Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive‐Stage Small Cell Lung Cancer

Abstract

Background

Small cell lung cancer (SCLC) represents approximately 15% of lung cancers, and approximately 70% are diagnosed as extensive‐stage SCLC (ES‐SCLC). Although ES‐SCLC is highly responsive to chemotherapy, patients typically progress rapidly, and there is an urgent need for new therapies. Immune checkpoint inhibitors (ICIs) have recently been investigated in SCLC, and this review provides guidance on the use of these agents in ES‐SCLC based on phase III evidence.

Methods

Published and presented literature on phase III data addressing use of ICIs in ES‐SCLC was identified using the key search terms “small cell lung cancer” AND “checkpoint inhibitors” (OR respective aliases). Directed searches of eligible studies were periodically performed to ensure capture of the most recent data.

Results

Six phase III trials were identified, with four assessing the benefits of ICIs plus chemotherapy first‐line, one evaluating ICIs as first‐line therapy maintenance, and one assessing ICI monotherapy after progression on platinum‐based chemotherapy. The addition of ipilimumab or tremelimumab to first‐line treatment or as first‐line maintenance did not improve survival. Two out of three studies combining PD‐1/PD‐L1 inhibitors with first‐line platinum‐based chemotherapy demonstrated significant long‐lasting survival benefits and improved quality of life with no unexpected safety concerns. PD‐1/PD‐L1 inhibitors as first‐line maintenance or in later lines of therapy did not improve survival. Biomarker research is ongoing as well as research into the role of ICIs in combination with radiation therapy in limited‐stage SCLC.

Conclusion

The addition of atezolizumab or durvalumab to first‐line platinum‐based chemotherapy for ES‐SCLC prolongs survival and improves quality of life.

Implications for Practice

Platinum‐based chemotherapy has been standard of care for extensive‐stage small cell lung cancer (ES‐SCLC) for more than a decade. Six recent phase III trials investigating immune checkpoint inhibitors (ICIs) have clarified the role of these agents in this setting. Although ICIs were assessed first‐line, as first‐line maintenance, and in later lines of therapy, the additions of atezolizumab or durvalumab to first‐line platinum‐based chemotherapy were the only interventions that significantly improved overall survival and increased quality of life. These combinations should therefore be considered standard therapy for first‐line ES‐SCLC. Biomarker research and investigations into the role of ICIs for limited‐stage disease are ongoing.

Short abstract

Immune checkpoint inhibitors have recently been investigated in small cell lung cancer. This review provides guidance on the use of these agents in extensive‐stage small cell lung cancer based on phase III evidence.

Introduction

Lung cancer is one of the most prevalent types of cancer, with an estimated 2.1 million new cases diagnosed resulting in approximately 1.8 million deaths worldwide in 2018 [1]. Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers [2] with 6.0 cases per 100,000 individuals in 2014 [3]. SCLC is strongly associated with exposure to tobacco and grows rapidly, with early widespread metastases and frequent brain involvement [4, 5]. This disease subtype is also associated with high mutation rates, including rare oncogenic drivers and inactivation of the TP53 and RB1 tumor suppressor genes [6]. Approximately 30% of patients with SCLC present with limited‐stage disease (LS‐SCLC), with the remaining 70% diagnosed with extensive‐stage SCLC (ES‐SCLC) where the tumor extends beyond one hemithorax or cannot be encompassed within standard radiation fields [4, 7, 8]. Overall prognosis for patients with ES‐SCLC is poor [8, 9, 10, 11].

ES‐SCLC is highly responsive to chemotherapy [4, 12], and standard first‐line treatment is a platinum plus etoposide doublet [4]. This treatment often achieves rapid responses with good overall response rates (ORRs, up to 75%) although these are often transient with a median progression‐free survival (PFS) of only 5.5 months and a median overall survival (OS) of less than 10 months [4, 8, 9, 10]. Second‐line options include the topoisomerase inhibitor topotecan or rechallenging with carboplatin‐etoposide. Topotecan is approved by the U.S. Food and Drug Administration (FDA) [13, 14] although not often used [15, 16], whereas carboplatin‐etoposide is commonly used in platinum‐sensitive patients [17, 18, 19, 20]. Given the rapid progression of SCLC, third‐line therapy is rare [20]. Options for SCLC have changed little in the last few decades [4, 21], underscoring the urgent need for new therapies.

Immune checkpoints prevent aberrant autoimmune damage to healthy tissues [22], and tumor‐mediated activation of these checkpoints allows immune response evasion [23]. Cytotoxic T‐lymphocyte–associated antigen 4 (CTLA‐4) expression can downregulate the early stages of T‐cell activation in lymphatic tissue [24, 25], and tumor expression of checkpoint regulator molecules such as programmed cell death ligand 1 (PD‐L1), which interacts with the programmed cell death protein 1 (PD‐1), can also downregulate immune responses locally [23, 25, 26]. Immune checkpoint inhibitors (ICIs) have been developed to disrupt these interactions [23, 27], allowing the reversal of tumor‐mediated immune suppression, which can often produce durable antitumor responses [21]. ICIs are approved in a variety of cancer settings [28, 29, 30, 31, 32, 33, 34] and have recently been investigated in SCLC, including the CTLA‐4 inhibitors ipilimumab and tremelimumab, the PD‐1 inhibitors nivolumab and pembrolizumab, and the PD‐L1 inhibitors atezolizumab and durvalumab [35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. Initial efficacy signals from phase I/II trials in recurrent SCLC including CheckMate 032, KEYNOTE‐028, and KEYNOTE‐158 [41, 42, 45], led to the approval of nivolumab and pembrolizumab in this setting [46, 47]. The first phase III trial of ICIs for the treatment of ES‐SCLC was reported in 2016 [43], followed by more recent reports from other phase III studies [37, 39, 40, 44, 48]. These new data require a comprehensive analysis of the efficacy and safety of ICIs in this setting with a thorough discussion of clinical implications. This review provides up‐to‐date guidance on use of ICIs for advanced ES‐SCLC based on current evidence from randomized phase III trials.

Materials and Methods

A search of published and presented literature was conducted to identify phase III trials reporting outcomes on the use of ICIs in the treatment of ES‐SCLC. PubMed (all time to June 4, 2020) and the proceedings of the 2019 and 2020 annual meetings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the World Congress on Lung Cancer were searched using the key search terms “small‐cell lung cancer” AND “checkpoint inhibitor” AND “extensive” (OR respective aliases). A supplemental bibliographic search of review articles and pooled/meta‐analyses was also conducted.

Records were vetted at abstract level and confirmed at full text as needed. Studies were excluded if they were nonoriginal research, preclinical studies only, correlative science, not specific to SCLC, not assessing ICIs, outside the extensive‐stage setting, retrospective studies, or prospective phase I, II, or IV studies or of undefined phase; duplicate, associated, or prior reports and studies without reported outcomes were also excluded. Directed searches for recent reports of eligible studies were periodically performed to ensure the most up‐to‐date data.

Results

The literature search identified a total of 142 records, which, after vetting, resulted in a total of six phase III trials reporting efficacy outcomes on the use of ICIs for the treatment of ES‐SCLC (the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses diagram is shown in Fig. 1) [37, 39, 40, 43, 44, 48].

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses diagram of phase III trials evaluating immune checkpoint inhibitors for the treatment of extensive‐stage SCLC.

^a Primary reports of eligible studies that were not identified through database search.

Abbreviations: ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; ICIs, immune checkpoint inhibitors; SCLC, small cell lung cancer; WCLC, World Conference on Lung Cancer.

First‐Line Therapy

Four phase III trials assessed ICIs plus chemotherapy as first‐line therapy for ES‐SCLC (Table 1) [37, 40, 43, 48]. CA184 156 randomized patients to receive chemotherapy (etoposide 100 mg/m² and cisplatin 75 mg/m² or carboplatin area under the curve 5) every 3 weeks for four cycles plus either ipilimumab 10 mg/kg (n = 478) or placebo (n = 476) during cycles 3 and 4 followed by ipilimumab or placebo alone for cycles 5 and 6 then maintenance ipilimumab or placebo every 12 weeks for up to 3 years. The primary endpoint was OS in patients who received at least a single dose of study therapy. At a median follow‐up of 10.5 months for the ipilimumab plus chemotherapy arm and 10.2 months for the placebo plus chemotherapy arm, median OS was not significantly improved for ipilimumab compared with placebo (11.0 vs. 10.9 months; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.81─1.09; p = .38) [43]. Median PFS was 4.6 months in the ipilimumab group versus 4.4 months for the placebo group (HR, 0.85; 95% CI, 0.75─0.97; p = .016, not formally tested for significance). ORRs were the same in both arms (62%), and the median duration of response (DoR) was 4.0 months for ipilimumab and 3.5 months in the placebo group. Rates of treatment discontinuation due to treatment‐related adverse events (TRAEs) and treatment‐related deaths were higher in the ipilimumab plus chemotherapy arm compared with the placebo plus chemotherapy arm, whereas rates of grade 3/4 TRAEs were comparable (Table 2).

Table 1.

Efficacy outcomes of phase III trials assessing immune checkpoint inhibitors for extensive‐stage small cell lung cancer

Trial name (NCT#)	Regimen(s)	n	Median follow‐up for OS, months	Overall response rate, % (95% CI)	Median duration of response, months (95% CI) [range]	Median progression‐free survival, months (95% CI)	Median overall survival, months (95% CI)
First‐line therapy
CA184‐156 (NCT01450761) [43]	Cisplatin 75 mg/m2 or carboplatin AUC 5 on day 1 and etoposide 100 mg/m2 days 1–3, Q3W × two cycles, followed by same CT plus ipilimumab 10 mg/kg on day 1, Q3W × two cycles followed by ipilimumab 10 mg/kg on day 1, Q3W × two cycles then ipilimumab 10 mg/kg Q12W × 3 years	478	10.5	62 (58─67)	4.0 (3.3─4.2)	4.6 HR 0.85 (0.75─0.97) p = .016	11.0 HR 0.94 (0.81─1.09) p = .38
	Cisplatin 75 mg/m2 or carboplatin AUC 5 on day 1 and etoposide 100 mg/m2 days 1–3, Q3W × two cycles followed by same CT plus placebo on day 1, Q3W × two cycles 3–6 followed by placebo on day 1, Q3W × two cycles then placebo Q12W × 3 years	476	10.2	62 (58─67)	3.5 (3.3─4.1)	4.4	10.9
IMpower 133 (NCT02763579) [50]	Atezolizumab 1,200 mg on day 1 plus carboplatin AUC 5 on day 1 and etoposide 100 mg/m2 on days 1–3, Q3W × four cycles, then atezolizumab 1,200 mg Q3W until progression	201	22.9	60.2	4.2 [1.4+ a ─24.3+]	5.2 b HR 0.77 (0.62─0.96) p = .02	12.3 HR 0.76 (0.60─0.95) p = .015
	Placebo on day 1 plus carboplatin AUC 5 on day 1 and etoposide 100 mg/m2 on days 1–3, Q3W × four cycles, then placebo Q3W until progression	202		64.4	3.9 [2.0─24.2+ a ]	4.3	10.3
CASPIAN (NCT03043872) [52]	Durvalumab 1,500 mg plus tremelimumab 75 mg on day 1 plus cisplatin 75–80 mg/m2 or carboplatin AUC 5–6 on day 1 and etoposide 80–100 mg/m2 on days 1–3, Q3W × four cycles, then durvalumab 1,500 mg Q4W until progression c	268	25.1	58.4	5.2 (4.9─5.6)	4.9 HR 0.84 (0.70─1.01) d	10.4 HR 0.82 (0.68─1.00) p = .045 e
	Durvalumab 1,500 mg on day 1 plus cisplatin 75–80 mg/m2 or carboplatin AUC 5–6 on day 1 and etoposide 80–100 mg/m2 on days 1–3, Q3W × four cycles then durvalumab 1,500 mg Q4W until progression	268		67.9	5.1 (4.9─5.3)	5.1 HR 0.80 (0.66─0.96) d	12.9 HR 0.75 (0.62─0.91) p = .0032
	Cisplatin 75–80 mg/m2 or carboplatin AUC 5–6 on day 1 and etoposide 80–100 mg/m2 on days 1–3, Q3W × four to six cycles	269		58.0	5.1 (4.8─5.3)	5.4	10.5
KEYNOTE‐604 (NCT03066778) [48]	Pembrolizumab 200 mg on day 1 plus cisplatin 75 mg/m2 or carboplatin AUC 5 on day 1 plus etoposide 100 mg/m2 on days 1–3, Q3W × four cycles then pembrolizumab 200 mg Q3W × 1.8 years	228	21.6	70.6 (64.2─76.4)	4.2 [1.0 + ─26.0+]	4.5 HR 0.75 (0.61─0.91) p = .0023	10.8 HR 0.80 (0.64─0.98) p = .016 f
	Placebo on day 1 plus cisplatin 75 mg/m2 or carboplatin AUC 5 on day 1 plus etoposide 100 mg/m2 on days 1–3, Q3W × four cycles then placebo Q3W × 1.8 years	225		61.8 (55.1─68.2)	3.7 [1.4 + ─25.8+]	4.3	9.7
First‐line therapy maintenance
CheckMate 451 (NCT02538666) [39]	Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W × four cycles then nivolumab 240 mg Q2W × 2 years	279	9 g	—	10 h	1.7 HR 0.72 (0.60─0.87) d	9.2 HR 0.92 (0.8─1.1) p = .37
	Nivolumab 240 mg Q2W × 2 years	280		—	11 h	1.9 HR 0.67 (0.56─0.81) d	10.4 HR 0.84 (0.70─1.0) d
	Placebo × 2 years	275		—	8 h	1.4	9.6
Second‐line plus
CheckMate 331 (NCT02481830) [44]	Nivolumab 240 mg Q2W until progression	284	7.0	13.7 i (10.0─18.3)	8.3 i (7.0─12.6)	1.4 i HR 1.41 (1.18─1.69)	7.5 HR 0.86 (0.72─1.04) p = .11
	Topotecan (i.v. 1.5 mg/m2 or oral 2.3 mg/m2) days 1–5 or amrubicin i.v. 40 mg/m2 on days 1–3, Q3W until progression	285	7.6	16.5 i (12.4─21.3)	4.5 i (4.1─5.8)	3.8 i	8.4

Efficacy outcomes of phase III checkpoint inhibitor trials in small cell lung cancer, ordered by line of therapy, then publication date.

Abbreviations: —, to; AUC, area under the curve; CI, confidence interval; CT, chemotherapy; HR, hazard ratio; NCT, National Clinical Trial; OS, overall survival; PCI, prophylactic cranial irradiation; QXW, every X weeks.

^aData for the lower rage of the response in the atezolizumab group and the upper range of the response in the placebo group are censored.

^bPrimary analysis with a median follow‐up of 13.9 months.

^cPatients in this arm received an additional dose of tremelimumab 75 mg post‐CT.

^dNot formally tested for statistical significance.

^eDid not meet threshold for significance (p = .0418).

^fDid not meet threshold for significance (p = .0128).

^gMinimum follow‐up.

^hIncludes only patients with measurable disease at baseline; nivolumab plus ipilimumab (n = 265), nivolumab (n = 261), placebo (n = 263).

ⁱPer local investigator.

Table 2.

Adverse events in phase III trials assessing immune checkpoint inhibitors for extensive‐stage small cell lung cancer

Parameter	CA184‐156 (NCT01450761) [43]		IMpower 133 (NCT02763579) [50]		CASPIAN (NCT03043872) [52]			KEYNOTE‐604 (NCT03066778) [48]		CheckMate 451 (NCT02538666) [39]			CheckMate 331 (NCT02481830) [44]
Treatment algorithm	Ipi + CT	PBO + CT	Atez + CT	PBO + CT	Durv + trem + CT	Durv + CT	CT	Pembro + CT	PBO + CT	Niv + ipi	Niv	PBO	Niv	Topo or amrub
Safety population, n	478	476	198	196	266	265	266	223	223	278	279	273	282	265
Grade 3/4 TRAEs, n (%)	231 (48.3) a	214 (45.0) a	134 b (67.7)	124 b (63.3)	187 b (70.3)	165 b (62.3)	167 b (62.8)	142 (63.7)	136 (61.0)	145 (52.2)	32 (11.5)	23 (8.4)	39 (13.8)	194 (73.2)
TRAEs leading to discontinuation of any treatment, n (%)	86 (18.0)	9 (1.9)	24 b (12.1)	6 b (3.1)	57 b (21.4)	27 b (10.2)	25 b (9.4)	33 b (14.8)	14 b (6.3)	80 (28.8)	22 (7.9)	1 (0.4)	17 (6.0)	38 (14.3)
TRAE‐associated deaths, n (%)	5 (1.0)	2 (0.4)	3 (1.5)	3 (1.5)	12 (4.5)	6 (2.3)	2 (0.8)	6 (2.7)	6 (2.7)	7 (2.5)	1 (0.4)	1 (0.4)	2 (0.7)	3 (1.1)

Abbreviations: amrub, amrubicin; atez, atezolizumab; CT, chemotherapy; durv, durvalumab; ipi, ipilimumab; niv, nivolumab; pembro, pembrolizumab; PBO, placebo; topo, topotecan; TRAE, treatment‐related adverse event; trem, tremelimumab.

^aGrade 3–5 events.

^bAny cause adverse events.

The IMpower 133 study randomized patients to receive atezolizumab 1,200 mg (n = 201) or placebo (n = 202) plus chemotherapy (etoposide and carboplatin) in both arms every 3 weeks for four cycles followed by maintenance atezolizumab or placebo. The co‐primary endpoints were OS and investigator‐assessed PFS. At a median follow‐up of 13.9 months, a significant improvement in median OS was seen for atezolizumab plus chemotherapy versus placebo plus chemotherapy (12.3 vs. 10.3 months; HR, 0.70; 95% CI, 0.54─0.91; p = .007) [37]. Median PFS was also significantly improved among patients in the atezolizumab versus placebo arms (5.2 vs. 4.3 months; HR, 0.77; 95% CI, 0.62─0.96; p = .02; Table 1). ORRs were 60.2% versus 64.4%, with median DoRs of 4.2 versus 3.9 months for the atezolizumab versus placebo groups. Clinically meaningful improvements in health‐related quality of life (HRQoL) that persisted beyond a year were also reported for the atezolizumab combination [49]. At a longer median follow‐up of 22.9 months, the improvement in median OS was maintained for the atezolizumab combination versus placebo (12.3 vs. 10.3 months; HR, 0.76; 95% CI, 0.60─0.95; descriptive p = .015) [50]. Rates of discontinuation due to adverse events (AEs) were higher in the atezolizumab arm, although rates of grade 3/4 TRAEs and treatment‐related death were comparable (Table 2).

The three arm, open label, CASPIAN trial evaluated durvalumab 1,500 mg, with or without tremelimumab 75 mg, in combination with etoposide and carboplatin or cisplatin every 3 weeks for up to four cycles (n = 268) compared with up to six cycles of platinum‐based therapy alone (n = 269), with durvalumab maintenance every 4 weeks in patients who received durvalumab. At a median follow‐up of 14.2 months, the primary endpoint of median OS was significantly improved for durvalumab plus chemotherapy compared with chemotherapy alone (13.0 vs. 10.3 months; HR, 0.73; 95% CI, 0.59─0.91; p = .005), and both PFS and ORR were comparable (Table 1) [40]. Global health status (measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core‐30) also favored durvalumab plus chemotherapy compared with chemotherapy alone (HR, 0.81; 95% CI, 0.63─1.05) [51]. At a longer median follow‐up of 25.1 months the OS benefit was maintained (12.9 vs. 10.5 months; HR, 0.75; 95% CI, 0.62─0.91; p = .0032), and both PFS and ORR remained comparable [52]. The addition of tremelimumab to durvalumab and chemotherapy failed to significantly improve survival compared with chemotherapy alone (10.4 vs. 10.5 months; HR, 0.82; 95% CI, 0.68─1.00; p = .045) with similar PFS and ORR seen in each arm. Grade 3/4 AEs of any cause, discontinuation due to TRAEs, and TRAE‐associated deaths were relatively comparable between the durvalumab plus chemotherapy and chemotherapy alone arms, whereas these safety parameters were all higher for durvalumab plus tremelimumab and chemotherapy compared with chemotherapy alone (Table 2).

The KEYNOTE‐604 trial randomized patients to receive pembrolizumab 200 mg (n = 228) or placebo (n = 225) plus chemotherapy (etoposide and carboplatin or cisplatin) in both arms every 3 weeks for four cycles followed by maintenance pembrolizumab or placebo. The co‐primary endpoints were OS and PFS. With a median follow‐up of 21.6 months, median OS was numerically improved among patients in the pembrolizumab versus placebo arms, although this did not achieve statistical significance according to prespecified criteria (10.8 vs. 9.7 months; HR, 0.80; 95% CI, 0.64─0.98; p = .016; Table 1) [48]. A significant improvement in median PFS was seen among patients receiving pembrolizumab (4.5 vs. 4.3 months; HR, 0.75; 95% CI, 0.61─0.91; p = .0023), and ORRs (70.6% vs. 61.8%), and median DoRs (4.2 vs. 3.7 months) were higher for the pembrolizumab versus placebo groups. AEs leading to withdrawal from any treatment were higher in the pembrolizumab versus placebo arms, although rates of grade 3/4 TRAEs and treatment‐related deaths were similar (Table 2).

First‐Line Therapy Maintenance

One phase III trial evaluated ICIs as maintenance after first‐line therapy in patients with ES‐SCLC who had an ongoing response to platinum‐based chemotherapy (Table 1). The three arm, double blind, CheckMate 451 trial assessed nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (maximum of four doses) given every 3 weeks (n = 279) or nivolumab 240 mg given alone every 2 weeks (n = 280), with both arms compared with placebo (n = 275). At a minimum follow‐up of 9 months, there was no significant improvement in the primary endpoint of median OS for nivolumab plus ipilimumab versus placebo (9.2 vs. 9.6 months; HR, 0.92; 95% CI, 0.8─1.1; p = .37; Table 1) [39]. The median OS for patients receiving nivolumab alone versus placebo was 10.4 versus 9.6 months (HR, 0.84; 95% CI, 0.7─1.0; not formally tested for significance). Median PFS was 1.7 months for nivolumab plus ipilimumab (HR, 0.72; 95% CI, 0.60─0.87) and 1.9 months for nivolumab alone (HR, 0.67; 95% CI, 0.56─0.81) compared with 1.4 months for placebo. ORRs were not reported, although these regimens resulted in clinical benefit rates of 45%, 47%, and 35% and median DoRs of 10, 11, and 8 months in the nivolumab plus ipilimumab, nivolumab alone, and placebo arms, respectively. Rates of TRAEs leading to discontinuation, grade 3/4 TRAEs, and treatment‐related deaths were higher in the nivolumab plus ipilimumab arm compared with the nivolumab alone and placebo arms (Table 2).

Second Line or Later

One phase III trial evaluated ICI monotherapy as second‐ or later‐line therapy in patients with LS‐ or ES‐SCLC (Table 1). The CheckMate 331 trial evaluated nivolumab 240 mg every 2 weeks (n = 284) compared with chemotherapy (n = 285, topotecan or amrubicin) with the majority of patients (74%) diagnosed with ES‐SCLC. With a median follow‐up of 7.0 months for nivolumab and 7.6 months for chemotherapy, the primary endpoint of median OS was not significantly improved for nivolumab versus chemotherapy (7.5 vs. 8.4 months; HR, 0.86; 95% CI, 0.72─1.04; p = .11; Table 1) [44]. Median PFS was 1.4 months for nivolumab and 3.8 months for chemotherapy (HR, 1.41; 95% CI, 1.18─1.69; not formally tested for significance). ORRs were 13.7% versus 16.5%, and median DoRs were 8.3 versus 4.5 months for nivolumab versus chemotherapy. Rates of TRAEs leading to treatment discontinuation and grade 3/4 TRAEs were lower for patients receiving nivolumab compared with chemotherapy, whereas rates of treatment‐associated deaths were comparable (Table 2).

Discussion

What Is the Efficacy of Immune Checkpoint Inhibitor Therapy in Advanced ES‐SCLC?

First‐Line Therapy

Etoposide and platinum‐based chemotherapy has been the standard of care for ES‐SCLC for several decades, so there is an urgent need for new treatments [9, 10, 53, 54]. Significant improvements in OS and/or quality of life shown in a phase III trial using these agents as first‐line therapy for ES‐SCLC would represent a new optimal treatment. Studies assessing ipilimumab or tremelimumab used with chemotherapy or in combination with a PD‐1/PD‐L1 inhibitor either as first‐line therapy or as first‐line maintenance therapy did not show improved survival [39, 43, 52], nor did the use of nivolumab alone as first‐line maintenance (not formally tested as per protocol) [44]. However, three studies combining PD‐1/PD‐L1 inhibitors with chemotherapy first‐line, IMpower 133, CASPIAN, and KEYNOTE‐604, showed more promise [37, 40, 48]. The three trials were similar in design, and all combined an ICI with chemotherapy and specified survival as a primary endpoint (Table 3). The key differences were that KEYNOTE‐604 used a PD‐1 inhibitor rather than a PD‐L1 inhibitor [48], IMpower 133 used only carboplatin rather than offering a cisplatin option [37], and CASPIAN used an open label rather than a placebo‐controlled design [40]. Patient populations were comparable in terms of age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and extent of central nervous system (CNS) metastases for IMpower 133 and CASPIAN [37, 40], whereas patients in KEYNOTE‐604 had a slightly higher proportion of patients with PS 1 and CNS metastases [48]. Although ICI survival benefits emerged between 6 and 7 months with curves remaining separate at a median follow‐up of approximately 20 months in all trials [48, 50, 52], the survival benefit reached statistical significance for IMpower 133 and CASPIAN [50, 52] and was narrowly missed for KEYNOTE‐604 (p = .016, OS superiority threshold p = .0128) [48]. ICI plus chemotherapy combinations improved HRQoL in IMpower 133 [49] and CASPIAN [51], although HRQoL data were not available for KEYNOTE‐604 [48]. Although caution should be exercised when considering cross‐trial comparisons, OS differences might be explained by a greater proportion of patients with poor prognosis enrolled in KEYNOTE‐604 as evidenced by the lower median OS for the control arm of this trial compared with IMpower 133 and CASPIAN (9.7 vs. 10.3 and 10.5 months, respectively) [48, 50, 52]. Another possibility could be that PD‐1 inhibitors are less effective at mediating immune responses compared with PD‐L1 inhibitors in SCLC, although this is unlikely given the improved survival demonstrated with the addition of nivolumab to chemotherapy in the phase II ECOG‐ACRIN 5161 study [55]. Based on enduring survival benefits and the improved HRQoL demonstrated for either atezolizumab or durvalumab combined with platinum‐based chemotherapy, these combinations are recommended as first‐line therapy for ES‐SCLC. Atezolizumab received FDA approval in March [56] and European Union approval in July 2019 [57], whereas durvalumab was FDA approved in March 2020 [58].

Table 3.

Selected methods and outcomes from first‐line trials assessing the addition of PD‐1/PD‐L1 inhibitors to chemotherapy in extensive‐stage small cell lung cancer

Methods, population, outcomes	IMpower 133 (NCT02763579) [37, 49, 50]	CASPIAN (NCT03043872) [40, 51, 52]	KEYNOTE‐604 (NCT03066778) [48]
Methods and population
Investigational agent	Atezolizumab PD‐L1 inhibitor	Durvalumab PD‐L1 inhibitor	Pembrolizumab PD‐1 inhibitor
Platinum backbone and control arm	Carboplatin AUC 5 × 4 (100%) and control arm same	Carboplatin AUC 5–6 (78.5%) or cisplatin 75–80 mg/m2 (24.5%) and control arm same with up to two additional cycles of the platinum‐based regimen	Carboplatin AUC 5 (71.1%) or cisplatin 75 mg/m2 (28.9%) and control arm same
Trial design and statistics	Co‐primary endpoints OS and investigator‐assessed PFS Double blind, placebo‐controlled Statistical plan permitted	Primary endpoint OS Randomized, open label Statistical plan permitted	Co‐primary endpoints OS and PFS Double blind, placebo‐controlled Statistical plan permitted
Outcomes
Population
Median age	64 years	62 years	64 years
ECOG PS (0 and 1)	36.3% and 63.7%	36.9% and 63.1% a	26.3% and 73.7%
CNS metastases	8.5%	10%	14.5%
Median OS control	10.3 months	10.5 months	9.7 months
Median follow‐up Reductions in risk of death	Interim analysis: 13.9 months, 30% Final analysis: 22.9 months, 24%	Interim analysis: 14.2 months, 27% Final analysis: 25.1 months, 25%	Interim analysis: NR Final analysis: 21.6 months 20% (NS, p = .0128 threshold)
Shape of log‐rank curve	Curves overlapping with ICI benefit emerging at 6.5 months	Curves overlapping with ICI benefit emerging at 6 months	Chemotherapy benefit then ICI benefit emerging at 6 months
HRQoL	Meaningful benefit persisted up to 54 weeks	Global HRQoL HR 0.81	NR
Common irAEs, any grade	Rash (18.7%), hypothyroidism (12.6%), hepatitis (7.1%)	Hypothyroidism (9.1%), hyperthyroidism (5.3%), pneumonitis and hepatitis (2.6% each)	Hypothyroidism (10.3%), hyperthyroidism (6.7%), pneumonitis (4.0%)

Abbreviations: AUC, area under the curve; CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; HRQoL, health‐related quality of life; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; NR, not reported; NS, not statistically significant; PD‐1, programmed cell death protein 1; PD‐L1, programmed death ligand 1; PFS, progression‐free survival; OS, overall survival.

^aWorld Health Organization health status.

Second‐Line Plus Therapy

ES‐SCLC is an aggressive disease, and many patients quickly progress on first‐line platinum‐based treatment [20]. Few effective treatment options exist after first‐line therapy. Therefore, if the incorporation of ICIs into later lines of therapy significantly improves OS and/or quality of life, it would represent a new optimal treatment. The recent phase III CheckMate 331 trial compared nivolumab with either topotecan or amrubicin mostly in patients with ES‐SCLC (70.5%) who progressed after first‐line platinum‐based chemotherapy [44]. As the use of nivolumab did not significantly improve median OS compared with controls (Table 1), it is not recommended as second‐line therapy. Nivolumab and pembrolizumab have received FDA approval for third‐line use [46, 47], although they are not recommended because the optimal approach is to add ICIs to first‐line therapy.

Are Immunotherapy Combinations for the Treatment of ES‐SCLC Safe?

PD‐L1 inhibitors were combined with first‐line chemotherapy in IMpower 133 [37], CASPIAN [40], and KEYNOTE‐604 [48]. The addition of PD‐1/PD‐L1 inhibitors to platinum‐based chemotherapy generally resulted in comparable rates of grade 3/4 TRAEs for the combinations relative to controls (Table 2) [48, 50, 52]. However, rates of discontinuation due to AEs were higher for the ICI arm relative to chemotherapy in both IMpower 133 and KEYNOTE‐604 [48, 50] and were comparable in CASPIAN [52]. The comparable rates for CASPIAN were likely due to higher rates of discontinuation due to AEs in patients receiving chemotherapy alone relative to IMpower 133 and KEYNOTE‐604 [48, 50], which may be explained by the optional administration of two additional cycles of chemotherapy in the control arm [52]. Rates of death due to TRAEs were higher for the combination arm relative to controls in CASPIAN and comparable in IMpower 133 and KEYNOTE‐604 [48, 50]. Rates of immune‐related AEs were low and patterns were comparable across trials with similar types of events reported including thyroid dysfunction, hepatic events, skin reactions, and pulmonary reactions (Table 3) [37, 40, 48]. Overall, the minimal increase in toxicity associated with the addition of ICIs to chemotherapy and the familiarity of most lung clinicians with ICI AE management supports their adoption as first‐line ES‐SCLC treatment.

What Is the Role of Biomarkers in Predictive Response to ICIs in Extensive‐Stage SCLC?

Biomarkers are powerful tools for selecting patients who may benefit from therapy, especially when benefits in the overall population are modest such as with ICIs in the ES‐SCLC setting. PD‐L1 expression and tumor mutation burden (TMB), two of the most widely researched biomarkers in non‐small cell lung cancer [59], have also been evaluated in SCLC. IMpower 133 did not screen for PD‐L1 due to the expected high rate of inadequate sample types (e.g., fine‐needle aspirates, bronchoscopy findings), the low prevalence of PD‐L1 expression on tumor cells, and the lack of association between response and PD‐L1 expression in the phase Ia trial of atezolizumab in SCLC [37, 60]. Although CASPIAN performed a subgroup analysis based on PD‐L1 status, only 51.6% of patients were PD‐L1 evaluable, and no significant interaction was observed with OS based on PD‐L1 expression as a continuous variable (tumor cell, p = .54 and immune cell, p = .23) [51]. A majority of patients (79.5%) in KEYNOTE‐604 were retrospectively evaluable for PD‐L1 status using the combined positive score, and a similar benefit was seen in patients with PD‐L1 expression ≥1 (51.4%) and in those with <1 PD‐L1 expression (48.6%), confirming that PD‐L1 status is not predictive in ES‐SCLC [48].

The predictive capacity of TMB can vary depending on the ICI therapy assessed as well as the cutoffs used and type of collection (blood vs. tissue) [61], making it challenging to assess its predictive value. To date, only IMpower 133 assessed the predictive capacity of TMB for ES‐SCLC and found no relationship between blood‐based TMB and atezolizumab benefit at thresholds of 10 mutations per megabase (≥10; HR, 0.68; 95% CI, 0.47–0.97 and < 10; HR, 0.70; 95% CI, 0.45–1.07) or 16 mutations per megabase (≥16; HR, 0.63; 95% CI, 0.35–1.15 and < 16; HR, 0.71; 95% CI, 0.52–0.98) [37]. An effective biomarker is sorely needed in this area of high clinical need, and other potential candidates, including SCLC subtypes with increased T‐cell infiltration, continue to be assessed [62]. However, no factor to date has been able to successfully predict response to ICIs used in combination with chemotherapy in extensive‐stage SCLC.

What Is the Role of ICIs in Treating Central Nervous System Metastases?

The brain is a common sanctuary site for SCLC metastases, and patients with CNS metastases typically have a poor prognosis [63]. The blood‐brain barrier limits the delivery of chemotherapy and ICIs to CNS disease, although T cells can more effectively cross, highlighting a potential role for ICIs in CNS metastases [64, 65, 66]. As accrual was limited to ECOG PS ≤1 patients and those with treated and or stable/asymptomatic CNS disease, relatively few patients with CNS metastases were accrued to IMpower 133 [37], CASPIAN [40], or KEYNOTE‐604 [48] (8.5%─14.5%, Table 4) compared with actual clinical practice (15%–20%) [67]. In CASPIAN, the addition of durvalumab improved survival for patients regardless of baseline CNS metastases [52, 68], suggesting benefit for the addition of durvalumab in patients with CNS disease. This benefit may be explained by reactivated T cells crossing the blood‐brain barrier to inhibit CNS disease or could be attributed to a greater proportion of patients having less favorable baseline characteristics on the ICI arm. This same benefit was not apparent for the addition of ICIs to chemotherapy in IMpower 133 [50] and KEYNOTE‐604 [48]. However, the limited patient numbers and potential heterogeneity within patient populations make it difficult to make strong conclusions about the role of one ICI over another in patients with baseline CNS metastases.

Table 4.

Chest and cranial irradiation and related outcomes in phase III trials assessing first‐line immune checkpoint inhibitors for extensive‐stage small cell lung cancer

Trial name (NCT#)	Treatment algorithm (Induction ➔ maintenance)	Chest radiation eligibility Rate of chest radiation at baseline	On protocol CCR Local relapse outcomes	Brain metastases eligibility Rate of CNS metastases at baseline	On protocol PCI metastases outcomes, HR (95% CI)
IMpower 133 (NCT02763579) [37, 50]	Atezolizumab plus CT ➔ atezolizumab	Prior chest radiation eligibility: NR Prior chest radiation at baseline: 12.4% vs. 13.9%	No CCR permitted during maintenance phase Local relapse PFS/OS: NR	Patients with treated asymptomatic CNS metastases were eligible CNS metastases at baseline: 8.5% vs. 8.9%	PCI permitted during maintenance phase (10.9% vs. 10.9%) 8.7% of patients had CNS metastases OS: 0.96 (0.46–2.01)
	Placebo plus CT ➔ placebo
CASPIAN (NCT03043872) [40, 52]	Durvalumab plus CT ➔ durvalumab	Patients with no history of chest radiation prior to systemic therapy or planned consolidation chest radiation were eligible Prior chest radiation at baseline: NR	No CCR permitted Local relapse OS: 9.7% of patients, 0.83 (0.44–1.54)	Patients with treated or asymptomatic and stable CNS metastases were eligible CNS metastases at baseline: 10.4% vs. 10.0%	PCI permitted during maintenance phase in control arm only (7.8%) 10.2% of patients had CNS metastases OS: 0.79 (0.44–1.41)
	CT
KEYNOTE‐604 (NCT03066778) [48]	Pembrolizumab plus CT ➔ pembrolizumab	Patients with history of chest radiation unknown Prior chest radiation at baseline: Not specified	CCR not specified Local relapse OS: not specified	Patients with treated and stable CNS metastases were eligible CNS metastases at baseline: 14.5% vs. 9.8%	PCI permitted during maintenance phase (11.8% vs. 14.2%) 11.9% of patients had CNS metastases OS: 1.32 (0.72–2.42)
	CT

Abbreviations: ; ➔ followed by; CI, confidence interval; CCR, consolidative chest radiation; CNS, central nervous system; CT chemotherapy; HR, hazard ratio; NCT, National Clinical Trial; NR, not reported; OS, overall survival; PCI, prophylactic cranial irradiation; PFS, progression‐free survival.

What Is the Direction of Ongoing Immune Checkpoint Inhibitor Research in SCLC?

The role of ICIs in ES‐SCLC is an area of ongoing investigation, and many questions remain regarding the optimal administration of these agents. As the OS benefits of ICIs emerge at 6 to 7 months in both IMpower 133 and CASPIAN [50, 52], there is a rationale for exploring the delayed administration of ICIs relative to chemotherapy in this setting. In CA184 156, ipilimumab was initiated after two cycles of platinum‐based chemotherapy, and although this trial did not significantly improve OS first‐line [43], assessing the merits of a delayed approach using atezolizumab or durvalumab may be warranted. Moreover, patients with a performance status of 2–4 as well as those with active or untreated brain metastases were excluded from IMpower 133 and CASPIAN [37, 40], so the role of ICIs in these patients is currently unknown. Finally, there are no ongoing phase III studies assessing treatments for immunotherapy refractory SCLC.

Both consolidative chest radiation (CCR) and prophylactic cranial irradiation (PCI) have been assessed with first‐line platinum‐based therapy in ES‐SCLC [69]. Evidence suggests that cell death from radiotherapy can prime the immune system, thereby potentially enhancing outcomes when given with ICIs [70]. The role radiation played in CASPIAN, IMpower 133, and KEYNOTE‐604, however, remains unclear. Some studies excluded patients with a history of CCR (CASPIAN), and there was no protocol‐mandated administration of CCR in any of the trials (Table 4) [37, 40, 48]. Few patients with CNS metastases were accrued to the trials, and maintenance PCI was administered to a minority of patients in IMpower 133 (10.9% vs. 10.9%) [37], KEYNOTE‐604 (11.8% vs. 14.2%) [48], and CASPIAN (control arm, 7.8%) [40], making it difficult to ascertain benefit. As CCR has improved 2‐year OS in a preplanned analysis of a prior phase III study in patients with ES‐SCLC [69], the modest benefits observed for ICIs in overall ES‐SCLC populations, and the rationale for radiotherapy to augment immunotherapeutic response [70, 71], there is a strong rationale for investigating the combination of radiotherapy in conjunction with ICI plus chemotherapy combinations in LS‐SCLC (Table 5) [72, 73]. The phase III LU005 trial (NCT03811002) is evaluating the addition of atezolizumab to concurrent chemoradiation [72], whereas the phase III ADRIATIC trial (NCT03703297) is assessing benefits of adding the CTLA‐4 inhibitor tremelimumab to durvalumab after concurrent chemoradiation for limited stage disease [73].

Table 5.

Ongoing phase III trials assessing immune checkpoint inhibitors for SCLC

Checkpoint inhibitor(s) (target)	Trial identifier (NCT#)	Patient population	Experimental regimen	Comparator	Primary endpoint(s)	Estimated PCD
Early‐stage disease
Durvalumab (PD‐L1) Tremelimumab (CTLA‐4) [73]	ADRIATIC (NCT03703297)	Stage I–III LS‐SCLC	cCRT ➔ durvalumab plus tremelimumab ➔ durvalumab	cCRT ➔ durvalumab plus placebo ➔ durvalumab	PFS, OS	December 2023
Atezolizumab (PD‐L1) [72]	LU005 (NCT03811002)	LS‐SCLC T1–T4, N1–3, M0	cCRT plus atezolizumab	cCRT	PFS, OS	May 2024
First‐line advanced disease
Atezolizumab (PD‐L1) [74]	Mauris/ML41118 (NCT04028050)	ES‐SCLC	Atezolizumab plus CT ➔ atezolizumab	NA	SAEs, irAEs	December 2022

Abbreviations: ➔ followed by; cCRT, concurrent chemoradiation; CT, chemotherapy; CTLA‐4, cytotoxic T‐lymphocyte‐associated antigen 4; ES‐SCLC, extensive‐stage SCLC; irAE, immune‐related adverse events; LS‐SCLC, limited‐stage SCLC; NA, not applicable; NCT, National Clinical Trial; OS, overall survival; PCD, primary completion date; PD‐L1, programmed cell death ligand 1; PFS, progressive‐free survival; SAE, serious adverse events; SCLC, small cell lung cancer.

Conclusion

The addition of either atezolizumab or durvalumab to first‐line platinum‐based chemotherapy significantly improves overall survival with clinically meaningful improvements in HRQoL among patients with ES‐SCLC. The use of ICIs in combination with platinum therapy resulted in net overall survival improvements of 2.0–2.7 months, and survival benefits remained significant at a median follow‐up of approximately 2 years in IMpower 133 and CASPIAN [50, 52]. These findings support the use of ICIs in combination with platinum‐based therapy as a standard first‐line treatment for ES‐SCLC. A biomarker to better select patients is not yet available, although it is sorely needed, and research into the role of ICIs in combination with radiation therapy in LS‐SCLC is an area of ongoing investigation.

Author Contributions

Conception/design: Barbara Melosky, Parneet K. Cheema, Anthony Brade, Deanna McLeod, Geoffrey Liu, Paul Wheatley Price, Kevin Jao, Devin D. Schellenberg, Rosalyn Juergens, Natasha Leighl, Quincy Chu

Provision of study material or patients: Barbara Melosky, Parneet K. Cheema, Anthony Brade, Deanna McLeod, Geoffrey Liu, Paul Wheatley Price, Kevin Jao, Devin D. Schellenberg, Rosalyn Juergens, Natasha Leighl, Quincy Chu

Collection and/or assembly of data: Barbara Melosky, Parneet K. Cheema, Anthony Brade, Deanna McLeod, Geoffrey Liu, Paul Wheatley Price, Kevin Jao, Devin D. Schellenberg, Rosalyn Juergens, Natasha Leighl, Quincy Chu

Data analysis and interpretation: Barbara Melosky, Parneet K. Cheema, Anthony Brade, Deanna McLeod, Geoffrey Liu, Paul Wheatley Price, Kevin Jao, Devin D. Schellenberg, Rosalyn Juergens, Natasha Leighl, Quincy Chu

Manuscript writing: Barbara Melosky, Parneet K. Cheema, Anthony Brade, Deanna McLeod, Geoffrey Liu, Paul Wheatley Price, Kevin Jao, Devin D. Schellenberg, Rosalyn Juergens, Natasha Leighl, Quincy Chu

Final approval of manuscript: Barbara Melosky, Parneet K. Cheema, Anthony Brade, Deanna McLeod, Geoffrey Liu, Paul Wheatley Price, Kevin Jao, Devin D. Schellenberg, Rosalyn Juergens, Natasha Leighl, Quincy Chu

Disclosures

Barbara Melosky: Merck, Roche, Bristol‐Myers Squibb, Boehringer Ingelheim, Eli Lilly & Co, Novartis, AstraZeneca (CA), Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, AstraZeneca (SAB); Parneet K. Cheema: Merck, AstraZeneca, Boehringer Ingelheim, Pfizer, Bristol‐Myers Squibb, Novartis, Takeda, Hoffman La Roche (C/A), Merck, Roche, Pfizer, Novartis, Takeda, Boehringer Ingelheim, AstraZeneca (SAB), Hoffmann La Roche, AstraZeneca, Novartis, Merck (RF); Anthony Brade: AstraZeneca (C/A); Geoffrey Liu: Takeda, AstraZeneca, Roche, Novartis, Pfizer, Boehringer Ingelheim, EMD Serono, Bayer (C/A), Takeda, EMD Serono, AstraZeneca (SAB), Takeda, AstraZeneca (RF), Pfizer, Takeda (ET); Paul Wheatley Price: Bristol‐Myers Squibb, AstraZeneca, Merck, Roche, Takeda, Novartis (C/A), Merck, Pfizer, Bayer (SAB); Kevin Jao: Merck, Roche, AstraZeneca, Bristol‐Myers Squibb (C/A, SAB); Devin D. Schellenberg: Eisai, AstraZeneca, Merck, Pfizer (SAB), Varian Medical Systems (RF); Rosalyn Juergens: Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, EMD Serono, Fusion Pharmaceuticals, Merck, Novartis, Pfizer, Roche, Takeda (C/A), Amgen, AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, EMD Serono, Merck, Novartis, Pfizer, Roche, Takeda (SAB), AstraZeneca, Bristol‐Myers Squibb, Merck (RF); Natasha Leighl: Merck Sharp & Dohme, Guardant Health, Array, Pfizer, Roche (RF); Quincy Chu: Abbvie, Amgen, AstraZeneca, Bayer, Bristol‐Myers Squibb, Boehringer Ingelheim, Eli Lilly & Co., Merck, Novartis, Pfizer, Precision Oncology, Roche, Takeda (C/A), Abbvie, Amgen, AstraZeneca, Bayer, Bristol‐Myers Squibb, Boehringer Ingelheim, Eli Lilly & Co., Merck, Novartis, Pfizer, Precision Oncology, Roche, Takeda (SAB), Abbvie, Amgen, Astellas Pharma, AstraZeneca, AurKa Pharma, Bayer, Bristol‐Myers Squibb, Boehringer Ingelheim, Celgene, Debio, Eli Lilly & Co., Epizyme, Esperas, GlaxoSmithKline, Merck, Novartis, Pfizer, Precision Oncology, Roche, Takeda, Turning Point Therapeutics (RF). Deanna McLeod indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board