Immunotherapy/Chemo Combos Remain Go-To Option in Growing Small Cell Lung Cancer Paradigm

Chemoimmunotherapy is the new frontline standard of care for patients with small cell lung cancer (SCLC), explained Taofeek K. Owonikoko, MD, PhD, adding that other novel agents, such as, bispecific T-cell engagers (BiTEs) are in the pipeline and gaining momentum for those who experience disease progression.

“Both atezolizumab [Tecentriq] and durvalumab [Imfinzi] have been shown to be beneficial and they are now part of our treatment strategy,” said Owonikoko, who is professor and chief in the Division of Hematology/Oncology, Stanley/Marks/OHA Chair in Oncology Leadership, and associate director for Translational Sciences at University of Pittsburgh Medical Center Hillman Cancer Center, shared insight on optimal treatment approaches in SCLC during the 16th Annual New York Lung Cancers Symposium.¹

“BiTEs targeting DLL3 as well as GD2 are now in clinical development and hopefully, they will give us newer options [in the relapsed setting].”

The regulatory approvals of the PD-L1 inhibitors atezolizumab and durvalumab combined with frontline chemotherapy in March 20192 and March 20203, respectively, have both demonstrated improvements in overall survival (OS) without the cost of significant toxicity, thus, shifting the landscape to a new approach in SCLC care.

Frontline Advancements

Atezolizumab

In the phase 3 IMpower133 trial (NCT02763579), 403 patients with measurable extensive-stage (ES)-SCLC with an ECOG performance status of 0 or 1 who had not received prior systemic therapy were randomized 1:1 to receive induction atezolizumab intravenously (IV) at 1200 mg on day 1, plus carboplatin area under the curve IV at 5 mg/mL/min on day 1, plus etoposide at 100 mg/m² IV on days 1 to 3, or placebo plus the chemotherapy regimen for four 21-day cycles. Patients then received maintenance therapy with atezolizumab or placebo until disease progression or loss of clinical benefit. Prophylactic cranial irradiation (PCI) was permitted.

Stratification factors included sex (men vs women), ECOG performance status (0 vs 1), or treated asymptomatic brain metastases (yes vs no). The coprimary end points of the trial were OS and investigator-assessed progression-free survival (PFS); secondary outcome measures were objective response rate (ORR), duration of response, and safety.

At a median follow-up of 22.9 months, results showed that the median OS with atezolizumab/chemotherapy was 12.3 months (95% CI, 10.8-15.8) compared with 10.3 months (95% CI, 9.3-11.3) with chemotherapy alone, leading to a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.60-0.95; P = .0154).⁴ The 12- and 18-month OS rates with atezolizumab were 51.9% and 34.0% vs 39.0% and 21.0% with chemotherapy alone, respectively.

Regarding safety, grade 3/4 AEs were comparable between the 2 arms at 67.2% and 63.8% with atezolizumab/chemotherapy and chemotherapy alone, respectively; treatment-related AEs were 94.9% and 92.3%, respectively. Serious AEs occurred in 37.4% of patients with atezolizumab and in 34.7% with those on chemotherapy alone; immune-related AEs were reported in 39.9% and 24.5% of patients, respectively. More patients did have AEs that led to treatment withdrawal with atezolizumab than placebo at 10.6% vs 2.6%, respectively. Three treatment-related deaths occurred in each arm.

Owonikoko also noted that the same doses of carboplatin (n = 4) and etoposide (n = 12) were given in each treatment group.

“We should not have any hesitation to use immunotherapy if we are going to use chemotherapy, and that is my practice pattern,” Owonikoko said. “For any patient who is eligible for chemotherapy, if there is no specific contraindication to immunotherapy, they will receive chemoimmunotherapy.”

Durvalumab

The 3-arm, phase 3 CASPIAN trial (NCT03043872) also included patients with treatment-naïve, measurable ES-SCLC, but with slightly different eligibility criteria, which included: a World Health Organization performance score of 0 or 1, asymptomatic or treated and stable brain metastases, and a life expectancy of at least 12 weeks.

In this trial, 805 patients were randomized 1:1:1 to receive durvalumab plus tremelimumab plus etoposide and cisplatin/carboplatin every 3 weeks for 4 cycles, durvalumab plus etoposide and platinum every 3 weeks for 4 cycles, or etoposide and platinum every 4 weeks for up to 6 weeks. In both durvalumab arms, maintenance treatment with the PD-L1 inhibitor was given every 4 weeks until progressive disease; in the etoposide-alone arm, PCI was optional as maintenance.

Patients were stratified by planned platinum-based therapy (carboplatin vs cisplatin). The primary end point of the trial was OS, and secondary end points were PFS, ORR, safety and tolerability, and patient-reported outcomes.

The 3-year OS update of CASPIAN, which was presented during the 2021 ESMO Congress, showed that at a median follow-up of 39.4 months (range, 0.1-47.5) in censored patients, durvalumab/chemotherapy led to a median OS of 12.9 months (95% CI, 11.3-14.7) compared with 10.5 months (95% CI, 9.3-11.2) with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.86; P = .0003).⁵

With durvalumab/chemotherapy, the 12-, 18-, 24-, and 36-month OS rates were 52.8%, 32.0%, 22.9%, and 17.6%, respectively; with chemotherapy alone, these rates were 39.3%, 24.8%, 13.9%, and 5.8%, respectively.

“It is very, very reassuring, that at 3 years, close to 20% of our patients are alive and doing well compared with the 6% who received chemotherapy alone,” Owonikoko noted.

The addition of durvalumab did not compromise the delivery of chemotherapy, he added. However, in the safety population of patients who received durvalumab plus tremelimumab and chemotherapy (n = 266) and durvalumab plus chemotherapy (n = 265), the median duration of durvalumab was 23.1 weeks (range, 0.1-190.0) in the arm with tremelimumab vs 28.0 weeks (range, 0.3-198.7) with just durvalumab/chemotherapy.

Do PCI and Consolidation Thoracic Radiation Have a Role as Routine Intervention?

The strategy of utilizing PCI in patients with ES-SCLC following frontline therapy has been debated. In a Japanese trial of PCI compared with imaging surveillance in this patient population, researchers found that PCI had a negative effect on OS (HR, 1.27; 95% CI, 0.96-1.68; P = .094).⁶

“My own practice is not to use PCI at this point, I also do not use thoracic radiation as a routine consolidation strategy outside of a clinical trial setting,” Owonikoko explained. “On the basis of this, for my extensive-stage patient, if I can continue to monitor the brain, I generally do not recommend PCI for them. For limited-stage disease, the jury is still out, but we are going to have some answers to that [question] very soon, I hope.”

In an earlier analysis of CASPIAN, which studied patterns of first progression following treatment, new lesions occurred in 41.4% of patients on durvalumab plus etoposide/platinum-based therapy compared with 47.2% of those on chemotherapy alone.7 Of the new lesions, 11.6% and 11.5% were in the brain/central nervous system (CNS), respectively.

“This suggests that even when you do not allow PCI to be given to patients, you are not putting them at risk of developing brain metastasis, and we are beginning to see these emerging data of potential benefit of using immunotherapy in terms of better brain protection and better control of the disease,” Owonikoko said.

Similar patterns of new lesions (42.8%) and site of new lesions (brain, 10.4%) were reported in patients who received atezolizumab plus chemotherapy on the IMpower133 trial.⁸

The ongoing, phase 3 randomized SWOG S1827 (MAVERICK) trial (NCT04155034) will directly answer the question of whether PCI with MRI surveillance for brain metastasis is optimal compared with MRI surveillance alone in patients with SCLC. The trial is slated to enroll close to 700 patients.⁹

As it relates to thoracic radiation (TRT), the CREST trial (NTR1527) examined whether TRT compared with observation improved outcomes in 498 patients with ES-SCLC. Results showed that the 1-year OS rate was 33% with TRT vs 28% in the control arm (HR, 0.84; 95% CI, 0.69-1.01; P = .066), demonstrating no survival benefit with TRT following frontline chemotherapy.¹⁰

Relapsed SCLC

Despite the encouraging clinical activity with frontline chemoimmunotherapy, many patients still relapse and are left with the following options: topotecan, lurbinectedin (Zepzelca), retreatment with a platinum-based doublet, retreatment with a platinum-based doublet plus immunotherapy, and nivolumab (Opdivo).

However, Owonikoko emphasized that some of these treatments may not be the go-to next step for select patients with relapsed SCLC. For example, topotecan should be avoided in those with a treatment-free interval of less than 60 days, liver metastasis, a performance status of 2, low albumin, anemia, and hyponatremia, based on retrospective data.¹¹

Lurbinectedin

The novel anticancer drug lurbinectedin is a synthetic, marine-derived tetrahydroisoquinoline alkaloid and is an analogue of the DNA-damaging agent trabectedin (Yondelis). The agent blocks activated transcription, produces DNA double-strand breaks, and therefore, generates apoptosis and modulates the tumor microenvironment through tumor-associated macrophage inhibition.

As a single agent, lurbinectedin is generally safe and linked with mostly grade 1/2 hematological adverse effects (AEs) such as anemia (87%), leukopenia (50%), neutropenia (26%), and thrombocytopenia (37%).¹² The tolerability of the drug bodes well for combinatorial potential, Owonikoko added.

Based on findings from the multicenter, open-label, multi-cohort PM1183-B-005-14 trial (NCT02454972), the FDA granted an accelerated approval to lurbinectedin in July 2020 for use in adult patients with metastatic SCLC who experienced disease progression on, or after, platinum-based chemotherapy.¹³

The anticipated confirmatory data came from the phase 3 randomized ATLANTIS trial (NCT02566993), which tested lurbinectedin at 2 mg/m² on day 1 every 3 weeks plus doxorubicin at 40 mg/m² on day 1 vs cyclophosphamide/doxorubicin/vincristine (CAV) on day 1 every 3 weeks or topotecan at 1.5 mg/m² on days 1 to 5 every 3 weeks in 600 patients with relapsed SCLC. Treatment was given until disease progression or unacceptable toxicity.

Patients needed to have received 1 prior line of chemotherapy with additional biologic lines permitted, an ECOG performance status of less than 2, and a chemotherapy-free interval (CTFI) that was greater than 30 days.

Stratification factors include ECOG performance status (0 vs ≥1), CTFI (≥180, 179-90, or <90), CNS involvement (yes vs no), prior PD-1/PD-L1 inhibition (yes vs no), and investigator preference for the control arm. The primary end point was OS.

Findings in the intention-to-treat population demonstrated that the median OS in the lurbinectedin/doxorubicin arm was 8.6 months (95% CI, 7.1-9.4) vs 7.6 months (95% CI, 6.6-8.2) in the control arm (HR, 0.967; 95% CI, 0.815-1.148; P = .7032).¹⁴

“Lurbinectedin remains an option, and my understanding is that we should be seeing some sort of additional follow-up trial to further support that accelerated approval,” Owonikoko noted.

Retreatment With Platinum-Based Doublets

Although retreating patients with platinum-based doublet therapy is a strategy that Owonikoko said all treating physicians implement in clinical practice, a large, randomized trial comparing the use of platinum-doublet chemotherapy with topotecan in patients with sensitive relapsed SCLC sought to prospectively address whether retreatment is beneficial in this population. Results showcased a median PFS of 2.7 months (90% CI, 2.3-3.2) with topotecan and 4.7 months (90% CI, 3.9-5.5) for platinum-based therapy (HR, 0.57; 90% CI, 0.41-0.73; P = .0041), but no OS benefit was observed with platinum-doublet treatment.¹⁵

“My own clinical judgement is if a patient struggled through the frontline platinum-doublet chemotherapy, I probably want to use something different and not expose them to a platinum doublet again,” Owonikoko emphasized. “That doesn’t mean I’m going to use topotecan; it just means I’m going to use something different.”

Nivolumab

The PD-1 inhibitor was explored in the second-line SCLC setting in the randomized, phase 3 CheckMate-331 trial (NCT02481830) of nivolumab (n = 284) vs topotecan or amrubicin (n = 285). Patients had SCLC and disease recurrence or progression following at least 4 cycles of frontline platinum-based chemotherapy or chemoradiation, an ECOG performance status of 0 or 1, no symptomatic CNS metastases, and no prior treatment with either a PD-L1/PD-L2, CTLA-4, or CD37 inhibitor. The primary end point of the trial was OS; secondary end points were PFS and ORR.

At a median follow-up of 7.0 months for nivolumab and 7.6 months for chemotherapy, the median OS was 7.5 months (95% CI, 5.7-9.2) and 8.4 months (95% CI, 7.0-10.0), respectively (HR, 0.86; 95% CI, 0.72-1.04; P = .11).¹⁶ The 6- and 12-month OS rates with nivolumab with 55% 37%, respectively; these rates were 60% and 34%, respectively, with chemotherapy.

“There is some signal that a subset of patients perhaps benefited [from nivolumab],” Owonikoko explained. “Beyond 6 months, you can see that there is some hint of nivolumab as better than topotecan in this study, but this will require us knowing who those patients are at the beginning. Therefore, we need a biomarker to use this strategy as a salvage regimen, and that will probably be those patients who did not receive immunotherapy in the frontline.”

Plenty of novel agents are on the horizon and of interest in SCLC, Owonikoko added, such as liposomal irinotecan, which is being examined in the RESILIENT trial (NCT03088813), in patients who have progressed on, or following, platinum-based first-line therapy.¹⁷

Additionally, tarlatamab, a half-life extended BiTE targeting DLL3, showed impressive preliminary activity in a phase 1 trial (NCT03319940) of patients with relapsed/refractory SCLC.¹⁸ Data showed a 20% response rate of confirmed partial responses, a 27% stable disease rate, and a 47% disease control rate. Tumor shrinkage was observed across the range of tarlatamab doses.

References

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8. Higgins KA, Curran W, Liu SV, et al. Patterns of disease progression after carboplatin/etoposide + atezolizumab in extensive-stage small cell lung cancer. Presented at: 2020 ASTRO Annual Meeting; October 24-20, 2020; virtual. https://bit.ly/3bQdo5f
9. SWOG S1827 (MAVERICK) testing whether the use of brain scans alone instead of brain scans plus preventive brain radiation affects lifespan in patients with small cell lung cancer. ClinicalTrials.gov. Updated July 12, 2021. Accessed November 6, 2021. https://clinicaltrials.gov/ct2/show/NCT04155034  
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13. FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer. FDA. News release. June 15, 2020. Accessed November 6, 2021. https://bit.ly/3bN92f7 
14. Paz-Ares L, Ciuleanu T, Navarro A, et al. Lurbinectedin/doxorubicin versus CAV or topotecan in relapsed SCLC patients: phase III randomized ATLANTIS trial. J Thor Oncol. 2021;16(10):S844-S845. doi:10.1016/j.jtho.2021.08.030
15. Baize N, Monnet I, Greillier L, et al. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1224-1333. doi:10.1016/S1470-2045(20)30461-7
16. Spigel DR, Vicente D, Ciuleanu TE, et al. Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331. Ann Oncol. 2021;32(5):631-641. doi:10.1016/j.annonc.2021.01.071
17. Study of irinotecan liposome injection (ONIVYDE) in patients with small cell lung cancer (RESILIENT). ClinicalTrials.gov. Updated July 28, 2021. Accessed November 6, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03088813
18. Owonikoko TK. Champiat S, Johnson ML, et al. Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immuno-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC). J Clin Oncol. 2021;39(suppl 15):8510. doi:10.1200/JCO.2021.39.15_suppl.8510