Annual progress of clinical research on targeted therapy for nonsmall cell lung cancer in 2022

Abstract With the rapid development of lung cancer molecular detection and precision therapy, targeted therapy has covered the entire process of diagnosis and treatment of nonsmall cell lung cancer patients. Overall mortality from lung cancer has decreased significantly over the past 20 years, especially since the introduction of targeted drugs in 2013. In 2022, targeted therapy for lung cancer has developed rapidly. The optimization of treatment modes and the exploration of new target drugs such as antibody‐drug conjugates will broaden the selection range of nonsmall cell lung cancer patients with positive driver genes. This article reviews the latest advances in targeted therapy for driver gene‐positive lung cancer in 2022.


| INTRODUCTION
Nonsmall cell lung cancer (NSCLC) accounts for approximately 85% of pulmonary malignancies and is the leading cause of cancer death [1,2].Currently, it is estimated that up to 69% of patients with advanced NSCLC harbor druggable mutations in numerous genes [3].With the rapid development of molecular detection and precision therapy of lung cancer, targeted therapy has significantly improved the survival rate of NSCLC patients with positive driver genes.This article summarizes the progress made in the field of NSCLC-targeted therapy until the end of 2022 (Table 1).

| EPIDERMAL GROWTH FACTOR RECEPTOR-MUTATED NSCLC
Epidermal growth factor receptor (EGFR) is a protein that drives cell survival, proliferation, and spread.Certain mutations in EGFR lead to protein activation, and some of these mutations are known to be susceptible to agents that bind to and inhibit the protein.The most common EGFR mutations in NSCLC often referred to as "EGFR-sensitizing mutations," are deletions of exon 19 (19Del) and a single amino acid substitution L858R in exon 21 (L858R), which together account for up to 85% of T A B L E 1 Summary of clinical studies in NSCLC with driver gene mutations.STARTRK- Abbreviations: ALK, anaplastic lymphoma kinase; DSR, disease control rate; EGFR, epidermal growth factor receptor; NSCLC, nonsmall cell lung cancer; ORR, objective response rate; PFS, progression-free survival;
EGFRm NSCLC.Meanwhile, the EVAN study was published, demonstrating for the first time a clinically meaningful overall survival (OS) improvement with adjuvant erlotinib compared with chemotherapy in Stage III EGFRm NSCLC, with median OS and 5-year OS rates of 84.2 months and 84.8%, respectively [39].The aboveupdated results further confirm the role of adjuvant targeted therapy.When we see that Stage III patients can achieve such excellent results, we should think that Stage I patients can achieve a higher 5-year survival rate than patients with Stage III.This is may be why more and more pharmaceutical companies and specialists are exploring treatments for patients with Stage I lung cancer, such as ADAURA2 (NCT05120349).
In the precision-assisted setting, a study conducted by Wu et al. [40] demonstrated that molecular residual disease (MRD) detection can predict the prognosis of NSCLC patients after surgery.Two hundred and sixtyone patients with Stage I-III NSCLC were enrolled and 913 peripheral blood samples were successfully tested by MRD assay.In the population, only six patients (3.2%) with undetectable longitudinal MRD relapsed, resulting in a negative predictive value of 96.8%.Correspondingly, the positive predictive value of longitudinally detectable MRD was 89.1%.This study demonstrates the prognostic value of longitudinally undetectable MRD in NSCLC patients after radical surgery for defining a potentially curable population in localized NSCLC.This is a promising direction for precision therapy for early-stage lung cancer patients.

| EGFR TKI monotherapy
In the Chinese Phase III trial FURLONG [4], compared with gefitinib, the third-generation EGFR-TKI furmonertinib in the first-line treatment of NSCLC with sensitive EGFR mutations can significantly prolong the median progression-free survival (PFS) (19.3 months vs. 9.9 months, HR = 0.46) and central nervous system PFS (20.8 months vs. 9.8 months, HR = 0.40).Similarly, other third-generation EGFR-TKIs, aumolertinib, and nazartinib showed promising results in the AENEAS study [5] and NCT02108964, respectively, with the median PFS of aumolertinib and nazartinib being 19.3 and 18.0 months, respectively.These studies have once again verified the value of third-generation EGFR-TKI recommended for the first-line treatment of NSCLC with sensitive EGFR mutations.Nearly 20 months has become the limit of third-generation EGFR TKIs, so a series of combination therapies have followed.

| EGFR-TKIs combination therapy
As for how to optimize the first-line treatment, the combination of EGFR TKIs is mainly explored.The impact of EGFR TKIs plus antiangiogenic therapy, chemotherapy, or bispecific monoclonal antibodies remains in the spotlight.
For EGFR TKI combined with antiangiogenic therapy, AfaBev-CS study was a randomized, open-label, multicenter Phase II trial comparing afatinib plus bevacizumab versus afatinib alone as first-line treatment for EGFR-mutated advanced NSCLC [6].This study failed to show an improvement in PFS with afatinib plus bevacizumab versus afatinib monotherapy (16.3 vs. 16.1 months, HR = 0.87, p = 0.55).Similarly, a Phase II WJOG9717L study [7] showed that first-line treatment with osimertinib plus bevacizumab failed to improve median PFS in patients with sensitive EGFR mutations (22.1 vs. 20.2months, HR = 0.86, p = 0.21).
For EGFR TKIs plus chemotherapy, the Phase II OPAL study [8], the ORR of osimertinib combined with platinum and pemetrexed was 90.9%, and the DCR was 97%, which will be further evaluated in Phase III study FLAURA2 (NCT04035486).
For EGFR TKIs plus bispecific monoclonal antibodies, at the 2022 WCLC conference, amivantamab plus lazertinib showed 100% ORR in untreated EGFRmutated NSCLC.The median follow-up was 22.3 months, median PFS was not reached, and the safety was consistent with other reports [9].

| Management of acquired resistance to EGFR TKIs
Despite the efficacy of highly potent EGFR TKIs, acquired resistance is inevitable and remains a critical unsolved challenge.Broadly speaking, acquired resistance can be classified as "on-target" or "off-target."For "on-target," the most common T790M mutation is the dominant mechanism of acquired resistance to first-/ second-generation EGFR-TKIs, and C797S mutation is associated with the common third-generation EGFR-TKI resistance.For "off-targets," such as MET amplification/ overexpression, HER2 amplification, BRAF mutation, RET fusion, small cell lung cancer (SCLC) transformation, and so forth, there have been a lot of research and exploration in this field.In the following sections, we will highlight recent advances in drug resistance research.The first human study of TROP2 ADC datopotamab deruxtecan (Dato-DXd) showed an ORR of 35% and a median duration response of 9.5 months in the treatment of NSCLC with actionable genomic alterations [42].According to the Phase I U31402-A-U102 study, HER3-DXd achieved an ORR of 39%, a DCR of 68%, and a median PFS of 8.2 months in patients with advanced EGFR-mutated NSCLC who had previously received osimertinib and platinumbased chemotherapy.The most common Grade ≥ 3 treatment-related adverse events (TRAEs) was hematologic toxicity [10].The Phase III study HERTHENA-Lung02 (NCT05338970) is currently ongoing.[11].The ORR was 32% (62/193) in the overall population (IHC 50% and/or FISH 5 + status) and 49% (52/108) in patients with IHC90 + and/or FISH10 + status (i.e., higher levels of proteins and/or mRNAs), and the median PFS was 5.3 months and 7.1 months, respectively.Improved outcomes were observed in patients with higher protein and/or mRNA levels, confirming the need for appropriate MET biomarkerbased patient selection in this population.The efficacy of savolitinib plus osimertinib is being further assessed in the Phase III SAFFRON (NCT05261399) study.Another novel drug is telisotuzumab vedotin (Teliso-V), a humanized monoclonal antibody targeting c-Met.In a Phase I/Ib study (NCT02099058) [12], Teliso-V plus osimertinib was effective in treating advanced NSCLC with MET overexpression after osimertinib resistance.Twenty-five patients received Teliso-V (1.6 mg/kg, n = 7; 1.9 mg/kg, n = 18) plus osimertinib.The ORR was 58% in all patients and 67% at 1.9 mg/kg in NSCLC patients with c-Met overexpression.Teliso-V plus osimertinib was well tolerated, with no dose-limiting toxicities reported.The major obstacle of MET in the future is detection, and detection methods and cut-off values need to be clarified.

| Combination therapy with immune checkpoint inhibitors (ICIs).
The second interim analysis of the Phase III ORIENT-31 study [13] reported at ESMO 2022 revealed that platinum-based chemotherapy plus sintilimab with or without a VEGF inhibitor significantly improved PFS compared with chemotherapy monotherapy.The median PFS was 7.2, 5.5, and 4.3 months for the four-drug combination group (Arm A), sintilimab plus chemotherapy (Arm B), and chemotherapy (Arm C), respectively.The safety profile of the treatment was acceptable, and no new safety concerns were identified.
Sunvozertinib (DZD9008) is an oral EGFR exon 20ins inhibitor developed by a Chinese company.The pooled data of the global multicenter trials (WU-KONG1, WU-KONG2, and WU-KONG6) [14] reported at the 2022 WCLC showed that the ORR of sunvozertinib in 84 chemotherapy failure patients with EGFR exon 20ins mutation advanced NSCLC was 52.4% and 44% for patients with brain metastases (n = 25).The most common Grade ≥ 3 treatment emergent adverse events were elevated creatine kinase (9.2%) and diarrhea (5.5%).The US FDA approved sunvozertinib as a breakthrough treatment in January 2022.The POSITION20 trial which explored high-dose osimertinib in patients with EGFR exon 20 mutation-positive advanced NSCLC, showed modest antitumor activity with a confirmed ORR of 28%, PFS of 6.8 months, and acceptable toxicity [15].

| ANAPLASTIC LYMPHOMA KINASE FUSION
In China, 3%-7% of NSCLC patients have an anaplastic lymphoma kinase (ALK) fusion, which is a common driver of the disease [47].
At the 2022 ESMO Conference, data from the Asian subgroup of the Phase III CROWN study [17] demonstrated that the median PFS (as assessed by BICR) was not reached in the loratinib group and 11.1 months in the crizotinib group (HR = 0.40; 95% CI: 0.23-0.71),and the 3-year PFS rates were 61% and 25%, respectively, further confirming the efficacy of the third-generation ALK-TKI.However, in the J-ALEX study, compared with crizotinib, alectinib did not prolong the OS of Japanese patients (HR 1.03, 95% CI: 0.67-1.58;p = 0.9105), which is likely to be confounded by cross-treatment.The 5-year OS rate was 60.9% (95% CI: 51.4-70.3)for alectinib and 64.1% (95% CI: 54.9-73.4) for crizotinib [18].Alectinib resulted in long-term survival in patients with advanced ALKpositive NSCLC, and although no OS extension was observed relative to crizotinib, it remains the standard of care for patients with advanced ALK-positive NSCLC.
In March 2022, a Phase II study (NCT03909971) reported results of lorlatinib in Chinese patients with previously treated ALK-positive advanced NSCLC.A total of 47 patients were previously treated with crizotinib (70.1%, 95% CI: 57.7-80.7,p < 0.0001) and 20 patients were previously treated with an ALK-TKI other than crizotinib (47.6%, 95% CI: 32.0-63.6)achieved an objective response [19].The National Medical Products Administration (NMPA) approved loratinib in April 2022 for the treatment of patients with ALK mutation-positive advanced NSCLC who were previously treated with an ALK inhibitor.
At present, ALK-TKI therapy presents a positive pattern of "three generations under one roof."More efficient and less toxic new-generation ALK inhibitors and combination therapy are expected to further improve the survival of ALK-positive patients.

| MET1EXON SKIPPING MUTATION (METEX14+)
MET14 exon skipping mutations (METex14+) are considered to be independent oncogenes of lung cancer, with an overall incidence of 3%-4% in NSCLC [49].Currently, several MET TKIs (capmatinib and tepotinib) are approved globally for the treatment of METex14+ NSCLC.The only MET inhibitor approved in China is savolitinib.
ELCC 2022 updated final OS and subgroup analysis of savolitinib in METex14+ NSCLC patients.In 36% of patients with pulmonary sarcomatoid carcinoma, 21% of patients with brain metastases and 60% of patients who had previously received savolitinib, ORR was 47.1%, PFS was 6.9 months and median OS was 12.5 months; The median PFS was 7.0 months and the median OS was 17.3 months in patients with non-PSC NSCLC; the median PFS was 7.0 months and the median OS was 17.7 months in patients with brain metastases [20].
The Phase II VISION trial (NCT02864992) included patients who had previously received less than secondline therapy and allowed recruitment of patients with asymptomatic brain metastases.Tepotinib-treated ME-Tex14+ patients had an ORR of 54.7%, a median PFS of 13.8 months and a median OS of 18.8 months [21].A new drug application was submitted for tepotinib in China in March 2022.
In the GLORY study [22], presented at the 2022 AACR Congress, patients who had previously received no more than two systemic therapies, such as chemotherapy and immunotherapy, received glumetinib (SCC-244).The ORR was 60.9% for overall patients, 66.7% for treatment-naïve patients, and 51.9% for previously treated patients.A priority review for SCC-244 was conducted in China on February 25, 2022.

| HER2 MUTATION
In January 2022, the DESTINY-Lung01trial demonstrated clinically significant antitumor activity of trastuzumab deruxtecan (also known as T-DXd or Enhertu) in patients with HER-2-mutant NSCLC.A total of 91 patients were enrolled, the ORR was 55%, median duration of response (DoR) was 9.3 months, median PFS was 8.2 months, and the median OS was 17.8 months [23].Also, in the Phase II clinical trial DESTINY-Lung02 [50], T-DXd in metastatic NSCLC with HER2 mutations showed an ORR of 53.8% and a median DoR of 8.7 months.On August 11, 2022, the FDA approved T-DXd for the treatment of advanced NSCLC with HER2 mutations.
At the 2022 WCLC, results of the first Phase I trial conducted in Chinese lung cancer patients with BRAF mutations were presented.A 75% ORR and a manageable safety profile were demonstrated with dabrafenib plus trametinib [24].
The NMPA-approved dabrafenib combined with trametinib for the treatment of BRAF V600 mutationpositive NSCLC in March 2022, becoming the first approved combination therapy in China.

| RET FUSION NSCLC
The frequency of RET fusions in NSCLC is 1%-3% [52].According to the ARROW study reported at ESMO 2022, pralsetinib had an ORR of was 83% in treatment-naïve patients and 82% in patients who had previously received platinum-based chemotherapy, while median PFS was 12.6 and 16.4 months, respectively.These data suggest that pralsetinib is able to provide clinical benefit in the majority of NSCLC patients with RET fusions [25].
Based on the updated data from the LIBRETTO-001 trial, selpercatinib had an ORR of 84.1% in 69 treatmentnaïve patients, with a median PFS of 22.0 months and a median DoR of 20.2 months; in 247 patients who had previously received platinum-based therapy, the ORR was 61.1%, while the median PFS was 24.9 months and the median DoR was 28.6 months [26].The LIBRETTO-321 study reported ORRs of 87.5% and 61.1% for selpercatinib in untreated and previously treated patients, respectively, confirming the satisfactory efficacy and safety of selpercatinib in Chinese patients with RET fusion NSCLC [27].
Currently, pralsetinib and selpercatinib are both approved in the United States and abroad for the treatment of patients with RET fusion NSCLC.
At the 2022 ASCO conference, Spira et al. reported the results of Phase I/II KRYSTAL-1 (NCT03785249) trial [29].Adagrasib (MRTX849) was indicated for the treatment of KRAS G12C mutated NSCLC patients who had received platinum-based chemotherapy and anti-PD-1/PD-L1 therapy.The ORR was 42.9%, DCR was 79.5%, DoR was 8.5 months, median PFS was 6.5 months, and median OS was 12.6 months.
Many drugs targeting KRAS mutations are still in the early stages of development.As reported at the WCLC conference in 2022, a Phase I study of GDC-6036 and D-1553 monotherapy demonstrated antitumor activity in patients with KRAS G12C -mutated NSCLC [54].

| ROS1 FUSION
Rearrangements of the ROS1 gene are found in 1%-2% of NSCLC.The 2022 ASCO annual meeting reported a prospective EUCROSS trial, which revealed that crizotinib was very effective in ROS1 fusion NSCLC, with an ORR of 70%, a median PFS of 19.4 months and a 4-year OS rate of 55.0% [30].
Entrectinib has been approved internationally and domestically for the treatment of patients with ROS1 fusion-positive NSCLC.According to the WCLC 2022 report, the ORR of entrectinib in patients with ROS1 fusion NSCLC was 68.7%, the median DoR was 35.6 months, the median PFS was 17.7 months, and the median OS was 47.7 months.Entrectinib has shown durable efficacy [31].
Unecritinib (TQ-B3101), as the first-line therapy for ROS1 fusion-positive Chinese NSCLC patients, showed an ORR of 78.4% and a median PFS of 15.6 months, suggesting good efficacy and manageable toxicity [32].

| NTRK GENE FUSIONS IN THE PAN-CANCER CONTEXT
The prevalence of NTRK fusions in NSCLC patients is estimated to be between 0.1% and 0.3% [55].Both larotinib and entrotinib have been approved by the FDA and NMPA for the treatment of NTRK gene-positive solid tumors.
At WCLC 2022, updated data on long-term follow-up of patients with NTRK gene fusions treated with larotinib were presented.The ORR was 83% and the median OS was as high as 40.7 months.For patients with brain metastases, the ORR was 80%, median PFS was 9.9 months, and median OS was 19.4 months [33].
Data from Chinese subgroup of the STARTRK-2 trial released at the ELCC Congress in 2022 showed that the ORR of 21 patients with NTRK fusion-positive solid tumors treated with larotinib was 81.0%, and the median PFS was 30.3 months [35].

| FUTURE DIRECTION
Although there are many studies on classic mutations such as EGFR and ALK, further optimization of treatment strategies and accurate screening of patients will be the focus in the future.
With the widespread development of high-throughput sequencing technology, new therapies for refractory mutation subtypes, such as EGFR 20ins and KRAS mutations, can be developed by exploring uncommon targets and developing new targeted drugs.
As a powerful and precise antitumor drug, ADCs have emerged as the most promising therapeutic approach.In the future, further exploration of combination therapy and screening of effective biomarkers will help the development of ADCs for precision therapy.
Combination therapy with ICIs holds promise for patients with rare genetic mutations or resistance to TKI therapy, and more evidence is expected to emerge in the future.

| CONCLUSION
With the development of precision medicine, lung cancer treatment has entered the era of individualized precision.Further efforts in patient identification, treatment optimization, and in-depth studies of resistance to thirdgeneration TKIs are required to maximize patient benefit.

2. 2
.3.1 | On-target resistance 2.2.3.1.1 | EGFR C797S mutation.Several fourthgeneration EGFR-TKIs, such as BLU-701, BLU-945, JIN-A02, LS-106, and BBT-176, have been developed to overcome EGFR C797S resistance.The robust in vivo and in vitro antitumor activity in osimertinib-resistant NSCLC models is promising and warrants further investigation.Whether the fourth-generation EGFR TKI can really change clinical practice may need to be further verified through large-scale clinical studies, and we also need to consider the degree of benefit and adverse events.At the 2022 ASCO meeting, there is a Phase I/II, openlabel SYMPHONY study (NCT04862780) to evaluate the safety, pharmacokinetics, and anticancer properties of BLU-945 monotherapy or in combination with osimertinib in patients with C797S mutation [41].2.2.3.1.2| Antibody-drug conjugates (ADCs).