimmunotherapy. What we know from CheckMate 451 is that maintenance immunotherapy before progression and after chemotherapy did not improve survival. We conducted an exploratory analysis of IMpower133 looking at the benefit of atezolizumab versus placebo in patients who reach that maintenance phase. What we found in this analysis was that atezolizumab offered a significant survival advantage over placebo, with an overall survival hazard ratio from the start of maintenance of 0.59. The median survival from the start of maintenance was 12.5 months with atezolizumab versus only 8.4 months with placebo, and there were no new safety signals. Grade 3/4 adverse events from the start of maintenance were seen in 28% of patients receiving atezolizumab, but also seen in 23% of patients receiving placebo. To me, these data reinforce the use of atezolizumab with induction chemotherapy but also with maintenance, and continuing atezolizumab maintenance is a critical piece of optimizing outcomes.

The good thing about first-line treatment of extensive-stage small cell lung cancer [ES-SCLC] is that it usually works, response rates are high. This is important because of how symptomatic patients with extensive-stage small cell are. Probably about one-third of my patients present with hospitalization due to extreme shortness of breath. And it’s very gratifying, when you give them their first cycle of treatment, they feel a lot better very quickly. The weakness is that it doesn’t last very long. Pretty much all patients relapse, and unfortunately relatively quickly. With appropriate monitoring and aggressive supportive care, most patients are eligible for second-line therapy. When you consider patients who are not physically eligible or the values-based choices of patients, I would say you’re left with about 75% or 80% of patients who get second-line therapy. This is very different by different practices in terms of patient values and physical characteristics. That’s roughly what I’m seeing in my practice.

We have multiple regimens that are either FDA approved or NCCN [National Comprehensive Cancer Network] guideline recommended for second-line use. The dominant ones in clinical practice are topotecan, lurbinectedin, and immunotherapy, meaning nivolumab, pembrolizumab, or IPI/NIVO [ipilimumab plus nivolumab]. I would note that while the results of immunotherapy are favorable, immunotherapy is now a part of first-line therapy. For example, in CheckMate-032, we had a randomized phase 2 study of nivolumab versus 2 studies of ipilimumab, nivolumab. The response rate went up with ipilimumab, nivolumab. It went from 12% to 22%, but survival didn’t. It was 5 or 6 months regardless. In KEYNOTE-028 and KEYNOTE-158, we saw pembrolizumab’s efficacy in this context. There were very similar data here, late-line pembrolizumab in second or third line here, a response rate of 19%, 2-month PFS [progression-free survival], 8-month survival. All of the immunotherapy regimens are roughly similar and active. 

In the theoretical case of seeing a patient who hadn’t received immunotherapy in the front line, these remain great options. In reality, they’re not great clinical options because patients have almost always received it as a part of first line. The dominant place we see this in practice is the patient with de novo limited-stage disease who subsequently relapses. And nivolumab, ipilimumab, nivolumab, or pembrolizumab are fine choices of agents in that limited context.

Other options, topotecan is approved in this context. Topotecan may be the most hated drug in all of thoracic oncology. The response rate isn’t that high, toxicity is rather dramatic, mostly related to myelosuppression and its downstream sequalae. And it’s fallen out of favor, particularly now that lurbinectedin has approval in this single-agent context. This was based on a basket trial, where the response rate looked a little better than topotecan, the adverse effect profile a little better, and it’s been rapidly adopted because of being a little better than topotecan. And it is my answer in my practice, at least when a patient is not eligible for trials.

There are 2 other contexts that deserve mention, one that I already mentioned, which is that clinical trials should be strongly considered for patients with small cell lung cancer, particularly in later lines of therapy. Unfortunately, our existing therapeutics are limited in efficacy. And there’s a lot that’s promising on the horizon and in clinical trials. The other thing that can be considered is that if a patient remains platinum sensitive, it’s quite reasonable to repeat the regimen they got before, or to restart platinum with a different partner agent.

Lurbinectedin is a transcription inhibitor. It received accelerated approval by the US FDA for small cell lung cancer that has progressed after platinum-based chemotherapy. This was based on a single-arm phase 2 study where lurbinectedin, given at a dose of 3.2 mg/m2 IV [intravenously] every 3 weeks, had a response rate of 35%. In patients with chemotherapy-sensitive relapse, the response rate was 45%, and those with chemotherapy-refractory disease, where we don’t have effective options, the response rate was a respectable 22%.

We now know that the confirmatory phase 3 ATLANTIS trial did not meet its survival end point. In that study, patients were randomized to lurbinectedin plus doxorubicin or standard chemotherapy with either topotecan or CAP [cyclophosphamide, doxorubicin, cisplatin]. That study we heard did not feature a survival benefit to lurbinectedin, but the dose used was lower, and it was in combination with doxorubicin. We need to see those data to understand the impact of lurbinectedin on survival in small cell lung cancer. I have used the agent myself many times. The main toxicity is myelosuppression, neutropenia more so than anemia, and thrombocytopenia. In my practice where I do use lurbinectedin, particularly in the chemotherapy-refractory set, it is my practice to use primary G-CSF [granulocyte colony-stimulating factor] prophylaxis with lurbinectedin.

Considerations for second-line treatment regimens, the role of immunotherapy in the relapsed/refractory setting, and using lurbinectedin for the management of ES-SCLC.

Management of ES-SCLC: Second Line and Beyond

Trilaciclib is an intravenous [IV] CDK4/6 inhibitor. It is approved as a myeloprotective agent given with chemotherapy for small cell lung cancer. We know that the primary toxicity with platinum/etoposide is myelosuppression, and trilaciclib was shown to reduce myelosuppression, decreasing neutropenia, reducing the need for transfusions. We don’t know if this will impact the rate of febrile neutropenia or the rate of hospitalizations, which I would say have more clinical impact. But I would say that it is a reasonable addition to therapy for patients who are particularly at risk. For me it does not influence first-line treatment, as the benefit I think would extend across the different available first-line regimens. While it is a reasonable addition, it is not part of my practice.

Trilaciclib is a short-acting IV CDK4/6 inhibitor. The idea is to keep the bone marrow progenitors out of cycle while the chemotherapy is washing by. This was first studied in extensive-stage small cell lung cancer because small cell is Rb null. That means that the cancer, for better and for worse, will not be affected by the agent. And any effects that you see are going to be related to the myeloprotection benefit.

Before diving into study design and results, I would like to disclose that I’ve been involved in these research efforts, and I’m unabashedly enthusiastic about the agent. That enthusiasm comes out of the quality-of-life data that I’m going to describe for you. Trilaciclib was studied in 3 randomized phase 2 efforts: carboplatin and etoposide with or without the drug; [carboplatin, etoposide, atezolizumab] with or without drug; and topotecan with or without drug.

Then looking at each of the individual studies or the combined analysis, which should be in the press within days, what you see is a myeloprotection benefit. All of the blood counts are protected. And the story is clean; it’s not just a numeric effect. The myeloprotection in terms of the numeric improvement in counts translates to a reduction in adverse events, of course driven mostly by the events you would expect for myeloprotection, but also interestingly alopecia as well. That reduction in adverse events translates to a reduction in supportive-care use, like blood transfusions and Neulasta use. And critically, all of this translates into an improvement in quality of life as determined by patient-reported outcomes. The one that impressed me the most is fatigue. By patient report, fatigue was decreased with the addition of trilaciclib to standardized chemotherapy. This is important to me because in my practice, fatigue is the effect that my patients suffer from the most, and it’s the one that I’m most unable to help with. We have very few agents that help with fatigue. In my practice, now that the agent is approved and once it becomes available, will be that every patient with extensive-stage disease who gets carboplatin/etoposide and atezolizumab, or who gets topotecan, will have it preceded by trilaciclib.

Stephen V. Liu, MD, and Jared Weiss, MD, share their thoughts on the impact of the recent approval of trilaciclib prior to platinum/etoposide-based chemotherapy for the treatment of ES-SCLC.

Using Trilaciclib for Treatment of ES-SCLC

The addition of PD-L1 inhibitory therapy, or atezolizumab or durvalumab, is absolutely the standard of care for first-line treatment of extensive-stage small cell lung cancer [ES-SCLC]. This initially came about as a consequence of the IMpower133 study. This was a well-designed and simple study. It was a randomization where half of the patients got the then standard of care, carboplatin and etoposide, and the other half got the standard of care plus the PD-L1 inhibitor atezolizumab. Appropriately, patients received combination therapy for 4 cycles and then either got maintenance therapy with atezolizumab or placebo. Thinking about other elements of trial design that matter, PCI [prophylactic cranial irradiation] was allowed but not mandated. Of note, consolidative thoracic radiation was not allowed. Primary end points of this study were progression-free [PFS] and overall survival [OS]. Total alpha was 0.05 allocated between these. The impact of my practice is that this is the absolute standard of care that all fit patients get in the front line as a result of a PFS and OS advantage.

In my practice, every patient with extensive-stage small cell lung cancer who is sufficiently fit and whose values are appropriately oriented receive the combination of carboplatin, etoposide, and a PD-L1 inhibitor. I get imaging after 2 cycles and after 4 cycles, and in the event of tolerance and nonprogression, I treat with indefinite maintenance therapy with the PD-L1 inhibitor.

My practice results nicely mirror the trial results. The PFS and OS advantage is unfortunately small, but is real. The regimen is well tolerated in my practice, very consistent with the trial results from IMpower133. We do see the same adverse effects of chemotherapy, which are the dominant adverse effects. There’s nothing about the addition of atezolizumab that protects against myelosuppression and its downstream sequalae: nausea, fatigue, etc, that come with chemotherapy. And there’s nothing about chemotherapy that protects against the immune-related events that occur with atezolizumab.

One question I am frequently asked is whether given that small cell is a cancer that can have these paraneoplastic syndromes, do we see more paraneoplastic syndromes with the addition of the PD-L1 inhibitor? The answer in my experience is no, we don’t. The playbook for managing these toxicities is identical to what you would have done before. The management of myelosuppression-related events is dose reductions, dose delays, the use of supportive therapy. Very recently we had the approval of trilaciclib, which can be used to prevent them. For the management of immune-related adverse events, it depends on the event, but the mainstay is usually high-dose steroids.

The use of either cisplatin or carboplatin is considered acceptable in extensive-stage small cell lung cancer. I have strong opinions to prefer carboplatin for my patients. The survival advantage with cisplatin is trivial. It’s on the order of days, whereas the toxicity difference of these agents is dramatic. Carboplatin has far less nausea than cisplatin. It doesn’t have the nephrotoxicity problem. It doesn’t have the neurotoxicity problem. It doesn’t cause tinnitus and hearing loss. The one thing to be aware of that’s a little worse with carboplatin is blood cell count suppression, but with trilaciclib and Neulasta, these are easily managed. Both are reasonable, but I strongly favor carboplatin.

The CASPIAN study was the second trial to show a survival benefit when immunotherapy was added to first-line chemotherapy. This was an open-label phase 3 trial for patients with extensive-stage small cell lung cancer and no prior therapy. This study did include patients with asymptomatic untreated brain metastases. Patients were randomized to 1 of 3 arms. The control arm was platinum plus etoposide, either cisplatin or carboplatin, for 4 to 6 cycles. There was an arm of platinum, etoposide with concurrent administration of the PD-L1 inhibitor durvalumab, followed by durvalumab maintenance. And the third arm was a combination of platinum, etoposide with durvalumab and the CTLA-4 inhibitor tremelimumab, followed by durvalumab maintenance alone. Prophylactic cranial irradiation was permitted only in the control arm, and no arms featured thoracic radiation.

This was a large study randomizing over 800 patients with small cell lung cancer. It showed that the addition of durvalumab to chemotherapy did improve overall survival. Median survival with chemotherapy alone was 10.5 months. With chemotherapy plus durvalumab, that improved to 12.9 months, with a hazard ratio for death of 0.75. The 18-month survival rate was 32% with durvalumab, 25% with chemotherapy alone. Based on this survival benefit, durvalumab was approved in combination with platinum/etoposide for the frontline treatment of extensive-stage small cell lung cancer.

Now, the third arm, the addition of durvalumab plus tremelimumab did not unfortunately improve outcomes. Median survival with durvalumab, tremelimumab plus chemotherapy was 10.4 months; compare that to 10.5 months with chemotherapy alone. Hazard ratio for death, 0.82. Dual checkpoint blockade, durvalumab/tremelimumab with chemotherapy, was also more toxic, with 1 in 5 patients, 21%, discontinuing therapy due to adverse events. Compare that to only 9% to 10% in the other 2 arms. The combination of durvalumab/tremelimumab and chemotherapy is not approved and not a part of our standard of care.

Both IMpower133 and CASPIAN were randomized phase 3 trials that demonstrated that the addition of a PD-L1 inhibitor to chemotherapy improved survival. While there are differences in study design, and these are 2 different drugs, the results are more similar than different. In fact, even with longer follow-up, those Kaplan-Meier curves for survival are almost overlapping. In my opinion, both agents are appropriate, both are approved, and I do not have a factor of one over the other. It comes down to comfort and perhaps nonclinical choices, such as cost or formulary restrictions. Both agents can be administered every 4 weeks as part of maintenance. The only salient difference between the trials that could come into play is the choice of platinum.

CASPIAN did permit either cisplatin or carboplatin, whereas IMpower133 only explored the use of carboplatin. I would be comfortable using cisplatin in combination with atezolizumab. I have no reason to expect they would perform differently, but the highest level of evidence with cisplatin is the durvalumab combination. I do not use cisplatin routinely. There are very few instances where I feel it’s appropriate to give cisplatin, a much more toxic drug in the setting of extensive-stage small cell lung cancer. But if, for example, someone had significant myelosuppression perhaps from marrow metastases and I was worried about the more myelosuppressive carboplatin, that may be an instance where I would use cisplatin. In that instance, the addition of durvalumab to cisplatin would be supported by more evidence and would be a reasonable choice. But overall, both agents improve survival, and are reasonable and appropriate.

Experts in thoracic oncology review data from the IMpower133 and CASPIAN trials as well as the use of chemotherapy with PD-L1 inhibitors for treatment-naïve ES-SCLC in clinical practice. 

Standard of Care for ES-SCLC

We are supposed to stage small cell lung cancer by the same TNM [tumor, nodes, metastases] system that is used for non–small cell lung cancer. Indeed, that system will give a more granular prognosis than the system we all actually use. The problem is prognosis isn’t as helpful in clinical practice as a system that tells you what to do. The simpler system of limited versus extensive stage is what’s used in clinical practice. The definition here is simple. Limited stage is if all the disease can be encompassed in a single radiation portal, and everything else is extensive-stage disease. Most limited-stage disease is treated with chemoradiotherapy with a goal of cure, and most extensive-stage disease is treated with carboplatin, etoposide, and a PD-L1 inhibitor.

The prognosis of these diseases is of course different. We treated limited-stage disease with a goal of cure. Unfortunately, we don’t get there as often as we’d like. We probably cure about a quarter of our patients, and this results in a median survival of only about 30 months. Of course, extensive-stage disease has a more adverse prognosis that’s about half of that with a median survival of 15 or 20 months. The demographics of small cell are unique. These tend to be patients with a heavy smoking history. That’s the biology of patients with small cell lung cancer. They’re more likely to be elderly, and they’re more likely to be male. Thinking about the presentation of small cell, this is a very aggressive disease; this is a disease where you need to diagnose it early, you need to treat it early. In fact, probably about 30% of presentations at my institution are inpatient, typically through the emergency department, typically with dramatic shortness of breath. And because treatment works, it works quite dramatically, quickly, it’s very important to recognize and treat early.

What do these presentations look like? Shortness of breath is certainly the most common. Small cell likes to present centrally in the chest where it can clip off airways, leading to shortness of breath, cough, and pneumonia. It can also cause pain, of course, wherever it metastasizes, and it’s famous for paraneoplastic syndromes. It can suppress blood counts in and of itself. It causes hypercalcemia in 5% or 10% of our patients. Hypercalcemia is manifested as anorexia, nausea, vomiting, constipation, lethargy. But in the modern world where everyone gets a blood test on the way in to the emergency department, this often manifests as a laboratory test result. Small cell causes SIADH [syndrome of inappropriate antidiuretic hormone secretion], which manifests as anorexia, nausea, and vomiting, and occurs in about 10% of patients. And again, in the modern world where everyone gets labs rather quickly, it manifests as low sodium on a blood test.

Small cell lung cancer causes a variety of neurologic syndromes, the most common and famous of these is the Lambert-Eaton myasthenic syndrome, or LEMs. But it also can cause a variety of others more rarely: cerebellar ataxia, sensory neuropathy, limbic encephalitis, encephalomyelitis, and a variety of long-named, easy-to-trip-over neurologic syndromes that are rare. There’s a very long list of things that rarely happen. Hypercoagulability, as with any malignancy, small cell is with non–small cell lung cancer in being very high up on that list. And hypertrophic pulmonary osteoarthropathy, most commonly seen as digital clubbing in our patients, but it can happen as a symmetric painful arthropathy in any joint. I often see ankles, knees, wrists, and elbows.

The historic standard for extensive-stage small cell lung cancer has been platinum plus etoposide chemotherapy. This regimen was first explored in the 1970s and became the clear standard of care in the mid-1980s. And it’s effective initially. Response rates are high, north of 60%. You can see complete responses, and the benefit is seen relatively quickly. It’s also pretty well tolerated. While there is myelosuppression, patients generally feel better with treatment and not worse. The problem is that responses are not durable, they are very transient. The median progression-free survival is on the order of about 4 months, and that’s from the start of therapy. Most patients are progressing either during or shortly after completing their initial induction chemotherapy.

Survival with chemotherapy alone has hovered around the 8-to-10-month range, and there have been repeated efforts to improve upon those first-line outcomes that have really failed. Dozens of phase 3 trials over many decades have not improved overall survival. It wasn’t until the introduction of chemoimmunotherapy that we saw improvements. With adding more agents, with alternating agents back and forth, looking at maintenance strategies, early second-line therapy, we were able to improve response rates, and at times make modest improvements in progression-free survival. But the only studies that impacted survival overall was the addition of immunotherapy to chemotherapy, seen first with IMpower133 and then with CASPIAN.

Insights on the differences between limited-stage and extensive-stage small-cell lung cancer and recent progress made with combination chemotherapy plus immunotherapy.

Jared Weiss, MD, University of North Carolina at Chapel Hill

Articles

Emerging Agents and Future of Small Cell Lung Cancer

Management of ES-SCLC: Second Line and Beyond

Using Trilaciclib for Treatment of ES-SCLC

Standard of Care for ES-SCLC

Staging for Small-Cell Lung Cancer