In this text module on current SoC therapy for ES-SCLC, I start by discussing the seminal clinical trial data from the phase III IMpower133 and CASPIAN trials that established the addition of an anti–PD-L1 checkpoint inhibitor to platinum-based chemotherapy as the first-line SoC for this disease.¹

The phase III IMpower133 trial evaluated carboplatin/etoposide with or without atezolizumab followed by atezolizumab or placebo maintenance, respectively, until PD in patients with measurable ES-SCLC and no previous systemic therapy, and including those with asymptomatic brain metastases (N = 403).^2,3 The coprimary endpoints were OS and progression-free survival (PFS) by the investigator.

The phase III CASPIAN trial evaluated the addition of durvalumab or durvalumab/tremelimumab (an anti–CTLA-4 inhibitor) to platinum/etoposide vs platinum/etoposide alone followed by either durvalumab, durvalumab/tremelimumab, or placebo maintenance, respectively, in patients with previously untreated ES-SCLC (N = 805).⁴ Asymptomatic or treated and stable brain metastases were allowed. The primary endpoint was OS. Secondary endpoints were PFS, overall response rate (ORR), safety, and patient-reported outcomes.

These studies were very similar other than a few minor nuanced differences. CASPIAN allowed cisplatin in addition to carboplatin to be paired with etoposide as well as included a third arm that combined both anti─PD‑L1 and anti─CTLA-4 with chemotherapy, which has not affected the SoC at this point. Furthermore, CASPIAN allowed treated and stable along with asymptomatic brain metastases.

As shown in these figures, both IMpower133 and CASPIAN demonstrated a survival benefit with the addition of immune checkpoint blockade, specifically anti–PD‑L1 therapy, to first-line chemotherapy in patients with ES-SCLC. Survival outcomes appear numerically similar between the 2 studies presumably because of a similar trial design and patient population.

The Kaplan-Meier curves on the left side of the slide show PFS and OS outcomes for atezolizumab plus carboplatin/etoposide vs placebo plus carboplatin/etoposide from IMpower133.³ Here, median PFS was 5.2 vs 4.3 months (HR: 0.77; P = .02) and median OS was 12.3 vs 10.3 months (HR: 0.70; P = .007), respectively. The 12-month PFS and 12-month OS rates with chemoimmunotherapy vs chemotherapy alone were 12.6% vs 5.4% and 51.7% vs 38.2%, respectively, favoring the atezolizumab-containing arm.

The Kaplan-Meier curves on the right show PFS and OS outcomes for durvalumab plus etoposide/platinum vs etoposide/platinum alone from CASPIAN.⁵ Here, median PFS was 5.1 vs 5.4 months (HR: 0.78) and median OS was 13.0 vs 10.3 months (HR: 0.73; P = .0047), respectively The 12-month PFS and 12-month OS rates with chemoimmunotherapy vs chemotherapy alone were 17.5% vs 4.7% and 53.7% vs 39.8%, respectively, favoring the durvalumab-containing arm.

Looking across the bottom row at OS, we can see that the 12-month OS rates are similar between the 2 studies, with ≥50% of patients alive and a median OS of ≥1 year.

Although the survival benefits shown here appear modest at approximately 2-3 months of OS with the addition of immune checkpoint inhibitor blockade across all comers, it yields a statistically significant improvement in OS for a very aggressive form of lung cancer.

We are eager to see if there is a tail of the survival curve for first-line chemoimmunotherapy in ES-SCLC, considering that SCLC is known as a tumor type that responds poorly to immunotherapy. Although true in aggregate, the 3-year OS update from CASPIAN showed that there does appear to be a tail of the curve, with a 3-year OS rate of 17.6% for the durvalumab-containing arm compared with 5.8% with platinum/etoposide alone.^4,6 In other words, we see an approximate tripling in the number of patients who achieved long-term survival with the addition of immunotherapy a 3-years or beyond.

Here, we see the 3-year update for OS by patient subgroup.⁴ If we look at the forest plot, we can see that most patient subgroups benefited from the addition of durvalumab to platinum/etoposide, regardless of their age (younger than 65 vs 65 years of age or older), sex (male vs female), smoking status (yes), or whether they received carboplatin or cisplatin. The few instances where we see that the HR interval crossed 1 are, in general terms, small subsets (eg, brain/central nervous system metastases, nonsmoker, stage III disease, Asian race, North/South America region) that were just statistically underpowered to identify a benefit. Based on these findings, there is no indication that the addition of durvalumab to chemotherapy in the frontline setting should be restricted to a particular patient population with ES-SCLC.

Regarding serious adverse events (AEs) reported in the 3‑year update from CASPIAN, the durvalumab-containing arm looked numerically similar to the chemotherapy‑alone arm.⁶ Serious AEs reported in ≥2% of patients were what we typically associate with chemotherapy and included febrile neutropenia (32.5% vs 36.5%), anemia (1.9% vs 4.5%), and thrombocytopenia (0.4% vs 3.4%) with the addition of durvalumab to chemotherapy vs chemotherapy alone, respectively.

There were no significant emergent immune‑related AEs in the durvalumab-containing arm, which would confirm that addition of durvalumab to platinum/etoposide is safe.

To look at long-term follow-up with addition of atezolizumab to carboplatin/etoposide, the IMpower133 study investigators launched the observational phase IV IMbrella A study (NCT03148418). IMbrella A is a single-arm, open-label nonrandomized study where patients who received atezolizumab plus carboplatin/etoposide in IMpower133 were followed beyond 5 years to assess long-term survival outcomes (n = 18).⁷

The Kaplan-Meier curve for OS from the IMbrella A extension study showed a similar tail to the curve as what was seen in the long-term follow-up for CASPIAN,^4,6 with a 5-year OS rate of 12%.⁷ We also see that the OS with platinum/etoposide plus placebo at approximately 3 years was already <12%. These numbers may not sound like much, but in ES-SCLC, this is a major improvement in long-term survival as compared with historical controls.

Together, these data suggest that a fraction of patients with ES-SCLC—<20%—derive long-term benefit from the addition of immune checkpoint blockade with either durvalumab or atezolizumab to platinum/etoposide chemotherapy.^4,6,7 Although this one-size-fits-all approach appears to be only benefiting a minority of patients, the magnitude of benefit is remarkable when comparing it with the expected outcome without immunotherapy in this population.

Although we have 2 first-line options (carboplatin/etoposide plus atezolizumab; platinum/etoposide plus durvalumab) for the management of ES-SCLC, there is general consensus worldwide that either of these is a reasonable option.

As seen in the data above, most patients with ES-SCLC will progress on frontline chemoimmunotherapy. Beyond the first-line therapy for ES-SCLC, treatment selection becomes more challenging with less consensus on what to do next for these patients.

Seen here are the current clinical guideline recommendations based on performance status and CTFI with a cutoff of ≤6 months or >6 months, which is a proxy for platinum resistance or sensitivity, respectively.¹ Of note, a clinical trial is recommended for any patient with relapsed ES-SCLC because there is room for improvement upon current treatment options.

Of importance, there has been variability for how the platinum‑sensitive CTFI cutoff has been determined in clinical trials,^8,9  but in simple terms, if CTFI is ≤6 months, there is less support for retreating with the same platinum-doublet regimen that was used previously. Instead, the guidelines recommend either a clinical trial, lurbinectedin, topotecan (orally or intravenously), or irinotecan, although retreatment with platinum-doublet can be considered if CTFI was 3-6 months.¹ There are other agents that may be considered if CTFI is ≤6 months, with some being off‑label recommendations. These include paclitaxel, temozolomide, cyclophosphamide/doxorubicin/vincristine, docetaxel, gemcitabine, or oral etoposide, and, in patients with performance status of 2, the PD-1 inhibitors nivolumab or pembrolizumab.

For patients who have a longer CTFI of >6 months—or potentially as short as 3 months—with disease remaining platinum sensitive, a clinical trial remains the preferred option.¹ Here, we can also offer retreatment with a platinum doublet, which is supported by data suggesting that patients will do just as well, if not better, with retreatment than any of the other available options.¹⁰ For example, in a randomized phase III trial conducted in France, carboplatin plus etoposide significantly prolonged PFS vs topotecan (4.7 vs 2.7 months, respectively; HR: 0.57; P = .0041), with similar OS (7.5 vs 7.4 months, respectively; HR: 1.03; P = .94), as second-line therapy in patients with ES-SCLC who relapsed or progressed ≥3 months from completion of first-line platinum/etoposide (ie, CTFI cutoff of ≥3 months).¹¹ Other options that may be considered in patients with recurrent ES-SCLC and CTFI of >6 months include lurbinectedin, topotecan (orally or intravenous), and irinotecan, especially in patients with central nervous system metastases.¹

Lurbinectedin, a synthetic, marine-derived tetrahydroisoquinoline alkaloid analogue of trabectedin (known for its use in sarcoma),¹² is among the newer agents available for the treatment of patients with relapsed SCLC.¹³

The mechanism of action of lurbinectedin is less well understood than that of other drugs used in relapsed ES-SCLC, but we do know that lurbinectedin inhibits gene transcription by binding to promoter regions in DNA, which subsequently prevents binding of transcription factors.^14,15 This effect is likely to be impactful in SCLC cells because of their known highly replicative nature and intrinsic high rate of gene transcription that, if inhibited, is likely to promote apoptosis.

We also know that lurbinectedin induces degradation of RNA polymerase II that, in turn, increases DNA damage and apoptosis of monocytes and tumor-associated macrophages in the tumor microenvironment.^14,16 Lurbinectedin is also thought to contribute to inhibition of cell migration and proinflammatory cytokines production (eg, CCL2 and CXCL8) and proangiogenic factors like VEGF in the tumor microenvironment.

The FDA’s approval of lurbinectedin in the second-line and beyond setting for ES-SCLC was supported by data from a single-arm, open-label phase II basket study including a cohort of 105 patients with a confirmed diagnosis of SCLC and disease relapse following 1 previous line of chemotherapy.^17,18 Exclusion criteria included brain metastases and inadequate organ function (Eastern Cooperative Oncology Group performance status >2). The primary endpoint of the study was ORR assessed by the investigator and according to the Response Evaluation Criteria in Solid Tumors v1.1.

The efficacy summary from the SCLC cohort was subdivided based on CTFI of <3 months or ≥3 months, which I should note is different from the 6-month cutoff referenced in the NCCN guidelines discussed above, yet the same as the earlier study evaluating platinum-doublet chemotherapy.^1,11 When we look at the table, we see a relatively stark contrast in response rates based on the platinum sensitivity or CTFI.¹⁷ The ORR with lurbinectedin was approximately 35% in all patients, 22% in those with CTFI <3 months, and 45% in those with CTFI ≥3 months. The same breakdown along CTFI lines—all patients vs CTFI <3 months vs CTFI ≥3 months— is seen in duration of response (median: 5.3 vs 4.7 vs 6.2 months, respectively), PFS (median: 3.5 vs 2.6 vs 4.6 months, respectively), and OS (median: 9.3 vs 5.0 vs 11.9 months, respectively).

One thing that caught my attention is that the median OS was approximately 1 year with second-line lurbinectedin in patients with the longer CTFI, which is comparable to the median OS values of approximately 1 year that we saw earlier with first-line chemoimmunotherapy.^3,5 So second-line lurbinectedin is extending the lives of patients with relapsed ES-SCLC by an additional year, which I think is remarkable. Based on these results, lurbinectedin received accelerated approval by the FDA as a second-line treatment for patients with SCLC who had PD on or after platinum-based regimen.¹⁸

Here we see the duration of response with lurbinectedin in the cohort of patients with relapsed ES-SCLC.¹⁷ These data highlight how important the length of CTFI appears to be in the durability of responses to lurbinectedin in this population. With the caveat that this is a small subset of patients, it is readily apparent that those with a longer duration of response almost always had a CTFI >3 months. There are also some durable responses here, more along the lines of what we see with immunotherapy or targeted therapy than with chemotherapy in solid tumors, even though lurbinectedin is an unconventional form of chemotherapy.

The table shows data from a subgroup analysis in a small population of 20 patients with CTFI ≥180 days (or >6 months)¹⁹―this is the same cutoff used in the NCCN guidelines.¹ With the caveat that this is a retrospective analysis of a small subgroup of patients, the ORR was 50% by independent review with only 1 patient experiencing PD.¹⁹  The trend continued with higher disease control rates, median duration of response, median PFS, and median OS for this cohort with CTFI ≥ 6 months as compared to the data covered above for the cohort with CTFI ≥3 months.

Overall, I think these data speak to the importance of platinum sensitivity or the length of the CTFI for informing what might be the optimal next therapy for patients with relapsed SCLC. We could argue that retreatment with a platinum doublet, such as platinum/etoposide, would be a reasonable option in these patients.

With lurbinectedin, the safety profile is reminiscent of conventional chemotherapies, including platinum agents, with hematologic toxicities. In the phase II study of second-line lurbinectedin, hematologic AEs of grade ≥3 included neutropenia (45.7%), leukopenia (28.6%), anemia (9%), and thrombocytopenia (6.7%).¹⁷ These must be planned for and managed appropriately, whether it is with growth factor support, dose reductions, or treatment discontinuation.

The most common grade 1/2 treatment-related AEs included fatigue (51%), nausea (32%), decrease appetite (21%), vomiting (18%), and diarrhea (14%). Laboratory values for liver and kidney function abnormalities were mostly of low grade but are worth monitoring. The most common grade ≥3 treatment-related AEs were fatigue (7%), febrile neutropenia (4.8%), and pneumonia (2%).

Overall, the safety profile of lurbinectedin is manageable with proper supportive medication and recommended dosing strategies, particularly in patients who may have poor performance status.¹⁸

As mentioned, lurbinectedin received accelerated approval by the FDA in second-line SCLC based on these results,¹⁸ and as shown in the table, there is a randomized phase III trial ongoing to confirm the observed benefit seen in the phase II basket trial,^17,19 along with comparing it with other approved second-line options. The phase III LAGOON trial is evaluating lurbinectedin vs lurbinectedin/irinotecan vs single-agent irinotecan or topotecan in patients with ES-SCLC and disease relapse following ≥1 previous platinum-based regimen and a CTFI of ≥30 days (N = 705; NCT05153239). The primary endpoint of that study is OS.

A potential role for lurbinectedin in earlier disease settings is also being explored. The randomized phase III IMforte trial is evaluating lurbinectedin as maintenance therapy after frontline chemoimmunotherapy, specifically, lurbinectedin plus atezolizumab vs single-agent atezolizumab maintenance after first-line induction with atezolizumab plus carboplatin/etoposide in patients with ES-SCLC who were previously untreated or were ≥6 months treatment free following chemoradiotherapy with curative intent (NCT05091567). The coprimary endpoints are PFS and OS assessed by an independent review facility. Of note, this study builds on the first-line chemoimmunotherapy regimen approved by the FDA based on the results of IMpower133²⁰ and harkens back to the notion that the mechanism of action of lurbinectedin may involve immunogenic cell death.

Finally, in the setting of relapsed ES-SCLC, the phase II LURBIMUNE trial is evaluating lurbinectedin plus durvalumab vs carboplatin/etoposide in patients with recurrent ES-SCLC after 1 previous platinum-based regimen and CTFI of ≥90 days (NCT05572476). The primary endpoint is 6-month PFS rate. This study has a similar strategy of combining lurbinectedin with immune checkpoint blockade, namely, durvalumab, in patients with a longer CTFI.

It will be interesting to see how these 3 studies pan out. Currently, lurbinectedin is widely used in the relapse setting of ES-SCLC, so it would be good to see confirmatory data showing that it is a better option than our other second-line alternatives and whether it should be integrated earlier into the treatment paradigm. As previously mentioned, ES-SCLC ultimately relapses and it would be ideal to be able to consolidate initial responses with chemoimmunotherapy and potentially reduce the number of cases with early relapse.

The big picture for ES-SCLC in the first-line setting is very simple: The SoC is to add a PD-L1 immune checkpoint inhibitor, either durvalumab or atezolizumab, to platinum-doublet chemotherapy for every patient who is eligible. This is based on the clinical benefit we see in the CASPIAN and IMpower133 clinical trials, which were comparable.^4,7 In both trials, there appears to be a small tail to the OS curve, with approximately 10% to 15% patients deriving long‑term benefit from these therapies.

Unfortunately, we currently lack biomarkers in ES-SCLC to inform which patients will derive the most benefit from adding immune checkpoint inhibitor to chemotherapy. PD‑L1 expression levels and tumor mutational burden, which have been shown to be predictive biomarkers for immune checkpoint inhibitor benefit in other settings,^21,22 do not have the same predictive value in ES-SCLC. There are ongoing research efforts aimed at defining subtypes of ES-SCLC with response to immunotherapy.^23,24

In the second-line setting, patients should be considered for a clinical trial because the need for new therapies and improved outcomes for these patients persists. However, because we do not want to leave patients with ES-SCLC untreated for multiple weeks while navigating the bureaucracy that comes with clinical enrollment, my advice is to look for opportunities to treat patients with a SoC therapy while clarifying eligibility for a clinical trial. From my experience, many trials in relapsed SCLC do incorporate bridging therapy in their designs or allow multiple prior lines of therapy. If a patient is not eligible for a clinical trial, lurbinectedin and topotecan remain FDA-approved SoC therapies that can be considered. As previously discussed, there also are numerous single agent chemotherapies and other agents that are recommended off label.

Finally, for the first time in a long time, numerous novel targeted agents are being evaluated for the treatment of SCLC that I am excited about, including bispecific T-cell engagers targeting DLL-3 (tarlatamab^25,26 and BI 764532²⁷) and antibody–drug conjugates (ifinatamab deruxtecan,²⁸ which targets B7-H3, and sacituzumab govitecan,²⁹ which targets TROP-2). These drugs have shown promising efficacy in the relapsed setting, and some are now even being explored as frontline therapy. The goal for the future is to eventually have a biomarker‑driven approach to help inform therapy selection in both the first-line and in the relapse setting, but we are not there yet.

For a review of SCLC subtyping efforts and the most recent clinical data on investigational therapies in the treatment of advanced ES-SCLC, please visit the companion module here.

Next, I discuss the role of radiation, if any, in ES-SCLC, starting with data on prophylactic cranial irradiation (PCI), which is part of the SoC for limited‑stage SCLC (LS-SCLC) based on a demonstrated OS benefit.³⁰

The controversial use of PCI in ES-SCLC, for about a decade between 2007-2017, was based predominantly on a randomized phase III trial conducted by the publication by Slotman and colleagues³¹ evaluating PCI vs no PCI in patients with ES-SCLC who had achieved a response with platinum-based chemotherapy (N = 286). The idea for using PCI in ES-SCLC, which is at high risk of developing brain metastasis, was to decrease the risk of intracranial relapse. In this study, they reported a statistically significant OS improvement for those who received PCI vs those who did not (HR: 0.76; P = .003), results that were promising and again, appear “on par” with what we saw in IMpower133 and CASPIAN.^3,5

However, criticisms of this study³¹ were immediate and fair. First, there was no consensus dosing for the PCI leading to heterogeneity in the dosage and number of fractions that patients received. Second, there also was no homogeneity in the chemotherapy treatment that preceded PCI. Finally, and most glaring, there was no requirement for MRI prior to PCI because the imaging protocol was defined by each center. As a result, this study failed to demonstrate that there were no brain metastases present at baseline before patients received PCI—it is really important to demonstrate that there are no previous brain metastases or the radiation may not be prophylactic.

A Japanese group subsequently performed a modified version of the above study, with corrections to the more controversial elements of the earlier study. This randomized phase III study evaluating PCI vs imaging surveillance restricted dosing of PCI to 25 Gy over 10 fractions and required baseline and follow-up MRIs.³²

This study was stopped early because of futility and concern that patients who were receiving PCI were trending toward worse OS outcomes than those who did not, thereby ending the tenure of PCI as part of the SoC for ES-SCLC. It seems that the initially reported OS benefit was likely attributable to some of the shortcomings in the trial design mentioned above.

The ongoing randomized phase III MAVERICK study (SWOG 1827) will attempt to definitively answer the long-standing question of the role of PCI in patients with LS-SCLC and ES-SCLC. In this study, patients are randomized to PCI vs no PCI after completion of first-line chemotherapy according to NCCN guideline recommendations. It is required for patients to not have brain metastases or to not have any on MRI after completion of first-line therapy. MRI surveillance is conducted at 3, 6, 9, 12, 18, and 24 months, with radiation therapy recommended at the time brain metastases are detected (whole-brain radiation therapy and stereotactic radiosurgery).

An interesting variable from the MAVERICK study is that we now have gamma knife capability, which is allowed but historically was not used in patients with SCLC although it is beginning to gain some traction worldwide.

It will be interesting to see the results from this study and whether it changes the treatment landscape of what we do.

Next, I discuss consolidative thoracic radiation in ES-SCLC, which is used in patients who have a favorable response to frontline therapy but are left with only intrathoracic disease.

Consolidative thoracic radiation was first evaluated in the randomized phase III CREST trial during a time when the first-line SoC was chemotherapy and there was no maintenance therapy, so if there was residual disease nothing else could be done but to observe and wait for eventual disease relapse.³³

In this trial, patients with ES-SCLC and World Health Organization performance score of ≤2 and residual disease following primary therapy were randomized to receive thoracic radiotherapy of 30 Gy over 10 fractions vs observation (N = 498). All patients had undergone PCI.

Although the survival benefit is difficult to see from these curves, we do note that the OS curve has a tail and it continues beyond the 2-year mark, showing that there are some long-term survivors in the landscape of SCLC with thoracic radiation compared with observation (HR: 0.8 vs 1.09; P = .35). But again, there are limitations to this study because this was before the immunotherapy era and before maintenance therapy with immunotherapy, so these patients had fewer options than what currently exist now.

The ongoing randomized phase II/III RAPTOR study, led by NRG Oncology, is attempting to integrate consolidative radiation into the immunotherapy era in ES-SCLC (NCT04402788). Patients with ES-SCLC who have completed first-line chemoimmunotherapy with a partial response or stable disease are randomized to continue atezolizumab maintenance or to receive atezolizumab maintenance with radiation therapy to consolidate their disease. This trial goes further in that it allows radiation not only to the thorax but to other sites of extrathoracic disease. I am participating in this study and look forward to seeing the long‑term follow-up of PFS and OS to see if consolidating the disease with radiation therapy can potentially eliminate the formation of resistance from residual disease sites.

The treatment landscape for SCLC has remained mostly unchanged for quite some time.^1,30

Patients with LS-SCLC are generally treated with concurrent chemoradiation, usually a platinum/etoposide backbone and, if they have a good response to therapy, will be offered either PCI with surveillance or close follow-up with routine MRIs. Ongoing studies may help answer the question whether or not immunotherapy plays a role in LS-SCLC, but for now, this is the extent of the limited‑stage first-line treatment paradigm.

In the ES-SCLC, as discussed previously, the SoC is to add an anti–PD-L1 inhibitor to platinum/etoposide,¹  with 2 competing options to choose between: atezolizumab plus carbpolatin/etoposide or durvalumab plus platinum/etoposide, based on data from the IMpower133 and CASPIAN regimens, respectively.^2-5 In either case, patients receive 4-6 cycles of initial chemoimmunotherapy, followed by immunotherapy maintenance. There appears to be no role for PCI in ES-SCLC, but there are ongoing trials to confirm this.

Finally, it remains to be seen whether consolidated thoracic radiation therapy plays a role now that chemoimmunotherapy is the SoC. In the second‑line setting for ES-SCLC, a clinical trial is recommended, but we may offer retreatment with a platinum-doublet if patients have a sufficient CTFI, or select from other reasonable single‑agent therapies like topotecan, and lurbinectedin, other off‑label options, or even immunotherapies (eg, nivolumab or pembrolizumab).¹