Precision oncology in small-cell lung cancer: a tough nut to crack

Since the identification of epidermal growth factor receptor (EGFR) mutations in non-squamous non-small cell lung cancer (NSCLC) in 2005 (1,2), other actionable oncogenic mutations have been identified and corresponding kinase inhibitors have received regulatory approval initially in the metastatic setting and more recently in the curative setting (3-6). Similar attempts to identify actionable mutations have been made for SCLC, but inactivating tumour suppressor gene mutations in TP53, pRB, NOTCH family genes and amplification of SOX2 are not yet actionable (7,8). It is logical to develop immune checkpoint inhibitors in SCLC as almost all patients are smokers (9,10) and carcinogens in cigarettes leads to higher number of neoantigens (7,8). But combining atezolizumab as in IMPOWER 133 (11) and durvalumab as in CASPIAN (12) with standard chemotherapy of platinum/etoposide improved the median overall survival (OS) by 2.5–3 months, though doubling the 2-year OS rate in extensive-stage SCLC (ES-SCLC).

The publication titled “Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide” represented the first attempt to identify clinical and molecular predictive biomarkers for benefit to atezolizumab in SCLC patients (13). Liu et al. reported long-term survivors, defined as those who lived more than eighteen months, were twice more common in those who received atezolizumab. These long-term survivors were more common to have an inflammatory signature with high cytotoxic T cells infiltration in the tumor or inflamed subtypes as defined by Gay et al. (14).

Definition of long-term survival

Given the median survival for chemotherapy treated ES-SCLC being 10 months, 2-year OS being 11–17% (11,12,15), and the median survival of good prognosis ES-SCLC was 16 months (16,17), the arbitrary selection of 18-month survival as long-term survival seems logical.

Clinical prognostic factors for ES-SCLC

Bremnes et al. evaluated 22 pretreatment clinical attributes from 436 limited stage (LS), or ES-SCLC patients enrolled in a prospective randomized trial with a minimum of 5-year follow-up. In the multivariate analysis of the 222 ES-SCLC patients, Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, absence of weight loss, white blood cell count ≤10×10⁹/L, normal alkaline phosphatase, lactate dehydrogenase (LDH), low burden of disease with one metastatic site, absence of liver and brain metastases were associated with better prognosis (18). A pool analysis of North Central Cancer Treatment Group trials identified advanced age, male, increased number of metastatic sites and elevated creatinine as predictive factors for poor outcome (19).

In addition to treatment with atezolizumab, this study confirmed the long known clinical characteristics of ECOG performance status of zero, normal LDH and low disease burden by the number of metastatic disease sites as favourable prognostic factors.

However, similar analysis was performed for CAPSIAN, which defined long-term survival be patients who were progression free at 12 months, and no clinical characteristics appeared to be predictive (20).

Programmed death-ligand 1 (PD-L1) expression as a predictive biomarker for immunotherapy

PD-L1 expression is an obvious predictive biomarker for benefit to programmed cell death-1 and its ligand [PD(L)1] therapeutics. In treatment-naïve, metastatic NSCLC, PD-L1 expression on tumour cells and/or immune cells predicts the benefit to pembrolizumab and atezolizumab (21-23). Unlike NSCLC, PD-L1 expression is detected more commonly in immune cells than tumour cells in SCLC (15,24).

Initial single arm studies with pembrolizumab either as maintenance therapy after initial response to platinum/etoposide or in the relapsed setting suggested PD-L1 expression of at least 1% of tumour associated stromal cells or both immune and tumour cells, combined positive score (CPS), is associated with better clinical outcome (25,26). Subsequent single arm trial of nivolumab in CHECKMATE 032 trial failed to show any relationship of PD-L1 expression on tumour cells and overall response rate (ORR) (27).

The preplanned retrospective analysis of PD-L1 expression on tumour and immune cells was 5%, 22% and 38.6% in CAPSIAN, KEYNOTE 604 and IMPOWER 133, respectively. All three studies failed to confirm PD-L1 expression predicts benefit to PD(L)1 therapy (11,12,15).

Tumour mutational burden (TMB)

As stated above almost all SCLC patients are either current or previous smokers, and the tumour is characterized by high mutational burden. Hellmann et al. reported recurrent SCLC patients after initial platinum-based chemotherapy who received nivolumab as in CHECKMATE 032 and had high TMB, defined as somatic missense mutation from whole exome sequencing, had higher ORR (high TMB defined as ≥248 mutations, intermediate TMB defined as 143–247 mutations and low TMB defined as <143 mutations) at 21% versus 7% versus 5%, respectively. But the corresponding median OS were comparable at 5.4, 3.9 and 3.1 months, respectively (28). KEYNOTE 158 also reported patients with high TMB of ≥10 mutations per mega base using the FoundationOne CDx assay correlated with higher ORR to pembrolizumab in previously treated solid tumours, which included 34 previously treated SCLC patients (29).

Based on these findings in the recurrent setting, TMB of baseline plasma samples using a validated blood-based assay from IMPOWER 133 was performed. Horn et al. reported no difference in OS by TMB (11). The exploratory analysis of samples from KEYNOYE 604 failed to show predictive significance of TMB using whole genome sequencing and survival (30). Tumour TMB using FoundationOne CDx was also analysed in CAPSIAN which failed to predict survival benefit with the addition of durvalumab to standard chemotherapy (20).

Immune cell activity in tumour microenvironment (TME)

Liu et al. examined both gene signatures associated with cytotoxic T-cell (T-eff), B-cell (B-eff) and interferon signalling using validated assays as well as T-eff and B-eff infiltration markers. These signatures were found to be associated with long-term survival for at least 18 months in both the atezolizumab/chemotherapy and chemotherapy arms (13).

Similar 18-gene expression profile for T-eff was examined in KEYNOTE 604, and the presence of such signature was found to predict more favourable OS, progression-free survival (PFS), and duration of response regardless of treatment arm (30).

In addition to the T-eff and B-eff cells, modulation of immune response can be modulated by T-suppressor (Tsup), T-memory cells, tumour associated macrophages (TAM) and myeloid derived suppressor cells (MDSC) (31). There are two subpopulations of MDSC: monocytic (mMDSC) and granulocytic (gMDSC) cells (32,33), which have prognostic and therapeutic impact in the treatment of lung cancer by modulating anti-tumour immune response, as well as tumour progression, tumour invasion and metastatic potential (34-38). In KEYNOTE 604, low mMDSC and gMDSC signatures were associated with better PFS, but not OS, with pembrolizumab and carboplatin/etoposide-treated patients (30).

Rudin et al. demonstrated that loss of antigen presentation machinery signatures due to epigenetic silencing by enhancer of zeste homolog 2 (EZH2) and lysine-specific histone demethylase 1 (LSD1), including major histocompatibility complex-I (MHC-I), led to decrease in T-eff infiltration which correlated with poorer outcome after treatment with nivolumab +/− ipilimumab (39).

SCLC subtypes

Initially reported by Rudin et al., SCLC can be categorized by the overexpression of transcription factors, which represents differentiating biology and thus therapeutic approaches, such as neuroendocrine subtypes that overexpress either achaete-scute homologue 1 (ASCL1) or neurogenic differentiation factor 1 (NEUROD1) and non-neuroendocrine subtypes that overexpress POU class 2 homeobox 3 (POU2F3) or yes-associated protein 1 (YAP-1) (40,41). Gay et al. performed RNA sequencing from SCLC specimens and confirmed ASCL1, NEURODO1 and POU2F3 subtypes but identified a novel inflamed subtype which had no to low express any of the four lineage transcription factors but was characterized by high expression of immune cell infiltration markers such as immune checkpoints, major histocompatibility complex and interferon gamma signature (14). Of note, there was substantial number of cases that co-expressed ASCL1 and NEUROD1, whereas the subtype that expressed POU2F3 seemed to be a distinct subgroup (40).

Two hundred and fifty-three samples from IMPOWER 133 were adequate to undergo RNA sequencing for ASCL1, NEUROD1 and POU2F3. Expression of ASCL1, NEURDO1 and POUU2F3 were reported in 66.4% and 91.1%, 36.7% and 31.1% and 10.7% and 8.2% of samples in the chemotherapy alone arm and in the atezolizumab/chemotherapy arm, respectively. The immune subtype was found in 38.2% and 32.4% of samples in the respective arm. A higher proportion of the inflamed subtype was reported in the long-term survivor subgroup in both chemotherapy and chemotherapy/atezolizumab arms (13). However, similar analysis using samples from KEYNOTE 604 failed to demonstrate differential OS benefit to chemotherapy/pembrolizumab (30).

Perspective and conclusion

Attempts have been made in the three recent phase 3 studies combining PD(L)1 with standard chemotherapy in ES-SCLC to identify predictive biomarkers for PD(L)1 therapy. Aside from confirming clinical baseline characteristics such as good performance status, low disease burden and normal LDH, the presence an inflamed gene expression profile in T-eff is prognostic. The presence of T-eff and antigen presentation signatures may represent a working immune system that can recognize neoantigens and is cytotoxic to SCLC. Cell kill from chemotherapy with or without PD(L)1 agents leads to release of tumour antigens that can further enhance the cytotoxic effect of functional T-eff cells, which may be partially confirmed by the enrichment of immune subtype SCLC as the long-term survivors in both chemotherapy and chemotherapy/PD(L)1 arms. The presence of MDSC negatively impacted on the PFS but not OS benefit of pembrolizumab in ES-SCLC. With the failure of adding tiragolumab, anti-TIGIT (anti-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains) antibody, which targets both T-eff and Tsup, to improve the outcome of treatment-naïve ES-SCLC patients treated with atezolizumab and platinum/etoposide (42), targeting T-eff may not the most relevant biological target for SCLC. Other immune cells such as MDSC or TAM in the TME may represent novel therapeutic avenue for the management of SCLC. But the TME at the primary and the metastatic sites may be different, and so the results these retrospective analyses should be interpreted with caution. Instead of being definitive, all conclusions should be considered as hypothesis generating. Prospective validation is needed in both primary tumour and metastatic sites before clinical development of these novel immunotherapeutic agents be pursued.

To enable translational research in SCLC, a more concerted effort to perform core biopsies of the metastatic disease and/or primary site without clinically unacceptable risk to patients and delay in therapy at the time of diagnosis or relapse is needed. Continual efforts should also be made during prospective clinical trials to further validate and/or refine the predictive biomarker for any therapeutic target.

The subtyping by transcription factor expression provides insight into the potential therapeutic approaches enabling precision oncology in ES-SCLC (43). Stringent evaluation of differential preclinical activity of these agents in each SCLC subtypes is needed as this will help to guide clinical trial design. Understanding that SCLC patients, particularly those with extensive disease and/or in the relapsed setting, only novel agents with preclinical activity that may lead to substantial clinical improvement should be transitioned into clinical development. For agents that are clearly beneficial to a certain subtype of SCLC, early clinical trials to evaluate the clinical activity in previously treated SCLC patients can be either a single arm trial that has the power to detect a large treatment effect (such as an improvement in ORR of ≥20%), and a low alpha-error or a randomized trial with standard option. For agents that do not have tentative biomarker in a certain subtype, randomization based on tentative biomarker for the agent should be performed to confirm or further refine the biomarker (Figure 1).

Figure 1 Potential early clinical trial designs. (A) Definitive biomarker for a therapeutic target; (B) not definitive biomarker for a therapeutic target.

The assumption of each SCLC to fall into one of the molecular subtypes is far from the reality. Some of the SCLC had either spatial heterogeneity with different molecular subtypes in different areas of the tumour or co-expression of more than one transcription factors in the same population of tumour cells (41,44). Further complicates drug development in SCLC is the evolution from one predominant molecular subtype to more than one upon treatment, making generalizability of the biomarkers of efficacy in the pre-treated setting to treatment-naïve setting and vice versa more complicated (14).

Overall, precision medicine in SCLC is far behind NSCLC and is facing substantial headwind. Collaborative efforts across translational oncology and clinical development are required to develop next generation of agents that can provide clinically relevant improvement of outcome.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-22/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-22/coif). Q.S.C.C. had received honoraria and served on the Advisory Boards of Abbvie, Amgen, AnHeart, Astellas, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squib, Daichii Sankyo, Eli Lilly, Glaxo Smith Kline, Janssen, Merck, Novartis, Ocellaris, Pfizer, Roche, and Takeda; had received research funding from Astra Zeneca and served on the Data Monitoring Board of Merck KgaA. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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