1 Introduction

Small cell lung cancer (SCLC), which accounts for about 15% of all lung cancer diagnoses, is an aggressive neuroendocrine cancer with limited treatment options and a dismally low overall survival rate of less than 5% at 36 months. Most, but not all, of the 150,000 patients diagnosed worldwide each year respond well to front-line platinum-based doublet chemotherapy but invariably relapse with drug-resistant disease and poor prospects for survival [1].

SCLC is virtually synonymous with tobacco abuse since 98% of cases arise in current or former heavy smokers (≥ 40 pack years). In the USA, as evidence of the direct link between SCLC and the carcinogenicity of tobacco, the incidence of the disease has decreased in parallel with cigarette use and with the widespread emergence of filtered cigarettes [2]. Other risk factors for SCLC worldwide and the main ones for never smokers are long-term exposure to indoor radon, second-hand smoke, and air pollution like nitrogen dioxide and particulate matter [3]. The exceptionally fast-doubling time of SCLC, combined with the propensity for early, widespread metastases that are not amenable to surgical resection [2], the ubiquity of comorbidities associated with tobacco smoking such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease, and the insurmountability of rapidly evolved chemoresistance make it the most lethal lung cancer subtype and one of the most notoriously hard to manage. The brain, liver, adrenal glands, bones, or bone marrow is the most common sites of metastasis [4].

In practice, although the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend the incorporation of tumor-node-metastasis (TNM) staging criteria, SCLC is most typically classified as limited or extensive. Around 30% of patients present with limited stage (LS) confined to the ipsilateral hemithorax and a single radiation field [5]. The majority (70%) are diagnosed with extensive-stage disease (ES), which extends beyond the confines of the ipsilateral hemithorax and a single radiation field [6]. The median overall survival (OS) for LS-SCLC is better than for ES-SCLC, around 17 months versus 8–13 months, respectively. Despite initial response rates of up to 80% in first line, the median survival for ES-SCLC patients with disease recurrence is 4–5 months [1, 4, 6].

2 Treatment for first-line LS-SCLC

The standard treatment for LS-SCLC is four to six cycles of curative intent platinum and etoposide chemotherapy plus thoracic radiotherapy (TRT) followed by prophylactic cranial irradiation (PCI) for responsive disease [7, 8].

3 Treatment for first-line ES-SCLC

The standard first-line treatment of ES-SCLC is four to six cycles of platinum and etoposide chemotherapy, with a general preference for carboplatin over cisplatin because of less toxicity, plus the programmed death-ligand 1 (PD-L1) blocking antibodies, atezolizumab, or durvalumab based on the Impower 133 and CASPIAN clinical trials, respectively [9]. For patients at risk of chemotherapy-induced neutropenia, prophylactic treatment with granulocyte colony-stimulating factor (G-CSF) or trilaciclib, a recently approved cyclin-dependent kinase 4/6 inhibitor, is potentially indicated [10].

4 Treatment-free interval (TFI) and second-line treatment

The choice of second line and subsequent regimens depends on performance status and the length of the treatment free interval (TFI). The TFI is a measure of the time between the last platinum dose and relapse or disease progression, which strongly predicts outcome. For patients with platinum sensitive disease, which ESMO guidelines define as a TFI ≥ 90 days, options include rechallenge with a platinum-based regimen, if performance status allows, or single-agent topotecan or lurbinectedin. For patients with platinum resistant disease (TFI ≤ 90 days), the alkylator, lurbinectedin, is the only FDA-indicated agent for disease that has no response to first-line chemotherapy [11].

Note that according to NCCN Guidelines, the TFI cutoff is 6 months (180 days) for sensitive SCLC and less than 6 months (180 days) for resistant SCLC. In any case, the expected response rates for platinum-resistant disease (≤ 10%) are lower than for platinum-sensitive disease (approximately 25%) [4]. Patients who do not respond or who progress during platinum chemotherapy are designated as platinum-refractory, and this designation correlates with the poorest outcomes. Topotecan, a topoisomerase I inhibitor, is only approved for chemotherapy-sensitive, relapsed SCLC. Irinotecan, another topoisomerase I inhibitor, is sometimes used in place of topotecan since dosing is less frequent and rates of myelosuppression are lower [11].

5 Second-line and beyond treatment

The treatment strategy beyond second line is unknown with no third-line (3L) regimen regulatory approvals in Europe and the USA although the orally administered tyrosine kinase inhibitor (TKI), anlotinib, is approved in China [11]. The FDA-revoked approval for the PD-1 inhibitor, nivolumab, in 3L SCLC after phase 3 randomized trial data failed to confirm an OS benefit [12]. However, in the absence of any other approved therapies, the NCCN SCLC Panel still recommends subsequent therapy with a PD-1 inhibitor for platinum-sensitive patients that did not progress on first-line atezolizumab or durvalumab [4]. Given the lack of an a priori best option, many patients may opt to enroll on a clinical trial.

A treatment algorithm for recurrent ES-SCLC is shown in Fig. 1.

Fig. 1
figure 1

Treatment algorithm for recurrent, second-line, or beyond ES-SCLC

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This leaves open the question of how—and with what exactly—to treat platinum-resistant patients since currently only the alkylating agent, lurbinectedin, based on single-arm clinical trial data is FDA-indicated for it. However, lurbinectedin failed to improve overall survival in a phase 3 clinical trial with doxorubicin vs. CAV (cyclophosphamide/doxorubicin/vincristine) or topotecan [10]. Below, we review six clinical-stage therapies/regimens with the potential to treat platinum-resistant disease more effectively based on reported results.

6 Tarlatamab (AMG 757)

This is a bispecific T-cell engager molecule, which binds both the inhibitory notch ligand deltalike ligand 3 (DLL3) on tumor cells and cluster of differentiation 3 (CD3) on T cells to stimulate T-cell tumor lysis [12].

In a recent phase 2 study (DeLLphi-301) of 220 SCLC patients who had received a median of two lines of treatment, 40% and 32% of patients achieved an objective response with 10 mg (n = 134) and 100 mg (n = 88) dosages of tarlatamab, respectively. Among responders, the median duration of response was at least 6 months in 59% of patients. Median progression-free survival was 4.9 months with the 10-mg dose and 3.9 months with the 100-mg dose. The 9-month estimated overall survival rates were close to 70% in both the 10-mg and 100-mg dose groups. Based on these results, the FDA granted priority review to tarlatamab in SCLC.

As the one black mark on the trial, 49% and 56% in the 10 mg and 100 mg groups, respectively, experienced cytokine release syndrome, which required intensive inpatient monitoring, although only < 3% of patients discontinued treatment because of it. A phase 3 trial (DeLLphi-304) is ongoing to compare tarlatamab in 2L SCLC at a dose of 10 mg every 2 weeks to the local standard of care, either lurbinectedin, topotecan, or amrubicin [12].

Neither DeLLphi-301 actively excluded (or included) patients with platinum resistance, and it is unknown whether they were among the responders; however, the likelihood is in favor because of the high ORR of around 40%. It is also unknown whether the presence of DLL3 is required for activity.

7 ABBV-706

ABBV-706 is an intravenously administered anti-seizure-related (SEZ) 6 monoclonal antibody conjugated to a topoisomerase 1 cytotoxic payload. In a phase 1, first-in-human clinical trial with ABBV-706 as monotherapy or with budigalimab, a programmed death 1 (PD-1) inhibitor, or carboplatin, or cisplatin, the objective response rate for previously platinum progressed SCLC patients that received three lines of therapy on average was 60% (14/23), likely indicative of platinum sensitization. The safety profile was manageable with two dose-limiting toxicities: 1 grade 4 leukopenia and neutropenia lasting > 7 days and 1 grade 4 thrombocytopenia [13].

8 RRx-001 (nibrozetone)

A bispecific small molecule, RRx-001 is a hypoxic nitric oxide (NO) donor with epigenetic activity and an inhibitor of the NLRP3 inflammasome [14,15,16]. In a single-arm phase 2 study, 26 SCLC patients who previously received 2 or more therapies were treated with 4 mg weekly RRx001 until progression followed by re-challenge with a platinum doublet from 1 L. 19/26 patients (73.1%) had platinum-resistant disease. The estimated median and 12-month OS were 8.6 months and 44.1%, respectively [17]. Based on these results, RRx-001 began a large phase 3 study called REPLATINUM in third-line or beyond SCLC in China and the US, which is well underway. As a potential treatment option for third-line and beyond ES SCLC, because of its unique platinum-sensitizing potential, RRx-001 may preferentially benefit platinum-resistant patients. Unlike topotecan, lurbinectedin, and FOLFIRI, RRx-001 is non-myelosuppressive with transient pain on infusion as its main, and arguably only, side effect [18, 19]. RRx-001 has received FDA Fast Track designation for the treatment of severe oral mucositis.

9 DS7300a (ifinatamab deruxtecan, I-DXd)

DS7300a is a B7-H3-specific monoclonal antibody (mAb) conjugated to DXd, a DNA topoisomerase I inhibitor. In a phase 1/2 clinical trial, 22 patients who had received a median of two prior lines of therapy with SCLC unselected for B7-H3 expression were treated with I-DXd. With 52.4% confirmed responses, and 4.8% complete responses, the median progression-free survival was 5.8 months and the median overall survival was 12.2 months. It is unknown whether platinum-resistant patients were among the responders [20].

10 Conclusions

Platinum-based chemotherapy is a mainstay of treatment for approximately half of all tumor types; these include SCLC, testicular cancer, bladder cancer, ovarian cancer, urothelial cancer, cervical and endometrial cancer, biliary cancer, esophageal cancer, mesothelioma, testicular germ cell tumors, non-small cell lung cancer (NSCLC), melanoma, and lymphomas [21,22,23]. Equally pervasive as the use of platinum-based chemotherapy is the primary and secondary resistance that initially presents or develops to it. Therefore, the onus is on the oncology community to identify and develop therapies with the potential to circumvent platinum resistance for better outcomes and quality of life.

Approximately 20% of ES-SCLC patients are platinum resistant. Options for ES-SCLC patients are limited to begin with, and platinum-resistant disease further limits those options. In poker terms, platinum-sensitive patients hold “stronger hands” than their platinum-resistant (PR) counterparts who, with few to no cards left to play, may choose to “fold ‘em” and enter hospice for comfort care or to take their chances with potential 2L therapeutic options like lurbinectedin (the only FDA-approved agent for PR), topotecan, cyclophosphamide, adriamycin, and vincristine (CAV), paclitaxel, irinotecan, and temozolomide (or a clinical trial) despite significantly inferior response rates.

The complex and incompletely understood mechanisms of platinum resistance, the exploration of which exceeds the narrow parameters of this review, include loss of tumor suppressor genes, retinoblastoma 1 (RB1) and tumor protein p53 (TP53), poor blood flow and poor drug delivery, increased DNA repair, upregulation of the oncogene myc, multidrug resistance (MDR), epigenetic modification, and platinum inactivation, as illustrated in Figs. 2 and 3 [24].

Fig. 2
figure 2

Potential mechanisms of platinum resistance in SCLC

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Fig. 3
figure 3

FDA timeline of approvals in SCLC

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Further elucidation of these mechanisms has the potential to improve treatment outcomes, but, as always with SCLC, to borrow a pathology phrase, “tissue is the issue” since the rarity of surgical resection, the rapidity of disease progression, and the prevalence of patient comorbidities make it difficult to obtain enough tissue biopsies [25]. In the meantime, liquid biopsies including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) may fill the gap due to their lack of invasiveness, ease of access, and good repeatability.

Having been lost at SCLC for over 2 decades since the introduction of cisplatin/etoposide and topotecan in the 1980s and 1990s, respectively, small cell lung cancer has found itself amid a revival of sorts with a spate of several approvals in first and second line. See the timeline of approvals above.

This revival may continue with the five clinical-stage therapies/regimens discussed in this review, all of which are possibly close to approval. Even more exciting is their crossover potential to sensitize not just SCLC but also multiple other platinum-resistant tumor types and engender hope and expectancy where none (or almost none) was available before.