In 2015, the FDA approved osimertinib for the treatment of patients with metastatic EGFR-mutant NSCLC who have acquired the EGFR T790M resistance mutation. The drug was then approved as the 1st-line therapy for advanced EGFR-mutated NSCLC in 2018 (34). Osimertinib is an oral, irreversible EGFR-TKI that is selective for both EGFR and T790M mutations and has activity in the central nervous system (CNS). AURA3 is a randomized, open-label, phase 3 trial that has been conducted to show the superiority of osimertinib over platinum therapy plus pemetrexed in patients with T790M-positive advanced NSCLC after 1st-generation EGFR-TKI therapy. The results showed that the median PFS time was significantly longer with osimertinib than that with platinum therapy plus pemetrexed (10.1 vs. 4.4 months; HR, 0.30; 95% CI, 0.23-0.41; P<0.001), which establish a standard protocol for the treatment of EGFR T790M-positive patients after failure of 1st-generation EGFR-TKI therapy, as well as targeted therapy for brain metastasis (17). The double-blind, phase 3 FLAURA trial compared the efficacy and safety of osimertinib with the standard EGFR-TKIs (gefitinib or erlotinib) in patients with untreated EGFR mutation-positive advanced NSCLC. It demonstrated that the median PFS time of untreated patients with EGFR mutation was significantly longer following osimertinib administration compared with that following gefitinib or erlotinib administration (18.9 vs. 10.2 months; HR, 0.80; 95% CI, 0.37-0.57; P<0.001) (19), as was the median OS time (38.6 vs. 31.8 months; HR, 0.46; 95% CI, 0.64-1.00; P=0.046) (35). In patients with measurable brain metastases, the objective response rate (ORR) was 91% with osimertinib versus 68% with the 1st-generation EGFR-TKIs (odds ratio, 4.6; 95% CI, 0.9-34.9; P=0.066) (36). Several studies have investigated the safety and efficacy of EGFR-TKIs in combination with other targeted therapies (37-39). The phase Ib TATTON study assessed the safety and tolerability of osimertinib in combination with selumetinib (MEK inhibitor), savolitinib [hepatocyte growth factor receptor (MET) inhibitor] or durvalumab, a human anti-programmed cell death-ligand-1 (PD-L1) antibody. The ORR in the selumetinib, savolitinib and durvalumab arms was 42, 44 and 43%, respectively (39).

Overall, osimertinib is a promising 3rd-generation EGFR-TKI in current lung cancer treatment regimens, and osimertinib-based combination therapy deserves broad investigations to improve outcomes in patients with advanced EGFR-mutated NSCLC.

Rociletinib (CO1686) is a small-molecule, orally administered and irreversibly selective EGFR-TKI that inhibits EGFR mutations, including Ex19del, L858R and T790M, but not exon 20 insertion (e20ins) (26). The TIGER-X trial (phase I/II study) and the TIGER-2 trial (phase II, open-label, multi-center study) evaluated the safety and efficacy of rociletinib in previously treated patients with EGFR-mutated NSCLC. A total of 130 patients were enrolled in the TIGER-X study. Of the 46 evaluable T790M patients, the ORR was 59% (95% CI, 45-73), and the estimated median PFS time was 13.1 months (95% CI, 5.4-13.1) (26). However, results of the TIGER-X and TIGER-2 trials using a pooled cohort of patients found that the rate of confirmed response was 28-34% for rociletinib, which significantly differed from the result of the TIGER-X trial. After independent analysis, the maturation confirmation response rate was updated to 45% and the median PFS time to 6.1 months (20). Sequist et al (40) reported that 9 patients with progression on rociletinib were subsequently treated with osimertinib. Among them, 2 patients exhibited a partial response, 3 presented with stable disease and 4 developed progressive disease. The 3 patients with brain metastasis after rociletinib treatment also showed improvement in CNS disease response to osimertinib. The development of rociletinib was terminated on May 6, 2016, due to a lower efficacy than osimertinib and incidences of adverse events such as high-grade hyperglycemia and corrected QT interval prolongation (41).

Abivertinib (AC0010) is one of the 3rd-generation EGFR-TKIs developed in China; it is a pyrrolopyrimidine compound, which is highly selective, irreversible and potent (42). A phase I study of abivertinib presented significant clinical benefits and a good safety profile in patients with NSCLC and acquired resistance to the 1st-generation EGFR-TKIs. The ORR in patients with T790M mutation was 42%, and the median PFS time estimated by Kaplan-Meier ranged between 14.0 and 35.6 weeks in those patients receiving a daily dose of 350-600 mg (42). A phase I, open, multicenter study explored the efficacy of abivertinib in patients with NSCLC and CNS metastasis. The median intracranial PFS time was 142 days (95% CI, 31.1-252.9) in 7 patients with brain metastasis, suggesting that abivertinib had good control of asymptomatic brain metastasis (43). A recent study reported that 9 patients received osimertinib treatment after progression on abiverinib, with a median total treatment duration of 15.9 months (95% CI, 12.5-19.3) (27). These results have demonstrated that osimertinib might be an option for subsequent therapy in patients with disease progression after abivertinib treatment. Further studies on abivertinib are required to investigate its interaction with osimertinib.

Several other 3rd-generation EGFR-TKIs are also under development. Nazartinib (EGF816) is a covalent and irreversible EGFR-TKI. Preliminary results from an open-label, multicenter, phase I/II study of 180 patients at 9 academic medical centers in Europe, Asia and North America demonstrated that nazartinib had an excellent safety profile, with low dermal toxicity and a primary adverse event of maculopapular rash (40%) (28). Olmutinib (HM61713), approved by the FDA in December 2015 for the treatment of NSCLC, has potent inhibitory activity against L858R/T790M mutant NSCLC cells (44). In a recently published single-arm, open-label, phase I/II trial, EGFR T790M-positive patients receiving olmutinib (800 mg/day) had an ORR of 55% (38/69 evaluable patients; 95% CI, 42.6-67.1) and an estimated median PFS time of 6.9 months (95% CI, 5.6-9.7). The common adverse events included diarrhea (59%), pruritus (42%), rash (41%) and nausea (40%) (29). On September 30, 2016, two cases of toxic epidermal necrolysis/Stevens-Johnson syndrome, one of which was fatal, were reported in a phase II trial of olmutinib in South Korea. On April 13, 2018, the development of olmutinib was terminated (41). Alflutinib (AST2818) is a newly developed 3rd-generation EGFR-TKI; its ORR was 77% (89 out of 116 patients), and 9% of patients (11 out of 130 patients) experienced grade 3 or higher drug-related adverse events (30). Almonertinib, a 3rd-generation EGFR-TKI developed in China, has also shown good efficacy in the treatment of T790M-positive NSCLC after EGFR-TKI resistance. In a phase II trial, it exhibited a median PFS time of 12.3 months, an ORR of 69% and acceptable toxicity. On March 19, 2020, almonertinib was approved by the Center for Drug Evaluation of the China National Medical Products Administration (31). Phase I/II clinical studies on lazertinib showed that lazertinib had a favorable safety profile and exhibited promising antitumor activity in patients with EGFR T790M-positive NSCLC, with a median PFS time of 11.0 months and an ORR of 58%. Lazertinib was approved for EGFR T790M-positive NSCLC in South Korea in 2021 (21,32). Naquotinib has anti-tumor activity in preclinical models of EGFR-mutant NSCLC that targets mutant EGFR, including EGFR T790M. In phase I trials, it had an ORR of 31% against T790M-positive NSCLC. However, the phase III clinical trial of naquotinib was terminated due to toxicity and limited predicted efficacy (24,33). Further investigations on 3rd-generation EGFR-TKIs are still ongoing.

EGFR e20ins occur in ~3% of lung adenocarcinoma patients and 9% of EGFR-mutated tumors. EGFR e20ins block EGFR-TKI binding to EGFR target sites, leading to primary resistance (45). For patients with EGFR e20ins, the overall effectiveness of 1st-line treatment with 1st- and 2nd-generation EGFR-TKIs is 3-8%, with a median PFS time of only 2 months. An in vitro study showed that NSCLC cells stably expressing EGFR e20ins were resistant to the 3rd-generation EGFR-TKIs, suggesting that EGFR e20ins might be primary mechanisms of 3rd-generation EGFR-TKI resistance (46). Qin et al (47) demonstrated that p.A767_V769dup (25%) and p.S768_D770dup (18%) were the 2 most common EGFR e20ins, accounting for 44% of cases and serving as primary targets for future drug development. In addition, different EGFR e20ins might be associated with different outcomes in patients with advanced NSCLC. p.A763_Y764insFQEA conferred better PFS times than the other e20ins when patients were treated with various EGFR-TKIs, while p.S768_D770dup showed a limited response and p.D770delinsGY patients experienced a short PFS time. Therefore, it is important to select the appropriate EGFR-TKIs according to the specific EGFR e20in type (47). van Veggel et al (48) reported that osimertinib (80 or 160 mg/day) treatment had an ORR of 5% and a median PFS time of 3.6 months (95% CI, 2.6-4.5) in 21 patients with advanced NSCLC and EGFR e20ins (48). Phase II clinical studies on osimertinib for EGFR e20ins in NSCLC are currently underway (NCT03414814 and NCT03191149).

BIM is a member of the BCL-2 family and a pro-apoptotic molecule. The BIM deletion polymorphism is present in ~21% of East Asian individuals, and is absent in African and European populations (49,50). Tanimoto et al (51) demonstrated that EGFR-mutant NSCLC cells with BIM deletion polymorphism were resistant to 3rd-generation EGFR-TKIs. Li et al (49) first reported that a patient with NSCLC plus the EGFR L858R/T790M mutation and the BIM deletion polymorphism exhibited a poor clinical outcome after treatment with osimertinib (49). In addition, another study indicated that the median PFS time of patients with BIM deletion polymorphism was significantly shorter than that of wild-type BIM patients (227 vs. 533 days; P<0.001). Multivariate Cox regression analysis showed that the BIM deletion polymorphism was an independent indicator of shorter PFS time (52). However, Liu et al (53) concluded that it was the concomitant genetic alterations, rather than BIM deletion polymorphism, that influenced the EGFR-TKI response. Cox multivariate regression analysis showed that TP53 mutations, NTRK1 mutations and amplifications, RB1 mutations and PIK3CA mutations were associated with poorer PFS. In addition, TP53 mutations, KEAP1 mutations and deletions were shown to have an impact on OS in patients treated with EGFR-TKI. By contrast, neither analysis showed an effect of BIM deletion polymorphisms on PFS and OS (53). The roles of BIM deletion polymorphism in the prediction of EGFR-TKI responses are still controversial. Further studies are required to explore the exact functions of BIM deletion polymorphism in the primary resistance of 3rd-generation EGFR-TKIs.

Patients enrolled in the AURA3 study all developed the T790M mutation after the 1st-line treatment with 1st- or 2nd-generation EGFR-TKIs, and 49% (36/73) of them had loss of T790M after osimertinib resistance (54). The frequency of T790M mutation loss in osimertinib-resistant patients in the studies by Le et al (56) and Oxnard et al (57) was 53% (21/40) and 68% (28/41), respectively. Oxnard et al (57) conducted tumor biopsies for genomic analysis in 41 patients, and suggested that the loss of T790M was associated with a small decrease in EGFR-activating mutations after 1-3 weeks of treatment. Another recent study demonstrated a markedly shorter median PFS time in the T790M-loss group than that in the T790M group (5.93 vs. 11.87 months, P=0.0004). Loss of T790M mutation was correlated with earlier disease progression and worse survival in the osimertinib-resistant patients (70). In addition, the loss of T790M was present in 50% (6/12) of patients resistant to rociletinib (71). In T790M cases, the resistant mechanism is mostly related to C797S mutation or bypass pathway activation, while patients without T790M often show EGFR-independent mechanisms (56,71).

Le et al (56) demonstrated that EGFR amplification occurred in 8 (19%) of 42 patients who developed resistance to osimertinib (56). One patient with progression after osimertinib treatment developed amplified copies of EGFR Ex19del, with amplification levels parallel to clinical and radiological progression (72). EGFR amplification is more commonly observed in patients treated with rociletinib. Piotrowska et al (71) reported that 25% (3/12) of patients resistant to rociletinib showed EGFR amplification. This was comparable to 29% (17/58) in the study by Helman et al (63). In addition, EGFR amplification in 7 (23%) patients was considered as putative mechanisms of abivertinib resistance. Among them, 4 patients had EGFR amplification after abivertinib treatment, and the other 3 had EGFR amplification prior to treatment but had elevated EGFR copy numbers at progressive disease (61).

FGFR signaling pathways regulate cell proliferation, migration, cycle progression, metabolism and survival (76). Kim et al (77) found that FGFR1 amplification and FGF2 expression were upregulated in patients resistant to osimertinib, suggesting that the FGF2-FGFR1 autocrine loop might be associated with osimertinib resistance (77). The plasma-based circulating tumor DNA (ctDNA) assay revealed that the FGFR3-TACC3 fusion mutation was present in patients with the T790M mutation, and disease progression occurred upon osimertinib and naquotinib treatment (78). These results suggested that abnormalities of the FGFR signaling pathway might contribute to 3rd-generation EGFR-TKI resistance.

IGF1R is present in numerous cell types in various tissues, such as muscle, cartilage, bone and brain; it is a tyrosine kinases receptor that is involved in the pathogenesis and progression of various malignancies, including lung cancer (79). Abnormalities of IGF1R confer resistance to 3rd-generation EGFR-TKIs by activating the EGFR bypass signaling pathway (79). Manabe et al (80) demonstrated for the first time that IGF2 autocrine-mediated activation of the IGF1R pathway in lung cancer cells was involved in osimertinib resistance. Immunohistochemistry confirmed the increased IGF2 expression in lung cancer patients with acquired osimertinib resistance (80). Phosphate-receptor tyrosine kinase array analysis of osimertinib-resistant cells showed that IGF1R was activated in PC9/T790M/AZDR and H1975/AZDR cells. Inhibition of IGF1R activation by small interfering RNA or linstinib (IGF1R inhibitor) significantly restored osimertinib sensitivity, suggesting that aberrant IGF1R activation might be one of the causes of 3rd-generation EGFR-TKI resistance (79).

AXL is a member of the receptor tyrosine kinases, which are involved in the regulation of cell survival, proliferation, migration and metabolism. A study by Taniguchi et al (81) demonstrated that the overexpression of AXL was associated with a poor response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting the feedback inhibition of SPRY4. Activated AXL interacted with EGFR and HER3 to maintain cell survival and induced osimertinib resistance, which could be delayed by AXL inhibitors (81). Another study demonstrated that AXL was upregulated in osimertinib-resistant lung adenocarcinoma cells. Osimertinib combined with cabozantinib (AXL inhibitor) inhibited the growth of these cells both in vitro and in vivo (82). In addition, AXL amplification was also detected in abivertinib-resistant patients (61). Therefore, AXL activation and AXL amplification might also contribute to the primary and acquired resistance to 3rd-generation EGFR-TKIs.

Marcoux et al (84) reported that 19 NSCLC patients developed SCLC transformation after treatment with the 3rd-generation EGFR-TKIs. The median time of transformation was 17.8 months (95% CI, 14.3-26.2) and the median survival time after SCLC transformation was 10.9 months (95% CI, 8.0-13.7). The incidence of squamous cell carcinoma (SCC) transformation after the 1st- and 2nd-line osimertinib treatment was 15 and 14%, respectively (85). SCLC and SCC transformation have not yet been identified in vitro, suggesting that the tumor microenvironment might play potential roles in these processes. The transdifferentiation of epithelial cells into mesenchymal cells, a process known as EMT, involves the loss of epithelial cell markers, such as E-cadherin, and the acquisition of mesenchymal markers, such as vimentin, N-cadherin, fibronectin, β-catenin and zeb-1, which confers on cancer cells increased tumor-initiating and metastatic potential (86). Nukaga et al (87) demonstrated that osimertinib- and rociletinib-resistant H1975 cells exhibited a shuttle cell-like morphology and acquired a more mesenchymal phenotype in vitro. NSCLC cells from patients with acquired osimertinib resistance were reported to exhibit EMT features, including decreased epithelial junction proteins and increased mesenchymal markers, confirming that EMT was closely associated with 3rd-generation EGFR-TKI resistance (88). Therefore, in addition to liquid biopsy to clarify the relevant mutant genes, it is also important to clarify the presence of histological/phenotypic transformation by tissue biopsy in osimertinib-resistant patients.

The AURA3 and FLAURA studies demonstrated that the frequency of cell cycle gene alterations was 11 and 12%, respectively, in patients with disease progression after osimertinib treatment as the 1st- or 2nd-line therapy (54,59). Both CCNE1 and CDK6 amplification occurred at a frequency of 7% (5/73) as the most common cell cycle gene alterations in the AURA3 study (54). The most common cell cycle gene alteration in the FLAURA study was CDK6 amplification (3%) (59). In the study by Le et al (56), CCND1, CCNE1 and CDKN2A deletions were also found. Alterations in cell cycle genes may be involved in the development of osimertinib resistance.

RET-ERC1 and NTRK1-TPM3 gene fusions were found in osimertinib-resistant patients in the AURA3 study (54). ALK gene fusion was detected in the FLAURA study (59). Schrock et al (89) identified BRAF, ALK, RET and FGFR3 gene fusions in 31 patients with osimertinib resistance. One of the patients with the T790M mutation had disease progression after osimertinib treatment. Analysis of tumor and blood-based ctDNA samples by NGS revealed a PLEKHA7-ALK gene fusion. Combined treatment of osimertinib and the ALK inhibitor alectinib alleviated the disease. A blood-based ctDNA test 4 months later revealed the disappearance of the PLEKHA7-ALK gene fusion (89). Batra et al (90) reported the case of a patient who developed echinoderm microtubule-associated protein like 4-ALK fusion after osimertinib resistance, and revealed that further treatment with the combination of osimertinib and alectinib was effective, suggesting that the oncogenic gene fusion might contribute to EGFR-TKI resistance (90).

When EGFR C797S and T790M mutations are in the trans structure (on separate alleles; 10%), the tumor is resistant to 3rd-generation TKIs, but sensitive to combined therapy with 1st- and 3rd-generation TKIs (105). Erlotinib combined with osimertinib was effective for a patient developing T790M and C797S trans mutations after osimertinib treatment. However, resistance reappeared 3 months later and liquid biopsies showed T790M and C797S mutations in cis (106). An ongoing phase I/II study investigated the safety and efficacy of osimertinib plus gefitinib as the 1st-line treatment for EGFR-mutated NSCLC. The adverse events were tolerable, and the ORR was 85.2% (95% CI, 67.5-94.1), consistent with the 1st-line ORR to osimertinib. The median PFS time was not yet reached (107).

In vitro studies have shown that NSCLC cells with EGFR Ex19del/C797S mutation and without EGFR T790M mutation are resistant to 3rd-generation EGFR-TKIs, but remain sensitive to 1st- or 2nd-generation EGFR-TKIs (105). One patient with EGFR Ex19del/C797S mutation had a partial tumor remission after gefitinib treatment (108). Rangachari et al (109) demonstrated that osimertinib-resistant NSCLC with EGFR C797S mutation responded transiently to the 1st-generation EGFR-TKIs, but acquired EGFR T790M/C797S mutation eventually (109). Yang et al (110) reported that afatinib was effective against EGFR L858R/L718Q mutation with T790M loss after osimertinib resistance, indicating that 2nd-generation EGFR-TKIs might be promising agents for selected osimertinib-resistant patients.

For drug resistance caused by RAS/RAF/MEK/ERK signaling pathway activation, 3rd-generation EGFR-TKIs combined with MEK inhibitors are potential therapeutic strategies. Preclinical studies demonstrated that the combination of osimertinib and selumetinib overcame the resistance caused by KRAS amplification and overexpression (83). In another in vitro study, MEK inhibitors restored the sensitivity of EGFR ex19del/T790M/C797S-mutated PC9 cells to osimertinib by modulating MEK/ERK-dependent degradation of BIM and MCL-1 (117). Osimertinib and MEK/ERK inhibitors synergistically promoted apoptosis and inhibited survival in osimertinib-resistant cells, and this combination could delay the emergence of osimertinib resistance both in vitro and in vivo (118). In 2017, the FDA approved the combination of dabrafenib (BRAF V600E inhibitor) plus trametinib (MEK inhibitor) for the treatment of patients with BRAF V600E mutations, with an ORR of 63 and 61%, respectively, for the 1st- and 2nd-line treatments (101). Xie et al (119) demonstrated that osimertinib combined with vemurafenib was effective to overcome BRAF V600E-mediated osimertinib resistance (119). More clinical trials are required to validate the roles of RAS/RAF/MEK/ERK signaling pathway inhibitors in osimertinib-resistant patients.

In a recent study, the 3rd-generation EGFR inhibitor WZ-4002 and the FGFR inhibitor dovitinib synergistically inhibited EMT-mediated resistant cell survival and prevented the generation of resistant clones. It was shown that FGFR signaling is critical for the emergence of mesenchymal-like drug tolerant clones. Dual EGFR plus FGFR inhibition might be a promising strategy to avoid resistance (120). Yochum et al (121) reported that the transcription factor TWIST1 inhibitor harmine and the Bcl-2/BclXL inhibitor ABT737 were able to target the EMT transcription factor TWIST1 in EGFR-mutant NSCLC. The study demonstrated that downregulated TWIST1 and upregulated BIM could overcome EMT- and BIM-mediated drug resistance (121). Another recent study demonstrated that combined treatment with osimertinib and aspirin promoted BIM-dependent apoptosis in osimertinib-resistant lung cancer cells. A retrospective analysis of 45 patients with NSCLC also confirmed that the median PFS time of the osimertinib plus aspirin group was significantly longer than that of the osimertinib alone group (104).

A recent study included 693 patients with EGFR e20ins and uncommon mutations (G719X, L861Q and S768). Afatinib was demonstrated to have broad activity against uncommon EGFR mutations and several e20ins, with an ORR of 60.0 and 24.3%, respectively (122). In vitro studies showed that cetuximab combined with afatinib was specifically sensitive to EGFR e20ins tumors, and this was also confirmed in clinical studies (123-125). Fang et al (123) reported that afatinib and cetuximab achieved long-term disease control in a patient with NSCLC and a rare EGFR e20ins. Poziotinib is a potent inhibitor of EGFR and HER2 e20ins mutations; it can effectively inhibit EGFR e20ins cells in vitro with 100-fold greater potency than osimertinib. In a phase II clinical study, the ORR of poziotinib in patients with NSCLC and EGFR e20ins was 64%, and the median OS was not achieved (46). In addition, the promising clinical activity of amivantamab and mobocertinib (oral EGFR/HER2 inhibitor) in ongoing phase I/II studies also provides hope for the treatment of patients with EGFR e20ins in future (126,127).

A retrospective analysis showed that anti-programmed cell death-1 (PD-1) monotherapy was poorly effective in EGFR-mutated patients, even for patients with PD-L1 expression ≥50% (131). In phase Ib TATTON study, osimertinib in combination with durvalumab had an ORR of 67% in patients with EGFR T790M mutation. However, the incidence of interstitial lung disease was 38% (132). The osimertinib plus durvalumab combination arm of the TATTON study was suspended due to severe adverse events. Immunotherapy combined with chemotherapy may provide new hope for patients resistant to the 3rd-generation EGFR-TKIs. A recent study reported that combined therapy of toripalimab (anti-PD-1 anti-body) and pemetrexed/carboplatin achieved a partial response for >8 months in a osimertinib-resistant patient. A phase II clinical trial of toripalimab combined with chemotherapy in patients without EGFR T790M mutation achieved an ORR of 50% and a median PFS time of 7.0 months (133). Clinical trials of nivolumab (anti-PD-1 antibody) in combination with chemotherapy or ipilimumab (anti-cytotoxic T lymphocyte-associated antigen-4 antibody) (NCT02864251) and pembrolizumab (anti-PD-1 antibody) in combination with chemotherapy (NCT03515837) in patients who were resistant to the 1st- or 2nd-line treatment of osimertinib are currently underway.

For patients who developed SCLC transformation, chemotherapy after osimertinib resistance is an option. Marcoux et al (84) demonstrated that patients with SCLC transformation had higher response rates to etoposide, cisplatin and paclitaxel. For patients with unknown resistant mechanisms, chemotherapy is still an option. If the patient is asymptomatic or has symptomatic local progression, osimertinib can be combined with local treatment according to National Comprehensive Cancer Network (NCCN) guidelines (134). Furthermore, carboplatin/paclitaxel/bevacizumab/atezolizumab (anti-PD-L1 antibody) are also options for patients who experience systemic progression after osimertinib treatment (135). Whether chemotherapy can delay resistance to the 3rd-generation EGFR-TKIs remains unknown. A study on osimertinib with or without chemotherapy as the 1st-line treatment in patients with EGFR-mutated NSCLC is currently recruiting (NCT04035486).