Developments in targeted therapy & immunotherapy—how non-small cell lung cancer management will change in the next decade: a narrative review

Introduction

Background

Lung cancer is the leading cause of cancer death worldwide, claiming 1.8 million lives annually (1). About 85% of lung cancers are non-small cell lung cancer (NSCLC). Patients with lung cancer have dismal prognoses, due to the fact that more than half of them present with metastatic disease, and recurrence is common among those who have early-staged disease (2). Conventional cytotoxic chemotherapy only offers a modest improvement in survival for NSCLC patients (3). The identification of actionable driver oncogenes such as EGFR and ALK, and immune checkpoints such as PD-L1, have led to the development of personalized cancer care. Over the past decade, significant advances in targeted therapy and immunotherapy have transformed the treatment paradigm and survival outcomes of patients with NSCLC. Patients receiving genotype-directed therapy achieve more rapid but durable tumour responses and usually less treatment related toxicities comparing to those who receive conventional chemotherapy. Nonetheless, therapeutic resistance remains a perennial challenge and much research is dedicated to this area.

Rationale and knowledge gap

A myriad of novel therapeutic approaches has shown promise with potential to change future practice. The treatment landscape of NSCLC is rapidly evolving and turning increasingly complex. An updated review in this topic offers oncologists and other clinical practitioners a succinct overview in the state-of-the-art and future trends in NSCLC management.

Objective

This review discusses the latest development in targeted therapy and immunotherapy in NSCLC management. This review also addresses the resistance mechanisms to targeted therapy and immunotherapy and discusses future research direction in this field. We present this article in accordance with the Narrative Review reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4444/rc).

Methods

On June 15^th, 2022, a systematic literature search was conducted by MSC Li and KKS Mok. Final approval of literature search was conducted by MSC Li and KKS Mok. An online search of literature utilizing PubMed was employed. Selection criteria included NSCLC, targeted therapy, immunotherapy, EGFR, ALK, ROS1, BRAF, MET, RET, KRAS, HER2, ERBB2, NRG1, immune checkpoint, PD-1, PD-L1, CTLA4, TIGIT, VEGF, cancer vaccine, cellular therapy, tumour microenvironment, cytokine, and gut microbiota from 2005 to 15^th June 2022. Only studies in English were included (Table 1).

Early staged NSCLC

Historically, neoadjuvant and adjuvant chemotherapy only provide an overall 5% survival benefit (4,5). Motivated by the success of immunotherapy in advanced stage lung cancer (6), much research on immunotherapy has been done in the neoadjuvant or adjuvant setting in recent years to improve this statistic.

Neoadjuvant immunotherapy in surgically resectable NSCLC

The concept of neoadjuvant immunotherapy is supported by the hypothesis that an in-situ tumour may serve as a neoantigen source for stimulation of tumour-specific T-cells (7). Most neoadjuvant clinical trials evaluated pathological response rate as their major study endpoints. While overall survival is the gold standard for study endpoint in neoadjuvant studies, surrogate endpoints are needed for practicality and cost effectiveness. Pathologic response is emerging as one important endpoint because it has strong correlation to recurrence and survival (8), and is more predictive than radiologic response (9).

Earlier trials investigated neoadjuvant immunotherapy with anti-programme death-(ligand)-1 (anti-PD-L1/PD-1) monoclonal antibodies alone. They resulted in major pathologic response rates (MPR, defined as 10% or less viable tumor in resected primary tumour) of 20–45% and pathologic complete response (pCR, defined as no viable tumour cells in resected primary tumour and lymph nodes) rates of 7–10% (7,10-12). A phase II study showed that dual immunotherapy with nivolumab and ipilimumab achieved higher MPR rate (38% versus 22%) and pCR rate (29% versus 9%) compared to nivolumab alone (12).

In general, pathological response rates with single agent immunotherapy were lower than immunochemotherapy combinations. Single arm studies testing neoadjuvant immunochemotherapy combinations reported MPR rates of 57–83% and pCR rates of 18–63%. Toxicity was understandably higher due to the addition of chemotherapy, but surgery was in general feasible (13-15).

The only published phase III trial evaluating chemo-immunotherapy to date was the CheckMate 816 trial, which compared three cycles of neoadjuvant nivolumab plus chemotherapy versus chemotherapy in stage IB (tumor size ≥4 cm) to IIIA patients (AJCC staging 7^th edition) without EGFR/ALK alterations. The primary outcomes were met, with an event-free survival (EFS) of 31.6 months versus 20.8 months (HR 0.63, 97.38% CI: 0.43–0.91), pCR of 24% versus 2% (odds ratio 13.94; 99% CI: 3.49–55.75) in the chemoimmunotherapy versus chemotherapy arms respectively. Patients with high PD-L1 expression (HR 0.24, 95% CI: 0.10–0.61) or stage III disease (HR 0.54, 95% CI: 0.37–0.80) benefited more from the neoadjuvant immunochemotherapy combination. The trial also validated that pCR was strongly predictive of EFS (16). A number of phase III neoadjuvant immunochemotherapy studies are underway (Table 2).

Future studies will explore combining neoadjuvant immunotherapy with antiangiogenic drugs such as lenvatinib (NCT04875585), apatinib (NCT04379739) and bevacizumab (NCT04973293), or relatlimab (NCT04205552), an anti-LAG3 checkpoint inhibitor. Tri-modality combinations with chemotherapy, immunotherapy, and radiotherapy are also being studied (NCT04245514, NCT05157542).

Adjuvant immunotherapy in surgically resected NSCLC

IMpower010 was the first published phase III immunotherapy study in the adjuvant setting in surgically treated lung cancer, comparing adjuvant atezolizumab up to one year versus supportive care after surgery and adjuvant chemotherapy (Table 2). This study showed improved disease-free survival (DFS) in stage II to IIIA patients with PD-L1 ≥1% (HR 0.66, 95% CI: 0.50–0.88; 3-year DFS 60% versus 48%) and in all comers of stage II to IIIA (HR 0.79, 95% CI: 0.64–0.96; 3-year DFS 56% versus 49%). Exploratory analysis suggested that the PD-L1 expression might be related to outcome, with a HR of 0.43 (95% CI: 0.27–0.68) in the ≥50%, but 0.97 (95% CI: 0.72–1.31) in the ≤1% group (17).

Data from the second interim analysis for adjuvant pembrolizumab was presented recently. The KEYNOTE-091 study was a triple blinded phase III randomized study comparing adjuvant pembrolizumab versus placebo for stage IB (≥4 cm) to IIIA patients (AJCC staging 7^th edition) after surgery with or without chemotherapy. The study reported a significant DFS benefit with pembrolizumab but unlike IMpower010, the DFS outcomes did not correlate with PD-L1 expression. The reason for this discrepancy in outcome was not clear (18). Other phase III trials testing adjuvant PD-(L)1 blockade in patients with resected NSCLC have completed accrual and will provide additional insight into the potential biomarkers (Table 2). More importantly, in future, testing clinically whether there are differences in outcome between a neoadjuvant and adjuvant approach should be further pursued.

Immunotherapy in locally advanced unresectable lung cancer

Definitive chemoradiotherapy followed by consolidation durvalumab for up to 1 year is now the standard for unresectable stage III NSCLC based on the landmark PACIFIC trial (19). In the latest update, durvalumab versus placebo was associated with median overall survival (OS) of 47.5 versus 29.1 months. Patients with PD-L1 expression ≤1% or EGFR/ALK alteration did not yield OS benefit from the study drug [HR 1.15 (95% CI: 0.75–1.75) and HR 0.85 (95% CI: 0.37–1.97) respectively] (20).

Building upon the PACIFIC trial, the COAST trial was a phase II trial incorporating oleclumab (anti-CD73 mAB) or monalizumab (anti-NKG2A mAB), novel drugs with immunomodulatory effects, to standard consolidation durvalumab. Encouraging response rates of 30.0% (oleclumab plus durvalumab), 35.5% (monalizumab plus durvalumab), versus 17.9% (durvalumab) were reported (21). This has now moved onto a phase III study (NCT05221840).

Integrating immunotherapy into chemoradiotherapy was feasible in a phase II trial involving pembrolizumab with response rate of about 70% and Grade 3 pneumonitis of 7–8% (22). Another similar trial involving concurrent durvalumab is underway (NCT03519971). Novel immunotherapy agents such as anti-TIGIT are being investigated as a component of consolidation therapy (NCT04513925, NCT05211895) and as part of the chemoradiotherapy regime (NCT04866017).

Neoadjuvant and adjuvant therapy in NSCLC with EGFR or other driver oncogene

Neoadjuvant tyrosine kinase inhibitor (TKI) is not yet an established standard treatment for patients with NSCLC harboring driver mutation. The EMERGING-CTONG 1103 trial compared neoadjuvant erlotinib with neoadjuvant chemotherapy in stage IIIA N2 patients with EGFR exon 19 or 21 mutations. While objective response (54.1% versus 34.3%, P=0.09) was numerically higher and progression free survival (PFS) was statistically significantly better of 21.5 months versus 11.4 months (P<0.001), neoadjuvant erlotinib did not improve overall survival (median OS 42.2 versus 36.9 months, HR 0.83, P=0.513) (23). This trial raised an important message that PFS benefit in an neoadjuvant targeted therapy study does not necessarily translate into OS benefit. NEOS, a single arm trial of 18 patients, reported response rate of 73.3% with neoadjuvant osimertinib (24). An ongoing phase III trial called NEOADAURA will determine whether osimertinib with or without chemotherapy is beneficial in the neoadjuvant setting (NCT04351555).

The most promising data on adjuvant epidermal growth factor receptor (EGFR) TKI involved osimertinib in the ADAURA trial. This was a phase III trial in which patients with resected stage IB to IIIA NSCLC (AJCC staging 7^th edition) with EGFR exon 19 deletion or L858R mutation were randomized to receive either up to three years of osimertinib or placebo. The reported 24-month DFS was an impressive 90% versus 44% (HR 0.17, P<0.001). Given the overwhelming DFS gain the study was unblinded early and the drug was Food and Drug Administration (FDA) approved for this indication. OS data has yet to mature (25).

Clinical data on perioperative TKI for NSCLC harboring other driver oncogenes (e.g., ALK, ROS1) is scarce due to rarity of these tumours. ALINA is an ongoing phase III study comparing adjuvant alectinib with standard platinum-based chemotherapy in patients with resected ALK positive NSCLC (NCT0456076). NAUTIKA1 is a phase II study in which patients receive genotype-directed, neoadjuvant TKI followed by surgery, adjuvant chemotherapy and 2 years of TKI (NCT04302025). Primary study outcome is MPR rate. At present, osimertinib is the only FDA approved targeted therapy for early staged NSCLC harboring a driver mutation.

Early-staged NSCLC: future direction

The phase III studies presented above have set the stage for immunotherapy and targeted therapy in early staged NSCLC. Future OS data and results of the other ongoing phase III studies will confirm the benefit of immunotherapy and targeted therapy in this setting. The classical notion that the histological subtype and molecular profile are irrelevant in early staged NSCLC management has become obsolete. EGFR mutation and PD-L1 expression should be tested at diagnosis to guide treatment plan. Multidisciplinary discussion is crucial for management of stage III, or even stage II NSCLC as different treatment approaches are now viable. Given the improving response rates of neoadjuvant treatment, tumours that are determined unresectable at diagnosis may be converted to resectable. As a result, the line between unresectable and resectable tumours may blur. Future studies will also focus on identifying patients, for example those who fail to achieve pCR, or those with minimal residual disease after surgery, who will benefit from intensive treatment.

Targeted therapy in metastatic NSCLC

Overview

The foundation of targeted therapy in lung cancer is based on the knowledge that certain genetic alterations act as primary drivers of cancer formation, such that inhibition of the driver oncogene leads to cancer growth arrest and cell death. Targeted therapies in NSCLC are conventionally referred to small molecule gene-specific tyrosine kinase inhibitors. Recently, innovations in drug designs have led to development of newer classes of targeted therapies like antibody-drug conjugates (ADC) and bispecific antibodies. Tyrosine kinase inhibitors (TKIs) have proven enormous success in NSCLC treatment as up to one half of lung adenocarcinomas (LUAD) harbour a driver oncogene (26-28) (Figure 1). To date, there are nine oncogenes in NSCLC with FDA approved therapies.

Figure 1 Prevalence of actionable driver alterations in lung adenocarcinoma. Frequency of driver oncogenes in LUADs in Caucasians, adapted from Jordan et al. (28). LUADs, lung adenocarcinomas.

EGFR mutation

Currently, 5 EGFR TKIs (namely erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) are approved for treatment naïve, advanced EGFR mutated NSCLC (Table 3) (29-41). The FLAURA study randomized 556 patients with untreated advanced EGFR-mutated NSCLC to receive osimertinib or a first-generation EGFR TKI. Osimertinib demonstrated superiority over first-generation TKI in terms of PFS, OS, intracranial objective response rate (ORR), as well as a more favourable side effect profile, and thus is the preferred first-line treatment option for advanced NSCLC harbouring a sensitizing EGFR mutation (42,43).

Treatment strategy upon osimertinib resistance is under active research. The standard treatment for patients after osimertinib resistance is cytotoxic chemotherapy. With growing understanding of the resistance patterns to osimertinib and advances in drug designs, multiple new treatment approaches have shown promise.

EGFR exon 20 C797S mutation is the most common EGFR-dependent mechanism of osimertinib resistance (7–26%) and interferes with drug binding to the EGFR protein (51). Preclinical data showed that fourth generation EGFR TKIs, such as BLU-701, BLU-945, BBT-176 and JBJ-09-063, were active against C797S resistance (52-55). Phase I/II studies are now underway to study the clinical efficacy and safety of these agents (e.g., NCT 05153408, NCT04820023).

MET amplification accounts for up to 20% of osimertinib resistance (51). The combination of EGFR TKI plus a selective MET inhibitor (e.g., tepotinib, capmatinib, savolitinib) was tested in patients with MET overexpression or amplification resistance in several phase Ib/II trials. Reported ORRs were around 30–60% supporting TKI combination as a treatment option for patients with acquired MET dysregulation (56-59). Phase III randomized studies such as GEOMETRY-E (NCT04816214) and SAFFRON (NCT-05261399) will compare such combinations with standard platinum-based chemotherapy. EGFR TKI resistance mediated by other actionable alterations are rare but treatment success of different TKI combinations have been reported in literature (60-62), highlighting the importance of repeating genomic profiling after TKI failure to search for druggable resistance mutations.

Amivantamab is a bispecific antibody against EGFR and c-MET (63). In the CHRYSALIS and CHRYSALIS-2 single arm phase II studies, the combination of amivantamab and lazertinib (a third-generation EGFR TKI) achieved response rates of 36% and 32% respectively in patients who progressed on osimertinib (64,65). These data supported bispecific antibody to be an alternative approach other than tyrosine kinase inhibition in targeting oncogene-addicted NSCLCs by induction of antibody-dependent cellular cytotoxicity (ADCC) and simultaneous inhibition of multiple signalling pathways (66).

HER3 is typically overexpressed on EGFR-mutated NSCLC (67) and patritumab deruxtecan (HER3-DXd) is an ADC against HER3. In a phase I study, ORR was 39% and median PFS was 8.2 months among 57 patients who had prior EGFR TKI and platinum-based chemotherapy and received HER3-DXd (68). The HERTHENA-Lung02 is a phase III study (NCT05338970) comparing HER3-DXd with platinum-based chemotherapy for patients with EGFR-mutated NSCLC failing osimertinib.

ALK rearrangement

Second and third generation ALK TKIs (namely ceritinib, alectinib, brigatinib, ensartinib, lorlatinib) have largely supplanted crizotinib for treatment-naïve, advanced ALK-rearranged NSCLC as all of them demonstrated superior PFS comparing with crizotinib in the upfront setting, except that ceritinib was compared with chemotherapy. (Table 3) (44-46,48-50,69). Although cross-trial comparison suggested that lorlatinib offered more durable disease control compared to the second generation ALK TKIs (3-year PFS 63% with lorlatinib, 45% with alectinib and 43% with brigatinib) (47,48,70), the optimal first-line treatment is still an open debate as lorlatinib usually remains effective after second generation ALK TKI failure (71).

Resistant ALK mutations most often occur in the gatekeeper region (e.g., L1196M and G1269A) or the solvent front region (e.g., G1202R) after first and second generation ALK TKI treatment (72). Serial ALK TKI treatment potentially predisposes to multiple resistant kinase mutations and lorlatinib resistance (73). Fourth generation ALK TKIs like TPX-0131 are designed to bind precisely to the adenine binding site of ATP to avoid clashing with the solvent front, hinge or gatekeeper area, and thus may overcome double- or triple-mutant resistant kinase mutations (74). TPX-0131 and NVL-655 are now being evaluated in phase I clinical studies which involve patients who have failed multiple lines of ALK TKI including lorlatinib (NCT04849273, NCT05384626).

ROS1 rearrangement

Crizotinib and entrectinib are approved therapies for ROS1-rearranged NSCLC. PROFILE 1001 was a single arm phase II study in which 50 patients with ROS1-rearranged NSCLC received crizotinib. Crizotinib achieved an ORR of 72% and a median PFS of 19.2 months (75). In the integrated analysis of three entrectinib studies (ALKA-372-001, STARTRK-1, and STARTRK-2), entrectinib achieved a similar ORR of 77% and a median PFS of 19.0 months (76). Entrectinib may be preferred in patients with brain metastases in view of its excellent intracranial activity (intracranial ORR 52.2%) (77). Besides crizotinib and entrectinib, ceritinib and lorlatinib are also both active in ROS1-rearranged NSCLC but are not FDA approved (78,79). ROS1^G2032R solvent-front mutation is the most common resistance mechanism following crizotinib progression and confers resistance to all commercially available ROS1 inhibitors (80). Interim data of the TRIDENT-1 phase I/II study showed that repotrectinib (TPX-005), a next generation ROS1/TRK inhibitor, was active against ROS1 TKI-naïve and pretreated patients (81). Enrollment of this study is now ongoing (NCT03093116).

MET exon 14 skipping

Three highly selective type IB MET inhibitors, namely capmatinib, tepotinib, and savolitinib, were proven highly efficacious in patients with advanced MET exon 14 skipping positive (METex14) NSCLC. In GEOMETRY mono-1, treatment naïve patients with advanced METex14 NSCLC achieved an ORR of 68% and median PFS of 12.4 months with capmatinib. In the pretreated cohort, ORR was 41% and median PFS was 5.4 months (82,83). In the VISION study, 152 patients with NSCLC harbouring METex14, either detected by tissue or liquid biopsy, received tepotinib. Response rates were similar at 50% either in the tissue-biopsy or liquid-biopsy group, regardless of number of lines of previous treatment (84). Both drugs exhibited intracranial antitumour efficacy (84,85). Savolitinib was evaluated in 70 patients with pretreated METex14 NSCLC in China. Notably, 25 patients (36%) had pulmonary sarcomatoid carcinoma (PSC), which was underrepresented in the GEOMETRY mono-1 and the VISION study (<8% of patients had PSC). ORR in the intention-to-treat population and PSC subgroup were 49% and 40% respectively (86). Peripheral oedema is the major toxicity from MET inhibitors. Currently, capmatinib and tepotinib are FDA approved and savolitinib is approved in China for advanced METex14 NSCLC. Multiple treatment strategies targeting MET-dysregulated NSCLC, such as type II MET inhibitor (e.g., merestinib, NCT02920996), MET-based ADC (e.g., telisotuzumab vedotin, NCT03539536) and bispecific antibody (e.g., amivantamab, NCT02609776), are under study.

RET rearrangement

Recently, two selective RET inhibitors, demonstrated high efficacy in RET rearranged NSCLC and received FDA approvals for this treatment indication. Selpercatinib was tested in 144 patients with RET-rearranged NSCLC in the LIBRETTO-001 multicentre single arm phase II study. In the treatment-naïve cohort, ORR was 85% and median PFS was not reached at data cutoff. In the platinum pretreated cohort, ORR was 64% and median PFS was 16.5 months (87). The ARROW study evaluated 121 patients with RET-rearranged NSCLC who received pralsetinib. ORR was 70% in the treatment naïve cohort and 61% in the pretreated cohort (88). Grade 3 and 4 toxicities due to RET inhibitors were rare and mainly included hypertension, deranged liver function, and cytopenia. The LIBRETTO-431 (NCT04194944) and ACCELE-RET (NCT04222972) are comparing selpercatinib and pralsetinib respectively, with platinum-based chemotherapy with or without pembrolizumab in patients with treatment-naïve advanced RET-rearranged NSCLC. Novel RET inhibitors (e.g., TPX-0046, NCT04161391; BOS172738, NCT03780517) designed to overcome acquired RET resistant mutations are now evaluated in phase I/II clinical trials (89,90).

BRAF V600E mutation

The combination of dabrafenib and trametinib is FDA approved for the treatment of advanced, BRAF V600E mutated NSCLC. Clinical efficacy achieved by the BRAF and MEK inhibitor combination (ORR 64% for both untreated and treatment naïve patients, median PFS 14.6 months for untreated cohort and 8.6 months for pretreated cohort) was considerably higher than BRAF inhibitor monotherapy (ORR about 40% and median PFS about 5–6 months) (91-93). Pyrexia is a specific and common (up to 50%) side effect from the drug combination which is usually ameliorated by antipyretics and dose adjustment.

NTRK rearrangement

Two TRK inhibitors, larotrectinib and entrectinib, received FDA approval as tumor agnostic therapies for patients with tumours harbouring NTRK fusions. In an updated integrated analysis of three phase I/II clinical trials which evaluated larotrectinib in 159 patients with NTRK fusion-positive solid tumours, ORR was 79% and median PFS was 25.8 months (94). Another integrated analysis of three phase I/II clinical trials analysed the clinical efficacy of entrectinib in 121 patients with NTRK fusion-positive tumours. The ORR was 61% and the median PFS was 13.8 months (95). Both larotrectinib and entrectinib showed high efficacy across a wide range of tumour types including NSCLC. TRK inhibitors are associated with specific on-target side events like cognitive impairment, dizziness, weight gain and drug withdrawal pain but drug discontinuation due to treatment-related adverse events is rare (<10%). In a small-scale study of 18 patients who progressed on first generation TRK inhibitors (larotrectinib or entrectinib), a resistant solvent front mutation was identified in 13 of them (96). Preclinical data showed that next generation TRK inhibitors such as taletrectinib, repotrectinib, and selirectinib, were effective against NTRK fusion positive tumours with secondary resistant NTRK mutations (81,97,98).

KRAS G12C mutation

KRAS was considered undruggable in the past due to the absence of an identifiable drug binding pocket on KRAS protein and its strong affinity to ATP rendering design of KRAS inhibitors inherently difficult (99). In 2013, the Shokat lab identified a small pocket adjacent to the switch-II region that was only present in GDP-bound, G12C mutant KRAS protein. The research team designed a small, KRAS G12C allele-specific molecule (ARS-1620) that could bind to this pocket and lock the KRAS protein in its inactive, GDP-bound state (100). Non-cancer cells that do not carry the KRAS G12C mutation could be spared from the toxicities, resulting in a much wider therapeutic index. Further refinement in drug structure designs have led to development of molecules with enhanced potency that are tested in clinic today.

Sotorasib (AMG510) was the first KRAS G12C inhibitor adopted in clinic setting. In CodeBreak 100 study, the drug was evaluated in 126 patients with pretreated KRAS G12C mutated NSCLC. The ORR was 37% and the median PFS was 6.8 months (101). Recently, the results of the phase III CodeBreak 200 trial were published. Sotorasib achieved superior PFS and ORR compared to docetaxel in patients who progressed after prior platinum-based chemotherapy and immune checkpoint inhibitor (102). Another KRAS G12C inhibitor, adagrasib (MRTX849), achieved treatment response rate of 43% and median PFS 6.5 months in the KRYSTAL-1 phase I-II study enrolling 116 patients (103). A number of KRAS G12C inhibitors, such as JDQ443, JAB-21822, and GDC-6036, are under clinical investigation (NCT05132075, NCT05276726, NCT04449874).

A heterogenous spectrum of resistance mechanisms have been identified in the setting of KRAS G12C inhibitor resistance, of which secondary KRAS mutations or alterations in RTK-RAS signalling pathway are most prevalent (104,105). These data supported the approach of combining a KRAS G12C inhibitor with an RTK or SHP2 inhibitor in order to achieved more sustained RAS inhibition (NCT04330664, NCT04185883).

Targeting KRAS mutants other than G12C is more challenging given the lack of a drug binding pocket and even higher affinity to GTP. Nonetheless, preclinical data on KRAS G12D, KRAS G12V, and pan-KRAS inhibitors is emerging (106-110).

EGFR exon 20 insertion

EGFR exon 20 insertion (EGFRex20ins) is well known to be EGFR TKI resistant due to its unique steric configuration. Recently, two drugs were approved by the FDA for treatment of advanced EGFRex20ins NSCLC in the second line setting. Mobocertinib is an oral TKI designed specifically targeting EGFRex20ins. The drug achieved an ORR of 28% and median PFS of 7.3 months in platinum-pretreated patients with advanced EGFRex20ins NSCLC (111). Amivantamab is a bispecific EGFR-cMET antibody achieving a tumour response rate of 40% and median PFS of 8.3 months in 81 patients in the CHRYSALIS study (112).

HER2 mutation

Studies in the past targeting HER2 mutation have yielded disappointing results. Various classes of anti-HER2 agents, including monoclonal antibodies, TKIs, and ADCs, have been investigated in HER2-mutated NSCLC. Recently, a few agents have demonstrated signals of antitumour activity (113-116). Among all anti-HER2 targeted therapies, trastuzumab deruxtecan (T-DXd) has shown the best promise. Compared to trastuzumab emtansine (T-DM1), T-DXd has a different cytotoxic payload and an enhanced linker-payload system enabling a higher drug-to-antibody ratio (1 to 8 for T-DXd compared to 1 to 4 for T-DM1) while maintaining high stability in plasma (117). Recently, the results of DESTINY-Lung01 trial were published. Total of 91 patients with HER2-mutated NSCLC were enrolled into the study. T-DXd achieved an ORR of 55%, DCR of 92% and median PFS of 8.2 months. Interstitial lung disease is a specific adverse event of T-DXd that occurred in a quarter of patients in this study (118). In August 2022, the FDA granted accelerated approval to T-DXd for patients with advanced HER2-mutated NSCLC failing first-line therapy. The upcoming DESTINY-Lung04 study will evaluate T-DXd versus standard of care in patients with untreated, advanced NSCLC harbouring a HER2 mutation (NCT05048797).

NRG1 rearrangement

NRG1-rearrangement represents a rare but targetable oncogene in NSCLC (0.2%) and causes cancer by inducing ErbB2-ErbB3 dimerization. Zenocutuzumab, a bispecific HER2/HER3 antibody, and seribantumab, an anti-HER3 monoclonal antibody, showed encouraging signal in targeting NRG1-rearranged solid tumours including NSCLC (119-121). Both drugs are now being studied in phase II studies (NCT02912949, NCT04383210).

Antibody-drug-conjugates under development

TROP2 is ubiquitously expressed on lung cancer cells and thus a favourable target for development of ADC (120). Sacituzumab govitecan is a TROP-2 ADC connected to an irinotecan derivative payload SN-38. In a single arm cohort enrolling 54 heavily pretreated patients, ORR was 17% (122). Datopotamab deruxtecan (Dato-DXd) is another TROP-2 ADC using deruxtecan as the cytotoxic payload. In the NSCLC cohort of the TROPION-PanTumor01 Phase I study, ORR was 24%. Interstitial lung disease was present in 11% of patients (123). Dato-DXd was also active in patients with actionable genetic alterations (124). Tusamitamab ravtansine, an anti-CEACAM5 ADC, has shown antitumour efficacy in NSCLC. Tumour response rate was 20% in a heavily pretreated population with CEACAM5 highly expressed NSCLC (125). These drugs are now compared with docetaxel in the platinum-refractory setting (NCT04656652, NCT05089734, NCT04154956), and combinations of TROP-2 ADC with immunotherapy are also explored (NCT04526691, NCT04612751, NCT05186974).

Targeted therapy: future direction

Advances in structural bioinformatics and computational biology have led to drug discoveries that target “undruggable” alterations such as KRAS and EGFRex20ins. Consequently, targeted therapies are no longer limited to TKIs and monoclonal antibodies, but also comprise allosteric inhibitors, ADCs and bispecific antibodies. Increasing adoption of high throughput genomic sequencing as well as liquid biopsy testing has facilitated detection of rare genetic alterations and depiction of drug resistance mechanisms. Ongoing research focuses on characterization of TKI resistance mechanisms and development of novel therapeutic approaches targeting actionable resistance alterations. As a result, molecular profiling is not only essential at the time of diagnosis, but it may be clinically relevant to track the evolution and genomic changes of the tumour during the treatment course in order to establish a personalized therapeutic strategy.

Immunotherapy in metastatic NSCLC

PD-L1 blockade

Immune checkpoint inhibitor (ICI), notably anti-PD-L1/PD-1 antibody, is the cornerstone of immunotherapy for multiple cancer types including NSCLC. PD-1/PD-L1 binding leads to intratumoral T-cell exhaustion thus blocking this interaction may reactivate exhausted T-cells for cancer cell killing. PD-(L)1 blockade is now considered standard of care for patients with advanced NSCLC without actionable oncogenic alterations. At present, multiple anti-PD-(L)1 agents have been approved for metastatic NSCLC, either as monotherapy or in combination with other drugs (Figure 2). Treatment efficacy of anti-PD-(L)1 directly correlates with PD-L1 expression on tumour cells. For patients with treatment naïve, EGFR/ALK negative NSCLC with PD-L1 tumour proportion score (TPS) ≥50%, first-line anti-PD-(L)1 monotherapy was superior to chemotherapy in terms of PFS and OS (126-128) (Table 4) In the KEYNOTE-024 study, five-year overall survival was 31% for patients assigned to the pembrolizumab arm (129). Pembrolizumab monotherapy is approved but generally not recommended for patients with NSCLC with PD-L1 TPS 1–49%, as subgroup analysis showed no survival benefit over chemotherapy (127,130).

Figure 2 Timeline of FDA approval of immunotherapy in metastatic NSCLC. PD-L1, programme death-ligand 1; NSCLC, non-small cell lung cancer; non-SqCC, non-squamous.

Addition of pembrolizumab to chemotherapy improved PFS and OS compared to chemotherapy alone regardless of PD-L1 expression and histology, and this regime has been adopted as the standard first-line treatment regime for advanced NSCLC without actionable alterations in multiple countries (131,133). Other studies testing immunochemotherapy combination with atezolizumab, sintilimab, tislelizumab, camrelizumab, or sugemalimab in addition to chemotherapy also consistently showed PFS improvement over chemotherapy alone (134-144) (Table 4). All of the studies above excluded patients with EGFR or ALK alterations. CheckMate 722 (NCT02864251) and KEYNOTE789 (NCT03515837) are phase III studies investigating the combination of anti-PD-(L)1 plus chemotherapy versus chemotherapy in advanced EGFR-mutated NSCLC NSCLC failing TKI. Results are eagerly awaited.

Despite the promise of anti-PD-(L)1 blockade, only a minority of patients experience durable benefit. Complex interplay between the immune system, tumour cells and tumour microenvironment (TME) are implied in the setting of immunotherapy resistance. ICI resistance can be broadly classified into tumour intrinsic and tumour extrinsic. Tumour intrinsic mechanisms include low tumour antigen production, defective antigen presentation or expression of co-inhibitory signals. Tumour extrinsic mechanisms include failure in T cell activation or infiltration into tumour, or intratumoral T cell dysfunction, either due to defects in host immune system or an immunosuppressive TME. To date, the landscape of ICI resistance is still poorly understood. Combinational strategies designed to overcome these resistance mechanisms are now investigated in clinical trials.

Immune checkpoints: CTLA4, TIGIT, and others

Cytotoxic T lymphocyte antigen 4 (CTLA4) is an immune checkpoint mechanistically distinct from PD-L1. It interferes with B7-CD28 binding and prevents T cell priming inside lymph nodes. It is also highly expressed by regulatory T (Treg) cells, thus blocking CTLA4 may both enhance T cell activation and downregulate Treg cells. CheckMate-227, MYSTIC and NEPTUNE study evaluated the anti-PD-L1/anti-CTLA4 combination without chemotherapy versus chemotherapy alone for treatment-naïve, EGFR/ALK negative, advanced NSCLC (Table 4). In the CheckMate-227 study, superior OS was achieved with nivolumab plus ipilimumab compared to chemotherapy, regardless of PD-L1 expression (146). Contrarily, both MYSTIC and NEPTUNE studies failed to achieve their primary endpoints—OS was not superior with dual immunotherapy in a biomarker-specified population (147,149). Both CheckMate-9LA and POSEIDON study showed that the four-drug combination of anti-PD-(L)1, anti-CTLA4 and chemotherapy was superior to chemotherapy alone in terms of PFS and OS, establishing the combination of dual immunotherapy plus chemotherapy as a valid first-line treatment option (146,150). Incidence of immune-related adverse events and rate of immunotherapy discontinuation was higher with dual immunotherapy compared to anti-PD-(L)1 monotherapy (145,149).

Prospective evidence is lacking in identifying patients who may benefit more from dual immunotherapy over anti-PD-(L)1 monotherapy. KEYNOTE-598 randomized patients with PD-L1 ≥50%, treatment-naïve advanced NSCLC to pembrolizumab single agent versus pembrolizumab plus ipilimumab. No PFS or OS improvement but only increased toxicities were observed in the dual immunotherapy arm (151). Based on this study, dual PD-(L)1 and CTLA blockade is not recommended for PD-L1 ≥50% NSCLCs.

Aside PD-L1 and CTLA4, multiple immune checkpoints are being evaluated as anticancer therapeutic targets. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a co-inhibitory immune receptor expressed on T cells. Preclinical data showed that dual TIGIT/PD-1 blockade enhanced antitumour immune response (152). The phase II CITYSCAPE trial randomly assigned 135 patients with treatment naïve, PD-L1 ≥1% to atezolizumab plus tiragolumab and atezolizumab alone. Patients in the atezolizumab plus tiragolumab arm achieved higher ORR (ORR 37% versus 21%), although the benefit was mainly driven by the PD-L1 ≥50% subgroup (ORR in PD-L1 ≥50% 69% versus 24%) (153). However, Roche recently reported that the phase III SKYSCRAPER-01 study, assessing tiragulomab plus atezolizumab versus atezolizumab alone for patients with PD-L1 high, EGFR/ALK negative, treatment naïve, advanced NSCLC, did not meet the co-primary end point of PFS (154). Apart from TIGIT, antibodies blocking other co-inhibitory immune checkpoints such as LAG3, TIM3 and VISTA and activating co-stimulatory receptors such as OX-40, ICOS, CD137 and GITR, are now studied in early-phase trials, either in monotherapy or in combination with anti-PD-(L)1 antibody (Table 5).

Combination with anti-VEGF

Abnormal vasculature is a hallmark of cancer. Anti-angiogenesis agents can potentially modulate an immunosuppressive TME and enhance trafficking as well as tumour infiltration of immune cells (155).

Despite the proven synergism between anti-PD-(L)1 and anti-vascular endothelial growth factor (VEGF) in multiple cancer types, such evidence is more controversial in NSCLC (156-158). The IMpower150 study was a positive trial showing improved PFS and OS in patients who received atezolizumab-bevacizumab-chemotherapy compared to bevacizumab-chemotherapy, but this study did not directly answer the question whether bevacizumab had added value on top of PD-L1 blockade (134). LEAP-007 randomized patients with untreated, EGFR/ALK negative, PD-L1 TPS ≥1% advanced NSCLC to pembrolizumab versus pembrolizumab plus lenvatinib. This was a negative study (OS 14.1 versus 16.4 months, HR 1.10, OS numerically lower in pembrolizumab/lenvatinib arm) (159). However, Reckamp et al. recently reported in a phase II study in which patients who were previously treated with ICI and platinum-based chemotherapy, OS was significantly improved with pembrolizumab plus ramucirumab compared to chemotherapy of physician’s choice [OS 14.5 versus 11.6 months, HR 0.69 (80% CI: 0.51–0.92)] (160). This suggested that antiangiogenic agents did resensitize tumours to ICI in a certain subset of patients. Ongoing clinical studies with biomarker analyses will further define patients who may potentially benefit from antiangiogenic agents (Table 5).

Cancer vaccines

Low tumour neoantigen expression and defective antigen presentation are two fundamental reasons of impaired T cell activation and ICI failure. Cancer vaccine primarily works by enhancing antigen-specific T cell antitumour responses. Most cancer vaccines tested in lung cancer clinical trials utilized tumour-associated antigens (TAAs), such as melanoma-associated antigen-A3 (MAGE-A3) and mucin 1 (MUC-1), self-antigens that are commonly overexpressed but not uniquely expressed on tumour cells. Two phase III studies, MAGRIT and START, evaluated MAGE-A3 vaccine and MUG1 antigen vaccine versus placebo respectively in the adjuvant setting. Both studies failed to report survival benefit with the study treatment (161,162).

Following the disappointing results of single-antigen vaccination, clinical research now focuses on multiple-antigen vaccination and personalized antigen vaccination. In the first part of the phase III ATALANTE-1 randomised trial, OSE-2101, a HLA-A2 restricted neoepitope vaccine targeting five TAAs (CEA, HER2, MAGE2, MAGE3, and P53) expressed on lung cancer cells, achieved superior OS over standard-of-care second-line chemotherapy in patients failing platinum-based chemotherapy and anti-PD-(L)1 treatment (163). Part 2 is now ongoing and will enroll 363 participants with OS as the primary endpoint (NCT02654587). Personalized antigen vaccination is constructed by whole exome and RNA sequencing of the tumour and identification of personalized immunogenic neoepitopes based on bioinformatic algorithms (164). In a phase Ib study, response rate was 39% with no extra safety signals reported in 18 patients in the NSCLC cohort who received NEO-PV-01 (a personalized neoantigen vaccine) concurrently with nivolumab (165). Multiple studies on personalized cancer vaccine are now ongoing either as monotherapy or given in combination with ICIs (Table 5).

Adoptive cellular therapy

Given the vital role of T cell in antitumour immunity, adoptive cellular therapy (ACT) developed to date has mainly focused on T cell therapy, although other cellular therapies (e.g., NK cell, B cell, macrophage) have demonstrated therapeutic potentials as well. Similar to cancer vaccine, the objective of ACT is to generate tumour-specific, activated immune cells (166). Adoptive T cell therapy includes tumour-infiltrating lymphocyte (TIL) therapy, T-cell receptor (TCR)-engineered T cell therapy and chimeric antigen receptor T-cell (CAR-T) therapy. TILs are polyclonal T cells isolated from patient’s tumour tissue, expanded ex-vivo and reinfused into the patient after lymphodepletion. In a recent phase I trial, TIL therapy was administered with nivolumab in 20 patients with advanced NSCLC upon progression on anti-PD-(L)1 treatment. The study met the end point of safety. Objective response was noted in three out of thirteen evaluable patients including two with durable complete responses (167). In TCR-engineered T cell and CAR-T cell therapy, autologous T cells are isolated from peripheral circulation followed by ex-vivo transduction of a tumour-antigen specific TCR or CAR (166). Despite its tremendous success in treating haematological malignancies, CAR-T for solid tumour treatment proves to be challenging due to factors like poor tumour infiltration, immunosuppressive TME, and off-target toxicities (168). Innovative approaches have been evaluated to overcome these resistance mechanisms. For instance, gene-edited T cells may enhance both safety as well as antitumour efficacy. In a phase I first-in-human study, CRISPR-Cas9 PD-1-edited T cells were safely given to 12 patients with advanced NSCLC without severe toxicities (169). Combination of cellular therapy with other modalities of immunotherapy, such as PD-L1 blockade or cytokine therapy, may further potentiate the therapeutic efficacy of tumour-specific immune cells (170,171).

Targeting tumour microenvironment, cytokine, and gut microbiota

Cytokines are pivotal in modulating immune cell function and thus have been actively investigated in enhancing antitumour efficacy of immunotherapy. This concept is supported by the fact that a minority of patients with melanoma and renal cell carcinoma achieved durable responses with high dose interleukin-2 (IL-2) therapy (172,173). A phase I study showed that the combination of NKTR-214 (a prodrug of polyethylene glycol (PEG)-conjugated IL-2) and nivolumab was safe and efficacious (three out of five patients with NSCLC achieved RECIST response) in immunotherapy-naïve patients with various cancer types including NSCLC (174,175). A global dose escalation study for treatment-naïve lung cancer patients is ongoing (NCT03138889). Another phase I study evaluated the combination of nivolumab and ALT-803, a modified IL-15/IL-15Rα/IgG1 Fc complex in patients with anti-PD-L1 antibody refractory NSCLC (NCT02523469). Twenty-one patients received study treatment and ORR was 29% (176).

Canakinumab, an anti-IL-1B monoclonal antibody, has been studied in multiple phase II and III studies after a significant reduction in lung cancer incidence and mortality was observed in the large scale CANTOS study which investigated the role of IL-1B in atherosclerosis (177). However, both the phase III CANOPY-1 (pembrolizumab plus chemotherapy with or without canakinumab in untreated metastatic NSCLC, NCT03631199) and CANOPY-2 (docetaxel with or without canakinumab in pretreated NSCLC) studies failed to improve PFS and OS (178,179). CANOPY-A and CANOPY-N are ongoing studies evaluating the drug in the neoadjuvant and adjuvant setting in early staged disease (NCT03447769, NCT03968419).

A multitude of enzymatic pathways and cellular components are associated with an immunosuppressive TME. These molecules have been explored as therapeutic targets in hope to modulate the TME and enhance immune activity. Histone deacetylase (HDAC) alters gene expression via epigenetic regulation and HDAC inhibitors are found to promote pro-immune activity within the TME. Two phase II studies reported antitumour activity and acceptable safety profile of HDAC inhibitor and anti-PD-(L)1 combination in patients with PD-(L)1 resistant/refractory NSCLC (180,181). Further clinical studies are warranted to select patients who may benefit from this drug combination. Other targets of interest, including indoleamine 2,3-dioxygenase (IDO), RORγ, AXL, MEK, PARP and CD73, are now being studied in early phase clinical trials enrolling NSCLC patients (Table 5).

Lastly, gut microbiota has emerged as a potential immune mediator that may affect clinical response to ICI treatment. Preclinical studies showed that a favourable gut flora composition is predictive of ICI response and modulation of gut flora may reverse ICI resistance (182). This strategy is now tested in prospective trials for patients with ICI failure, mainly by introducing favourable gut flora via faecal microbial transplantation and ICI rechallenge.

Immunotherapy in advanced NSCLC: future direction

Although the adoption of PD-L1 blockade has marked a new milestone of NSCLC management, ICI resistance and lack of predictive biomarker remain two major challenges. While various resistance models have been proposed, ICI resistance in reality is likely multifactorial and methods for ascertaining ICI resistance mechanisms are currently lacking. Combinational immunotherapy approaches targeting different phases of antitumour immunity have shown encouraging signals. However, most of these approaches were not tested in a biomarker-based fashion, which might explain the failure of some phase II/III trials despite favourable results seen in early phase studies. More translational research is required to identify predictive biomarkers of ICI response or resistance. Advances in diagnostic and analytic tools like multiomic analysis, single cell sequencing, and deep learning approaches, may offer further insight into the dynamic interaction between the host immune system, cancer cells and TME.

Strengths and limitations of this review

This review offers a succinct overview in the latest update in targeted therapy and immunotherapy for NSCLC management, identified resistance mechanisms, and current research direction to overcome treatment resistance and further improve treatment outcome. Owing to the breadth of the topic, some sections cannot be discussed in depth. While the authors agree that the advances in molecular diagnostics and biomarker research is also crucial for the successful development of novel therapeutics, this topic is beyond the scope of this review.

Conclusions

Deeper understanding of the molecular and immune biology of NSCLC has led to rapid development of targeted therapy and immunotherapy in this field. The indications of targeted therapy and immunotherapy have now extended to early staged NSCLC as randomized studies have confirmed that these agents reduce disease recurrence. Comprehensive genomic profiling at diagnosis of advanced disease maximizes the chance for patient to benefit from highly efficacious molecular therapies. At the time of treatment resistance, next generation molecular therapies and novel drug combinations tailored to specific resistance mechanisms may now be considered. Currently, only a minority of patients experience durable clinical benefit with immunotherapy and innovative strategies targeting various immune resistance mechanisms have yielded early promise. As the therapeutic landscape of NSCLC is becoming increasingly complex, identification of predictive and resistance biomarkers is key to success in future drug development. The importance of multiomic profiling and translational studies alongside clinical trials cannot be overemphasized.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Calvin S. H. Ng) for the series “Lung Cancer Management—The Next Decade” published in Annals of Translational Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-4444/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4444/coif). The series “Lung Cancer Management—The Next Decade” was commissioned by the editorial office without any funding or sponsorship. MSCL reports honoraria as a speaker for Novartis and advisory fees from Pfizer. KKSM reports reimbursement for travel expenses for ESMO course. TSKM reports research grants (paid to institution) from AstraZeneca, Bristol Myers Squibb, Pfizer, Roche, Novartis, SFJ Pharmaceuticals, MSD, G1 Therapeutics, Takeda, XCovery and Merck Serono; consulting fees from Amoy Diagnostics, Boehringer Ingelheim, Amgen, Bristol Myers Squibb, C4 Therapeutics, Curio Science, Daiichi Sankyo, Eisai, Gilead Sciences, Guardant Health, Ignyta, Inivata, Janssen, Lunit USA, Lucence Health, MSD, MoreHealth, Origimed, Pfizer, Qiming Development (HK), Sanofi-Aventis, Takeda Pharmaceuticals, Yuhan Corporation, Berry Oncology, AstraZeneca, BeiGene, Blueprint Medicines, Alpha Biopharma, Covidien LP, CStone Pharmaceuticals, D3 Bio Ltd., Fishawack Facilitate, Elevation Oncology, Gritstone Oncology, Hengrui Therapeutics, Incyte Corporation, IQVIA, Lilly, Loxo-Oncology, Merck Serono, Mirati Therapeutics, Novartis, OSE Immunotherapeutics, Puma Biotechnology, Roche Pharmaceuticals, SFJ Pharmaceutical and Vertex Pharmaceuticals; speaker fees from ACEA Pharmaceuticals, Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals Inc., Daiichi Sankyo, Fishawack Facilitate, Janssen, Lucence Health, Medscape LLC, Merck Sharp & Dohme, OrigiMed Co., Ltd., PeerVoice, Pfizer, Research to Practice, Sanofi-Aventis, Liangyihui Network Technology, Takeda Oncology, Alpha Biopharma, Amoy Diagnostics, BeiGene, Bristol Myers Squibb, Daz Group, InMed Medical Communication, Lilly, MD Health Brazil, Merck, Novartis, P. Permanyer SL, Physicians’ Education Resource, PrIME Oncology, Roche Pharmaceuticals/Diagnostics/Foundation One, Shanghai BeBirds Translation & Consulting, Taiho Pharmaceutical and Touch Independent Medical Education; he serves as the Advisory Board Member for AbbVie, Amgen, Berry Oncology, Boehringer Ingelheim Pharmaceuticals, C4 Therapeutics, CStone Pharmaceuticals, D3 Bio Ltd., Eisai, G1 Therapeutics Inc., Gritstone Oncology Inc., GeneDecode Co Ltd, Hutchmed, Incyte Corporation, IQVIA, Lilly, Lunit, Merck Sharp & Dohme, Novartis, Puma Biotechnology, Roche/Genentech, SFJ Pharmaceutical, Vertex Pharmaceuticals, Yuhan Corporation, ACEA Pharma, AstraZeneca, Blueprint Medicines Corporation, Bristol-Myers Squibb Company, Covidien LP, Curio Science, Daiichi Sankyo, Fishawack Facilitate, Gilead Sciences, Guardant Health, Hengrui Therapeutics, Ignyta, Inivata, Janssen, Loxo-Oncology, Merck Serono, Mirati Therapeutics, Origimed, Pfizer, Sanofi-Aventis R&D, Takeda and Virtus Medical Group; he serves as the Board of Directors (remunerated) for AstraZeneca PLC, Lunit USA, HutchMed and ACT Genomics-Sanomics Group; he has the leadership role (non-remunerated) in Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Therapy Society (HKCTS), Asian Thoracic Oncology Research Group (ATORG), American Society of Clinical Oncology (ASCO), Chinese Lung Cancer Research Foundation Limited (CLCRF), Hong Kong Cancer Fund (HKCF) and International Association for the Study of Lung Cancer (IASLC). Besides, he holds equities in Aurora Tele-Oncology Ltd., HutchMed and ACT Genomics-Sanomics Group. The authors have no other conflicts of interest to declare.

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