Treatment strategy for patients with relapsed small-cell lung cancer: past, present and future.

Although the incidence rate of small cell lung cancer (SCLC) has consequently decreased, SCLC still accounts for approximately 13% of all lung cancers (1). SCLC is sensitive to chemotherapy and radiation therapy. However, disease relapse or progression will occur in almost all patients with SCLC. Because patients with relapsed SCLC has poor prognosis and the number of available drugs is limited, more effective second-line chemotherapy is warranted.

Zhao et al. retrospectively reported the efficiency of second-line treatment for relapsed SCLC in Translational Lung Cancer Research. They analyzed the efficacy of four drugs that were used in second-line chemotherapy: topotecan, irinotecan, paclitaxel, and docetaxel. All patients received platinum and etoposide as the first-line regimen. Although there was no significant difference in patient characteristics, the proportions of patients with limited-stage disease and a longer treatment-free interval (TFI) were higher in the irinotecan group. In addition, all patients in the paclitaxel group received platinum as second-line chemotherapy. The median progression-free survival (PFS) times for patients treated with irinotecan, topotecan, paclitaxel, and docetaxel were 91, 74.5, 81, and 50 days, respectively, with no significant differences among the treatments (P=0.6445). The median survival time (MST) of these groups were 595, 154, 168.5, and 184 days, respectively, and there were significant differences among the groups (P=0.0069). In addition to assessment of second-line treatment, they also assessed the prognostic factors for patients with relapsed SCLC. TFI <90 days, lactate dehydrogenase (LDH) ≥225 U/L, and neutrophil-to-lymphocyte ratio ≥3.5 were identified as prognostic factors in patients with relapsed SCLC received second-line treatment. They concluded that second-line chemotherapy with topotecan may provide better overall survival benefits in patients with SCLC. Although I thought that topotecan was a mistake for irinotecan, it was considered that the patient characteristics had a significant effect on the efficacy of second-line treatment, as mentioned by the authors. However, it is difficult to conduct a study comparing these drugs, and real-world data such as those discussed in this study are worthwhile.

The efficacy of second-line chemotherapy is different according to TFI and relapse is conventionally defined as sensitive and refractory or resistant based on TFI. The prognosis of patients with refractory relapsed SCLC was worse than those with sensitive relapsed SCLC. There have been few phase III trials of patients with relapsed SCLC. The results of phase III trial comparing oral topotecan with best supportive care (BSC) were reported in 2006 (2). Topotecan significantly prolonged MST compared with BSC [MST: 25.9 versus 13.9 weeks, hazard ratio (HR) =0.64, 95% confidence interval: 0.45–0.90, P=0.0104]. Amrubicin is a synthetic 9-amino-anthracycline that produced response rates of 40–50% in phase II trials (3,4). However, a phase III trial comparing topotecan with amrubicin in second-line setting did not show the superiority of amrubicin (5). The MST in the amrubicin arm was 7.5 months, compared with 7.8 months for the topotecan arm (HR =0.880, P=0.170). Although it was a subgroup analysis, amrubicin significantly prolonged MST compared with the effects of topotecan among patients with refractory relapsed SCLC (HR =0.766, P=0.047). In 2016, the results of a phase III trial comparing cisplatin, etoposide, and irinotecan combination therapy (PEI) with topotecan for patients with sensitive relapsed SCLC were reported (6). The MST of PEI group was 18.2 months and MST of topotecan group was 12.5 months. PEI significantly prolonged MST (HR =0.67, P=0.0079). Although PEI is the only treatment strategy that has displayed superiority over topotecan, PEI is rarely used in the world because of the complexity of dosing schedule and topotecan remains the control arm in many clinical trials of sensitive relapsed SCLC.

In the National Comprehensive Cancer Network (NCCN) guideline, patients with relapsed SCLC are recommended to participate in clinical trials (7). As selectable drugs other than topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, and nivolumab are recommended for relapsed SCLC with TFI ≤6 months and performance status of 0–2. However, no phase III results are available for these drugs, and there is little evidence supporting their clinical use. presents the efficacy of various drugs for patients with relapsed SCLC. Individual cytotoxic drugs had low efficacy excluding topotecan, which displayed superiority over BSC in a phase III trial. The MST of individual drugs ranged 3–7 months. The efficacy of combinations of cytotoxic drugs was also reported. However, toxicity was enhanced, and the efficacy was limited. Targeted drugs, such as bevacizumab, nintedanib, sunitinib, linsitinib, and pazopanib, were less effective, and the primary endpoint was not met (27,32,39,41,42,45,47). Although a trial of immune checkpoint inhibitors did not meet the primary endpoint of overall response rate (ORR), the drugs were linked to long durations of response (41). Recently, a phase III trial (IMpower 133) demonstrated that the addition of atezolizumab to chemotherapy for patients with untreated extensive stage SCLC significantly prolonged PFS compared with the effects of chemotherapy alone (50). These data suggested that immune checkpoint inhibitors are effective in some patients with relapsed SCLC.

Table 1

The results of clinical trials for patients with relapsed small-cell lung cancer

Drug	ORR (%)				median PFS or TTP (months)				MST (months)			Reference
	All	Sensitive	Refractory		All	Sensitive	Refractory		All	Sensitive	Refractory
Cytotoxic drug
Topotecan	13–22	15–38	0–9		2.2–3.5	3.0–4.4	1.5–2.6		5.4–8.4	6.9–12.5	4.7–5.7	(3,5,8-11)
Amrubicin	31–53	41–67	17–60		3.5–4.1	3.9–5.5	2.6–3.2		7.5–11.2	9.2–14.4	5.3–10.3	(3-5,11-13)
Irinotecan	47	–	–		–	1.7	1.9		6.2	8.6	3.8	(14)
Paclitaxel	24–29	27	20		2.2	–	–		3.3–5.8	–	–	(15)
Docetaxel	25	–	–		–	–	–		–	–	–	(16)
Temozolomide	12–14	11–23	13–15		1.6–2.0	1.6	1.0		5.8–7.0	6.0	5.6	(17,18)
Vinorelbine	13–16	–	–		–	–	–		–	–	–	(19,20)
Etoposide	46	–	–		–	–	–		3.5	–	–	(21)
Gemcitabine	12–13	17	6		2.0	–	–		4.3–7.1	7.3	6.9	(22,23)
Bendamustine	26	33	17		4.0	4.2	3.4		4.8	5.7	4.1	(24)
S1	4	8	0		1.1	1.1	1.1		5.3	8.4	4.0	(25)
Topotecan + amrubicin	43	53	27		4.7	5.8	3.3		10.2	10.2	10.5	(26)
Irinotecan + gemcitabine	17–37	10–45	11–27		3.0–3.4	3.1–4.3	1.6–2.5		5.8	4.5–14.4	3.5–8.7	(27-29)
Irinotecan + paclitaxel	21	25	14		–	2.0	3.0		6.4	7.6	5.5	(30)
Cisplatin + irinotecan	80	78	81		3.6	–	–		7.9	–	–	(31)
Carboplatin + irinotecan	31	38	23		3.5	–	–		6.1	6.1	5.7	(32)
Platinum rechallenge	–	43	–		–	5.1	–		–	14.3	–	(33)
Cisplatin + etoposide + irinotecan	–	78–84	–		–	5.0–5.7	–		–	11.8–18.2	–	(6,34)
Antiangiogenic agent
Topotecan + bevacizumab	16	22	9		4.0	6.2	2.9		7.4	8.5	6.1	(35)
Topotecan + aflibercept	–	2	2		–	1.8	1.4		–	6.0	4.6	(36)
Irinotecan + bevacizumab	–	–	25		–	–	3.0		–	–	6.0	(37)
Paclitaxel + bevacizumab	–	18	20		–	3.7	2.8		–	7.5	6.3	(38,39)
Nintedanib	5	–	–		1.0	–	–		9.8	–	–	(40)
Immune checkpoint inhibitor
Nivolumab (3 mg/kg)	10	–	–		1.4	–	–		4.4	–	–	(41)
Nivolumab (1 mg/kg) + ipilimumab (3 mg/kg)	23	–	–		2.6	–	–		7.7	–	–	(41)
Nivolumab (3 mg/kg) + ipilimumab (1 mg/kg)	19	–	–		1.4	–	–		6.0	–	–	(41)
Paclitaxel + pembrolizumab	23	–	–		5.0	–	–		9.1	–	–	(42)
PARP inhibitor
Temozolomide + veliparib	39	41	37		3.8	–	–		8.2	–	–	(43)
Temozolomide + olaparib	42	47	29		4.2	4.5	2.9		8.5	9.4	7.4	(44)
Other
Sunitinib	9	25	0		1.4	–	–		5.6	–	–	(45)
Linsitinib	0	–	–		1.2	–	–		3.4	–	–	(46)
Pazopanib	14	18	5		2.5	3.7	2.0		6.0	8.0	4.0	(47)
Navitoclax	2.6	–	–		1.5	–	–		3.2	–	–	(48)
Rovalpituzumab tesirine	12	–	–		3.5	–	–		5.6	–	–	(49)

ORR, overall response rate; PFS, progression-free survival; TTP, time to progression; MST, median survival time; PARP, poly(ADP-ribose)polymerase.

It was reported that patients with sensitive relapsed SCLC responded to the same initial chemotherapy, generally termed rechallenge chemotherapy. Rechallenge chemotherapy is recommended for relapsed SCLC among patients with TFI >6 months in the NCCN guideline (7). In 1988, Giaccone et al. and Postmus et al. were reported the efficacy of rechallenge chemotherapy for patients with sensitive relapsed SCLC in 1988 (51,52). The ORR of rechallenge chemotherapy was 50–62%. Although the results of their reports suggest the efficacy of rechallenge chemotherapy, reported chemotherapy are not standard regimens at this time. In 2015, a randomize phase II trial assessing the efficacy of amrubicin and rechallenge chemotherapy for patients with sensitive relapsed SCLC was reported (33). The primary endpoint was ORR and only amrubicin group met the primary endpoint (Amrubicin group: 67% and rechallenge chemotherapy group: 43%).

Recently, molecular targeted drugs and immune checkpoint inhibitors have been developed for SCLC, and many clinical trials of patients with relapsed SCLC are ongoing (). New drugs for SCLC are classified into six types according to the mechanism of action as follows: antiangiogenic agents, poly(ADP-ribose)polymerase (PARP) inhibitors, immune checkpoint inhibitors, inhibitors of cell cycle proteins such as Wee1 and Aurora kinase A, antibody-drug conjugates (ADCs) targeting delta-like canonical Notch ligand 3 (DLL3), and enhancer of zeste homologue (EZH2) inhibitors. PARP plays an important role in repair of single-strand DNA breaks (53). It was reported that PARP protein was upregulated in SCLC compared with its expression in other lung cancers, and SCLC cell lines were sensitive to PARP inhibitors (54). In a randomized phase II study, veliparib in combination with cisplatin and etoposide significantly prolonged PFS compared with the effects of placebo combined with cisplatin and etoposide. Many trials of PARP inhibitors are ongoing. EZH2 is the enzymatic histone-lysine N-methyltransferase subunit of polycomb repressive complex 2, and it mediates histone H3 lysine 27 dimethylation and trimethylation (H3K27me2 and H3K27me3, respectively) (55). EZH2 is frequently overexpressed in many types of tumors, and higher EZH2 expression is associated with the activity of cancer (56). It was reported that EZH2 was associated with chemoresistance in patient-derived xenografts (57). According to , AZD1775 is a Wee1 inhibitor, rovalpituzumab tesirine is an ADC-targeting DLL3, and PF-06821497 is an EZH2 inhibitor. Because more effective treatments for patients with relapsed SCLC are desired, the results of these clinical trials are awaited.

Table 2

Ongoing clinical trials of relapsed small-cell lung cancer

Trial number	Phase	Treatment	Primary endpoint
Antiangiogenic agent
NCT03651219	III	Irinotecan + apatinib	Duration of treatment
		Irinotecan
NCT03823118	II	S1 + anlotinib	ORR, PFS
NCT03732846	II	Anlotinib	PFS
PARP inhibitor
NCT03009682 (SUKSES-B)	II	Olaparib	ORR
NCT03428607 (SUKSES-N2)	II	Azd6738 + olaparib	ORR
NCT02769962	I/II	Crlx101 + olaparib	ORR, MTD, RP2D
NCT03672773	II	Talazoparib + temozolomide	ORR
NCT02734004 (MEDIOLA)	I/II	Olaparib + MEDI4736	DCR, safety, etc.
		Olaparib + MEDI4736 + bevacizumab
NCT02498613	II	Olaparib + cediranib	ORR
Immunocheckpoint inhibitor
NCT02701400	II	Durvalumab + tremelimumab + RT	PFS, ORR
		Durvalumab + tremelimumab
NCT02247349	I/II	BMS-986012 ± nivolumab	Safety
NCT03728361	II	Nivolumab + temozolomide	ORR
NCT04173325	I	Nivolumab + irinotecan	Frequently & severity AE
NCT03554473	I/II	M7824	Efficacy
		M7824 + topotecan
		M7824 + temozolomide
NCT03994744	II	Sintilimab + metformin	ORR, safety
NCT04056949	II	(Nab-)Paclitaxel + sintilimab	PFS
NCT03639194	I	ABBV-011 ± ABBV-181	MTD, RPTD
Cytotoxic drug
NCT02566993 (ATLANTIS)	III	Lurbinectedin + doxorubicin	OS
		Cyclophosphamide + doxorubicin + vincristine
NCT03613753	II	Irinotecan + lobaplatin	ORR
		Irinotecan
NCT01876446	II	Pegylated irinotecan	18-week PFS rate
NCT02769832	II	Nab-paclitaxel + gemcitabine	RR
Other
NCT03061812 (TAHOE)	III	Rovalpituzumab tesirine	OS
		Topotecan
NCT03098030 (IV-SCLC-301)	II/III	Irinotecan + dinutuximab	OS
		Irinotecan
		Topotecan
NCT02593019	II	AZD1775	ORR
NCT03896503	II	Topotecan + M6620	PFS
		Topotecan
NCT04210037	I/II	Paclitaxel + APG-1252	DLT, MTD
NCT02649673	I/II	Topotecan + LCL161	DLT
NCT03366103	I/II	Navitoclax + vistusertib	Adverse events, ORR
NCT03460977	I	PF-06821497	DLT, safety

ORR, objective response rate; PFS, progression-free survival; MTD, maximum tolerated dose; RP2D/RPTD, recommended phase II dose; DCR, disease control rate; AE, adverse events; OS, overall survival; RR, response rate; DLT, dose-limiting toxicity.

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