Author introduction
Han Baohui Professor
Professor, doctoral supervisor, chief physician
Honorary Director of the Department of Respiratory Medicine, Shanghai Chest HospitalHonorary Director of the Department of Respiratory Medicine
Shanghai's leading talent, Shanghai's outstanding subject leader, State Council Special Allowance Winner
Former Chairman of the CSCO Vascular Targeting Special Committee
Deputy Chairman of the CSCO Non-Small Cell Lung Cancer Special Committee
Deputy Chairman of the Precision Cancer Treatment Committee of the Chinese Anti-Cancer Association
Chairman of the Cancer Branch of the Asia-Pacific Society of Biology and Immunology
Executive President of the Chinese Lung Cancer College
Vice President of the Respiratory Medicine Physician Branch of Shanghai Medical Doctors Association
Progress in Targeted Treatment of Non-Small Cell Lung Cancer in 2022
Han Baohui
(Shanghai Chest Hospital, Department of Respiratory Medicine, Shanghai, 200030)
Corresponding author : Han Baohui
E-mail: [email protected]
Abstract: Lung cancer is the most common malignant tumor, non-small cell lung cancer accounts for about 75% of the total number of lung cancers, and most patients have metastasized at the time of diagnosis and are inoperable. With the deepening understanding of the molecular biological behavior of lung cancer, the application of targeted therapeutic drugs has not only improved the prognosis of patients, but also improved the quality of life of patients. Therefore, it has become the first-line standard treatment for these patients. This review systematically takes stock of the progress in the field of targeted therapy for non-small cell lung cancer in 2022.
Keywords: non-small cell lung cancer; targeted therapy; 2022
Targeted therapy for non-small cell lung cancer (NSCLC) is a representative of modern precision cancer treatment. Targeted therapy drugs given for different driver mutations not only greatly improve the patient's survival time, but also improve the patient's quality of life.
In 2022, the field of targeted therapy for lung cancer will continue to make important progress. Generally speaking, it is reflected in the following aspects:
First of all, the research and development of drugs for rare and difficult-to-treat targets continues to flourish. Due to the large population base of lung cancer patients, even a low mutation ratio still represents a larger patient group. Against the background of fierce competition in traditional classic pathways such as EGFR/ALK, drug development for rare/refractory mutations has become an important direction, including EGFR insertion mutations, HER-2 mutations, mutations, and RET fusions. There have been important research progresses;
Secondly, the establishment of treatment models after drug resistance is still being explored. Whether it is mechanism-based targeted drugs or other treatment methods based on new theories, relevant explorations and promising data have been obtained;
Third, national enterprise drug research and development continues to flourish. This is especially evident in the EGFR pathway. At present, a number of third-generation EGFR-TKIs have successively announced their first-line and later-line efficacy and safety data, which is expected to bring new options for the treatment of these patients in the near future.
Finally, antibody drug conjugates are developing rapidly and are expected to open up a new track for the diagnosis and treatment of lung cancer. Overall, the release of relevant evidence-based medicine data provides a more sufficient basis for the optimization of clinical diagnosis and treatment strategies.
1. The arduous exploration of rare targets
The development of highly efficient and low-toxic targeted drugs for rare and difficult-to-treat targets has always represented an unmet clinical need. Starting in 2020, drug research and development targeting rare/difficult-to-treat targets has continued to make breakthroughs and progress. This year, the release of multiple research data in this field is expected to provide new treatment options for patients. Although
1, HER-2 pathway
belongs to the same family as the EGFR pathway, the drug development progress of the HER-2 pathway lags far behind that of the EGFR pathway, and the efficacy is even inferior to that of the EGFR pathway.
In January this year, JCO magazine published the efficacy and safety data of trastuzumab , pertuzumab combined with docetaxel in the treatment of HER-2 mutated NSCLC patients [1].In this open-label, phase II clinical study , researchers included patients with HER-2 exon 20 point mutations and insertion mutations who had disease progression after receiving at least one platinum-based drug. Finally, a total of 45 patients were enrolled, and the proportions of patients who had received first-line, second-line, and third-line treatment were 74%, 22%, and 4% respectively. The ORR of the entire group of patients was 29%, the DCR was 58%, the median PFS was 6.8 months, and the median OS was 17.6 months. The presence of brain metastases significantly affects the patient's efficacy. For patients with and without brain metastases at baseline, the ORR was 14.3% and 35.5%, respectively. The safety of this combination needs to be taken seriously. In the study, the incidence rate of grade 3 or above adverse reactions in the entire group of patients reached 64%. The most common grade 3 or above treatment-related adverse reaction was neutropenia of 33%. The release of clinical research data related to
2, KRAS G12C mutation
AMG-510 ended the history of KRAS G12C being undruggable, and thus opened up competition for a series of subsequent compounds in this field. In February this year, JCO magazine announced the efficacy and safety of Adagrasib (MRTX849), the second drug targeting KRASG12C mutation, in treating patients with solid tumors carrying KRAS G12C mutation[2]. The study used 150 mg orally once a day as the initial dosage, and ultimately recommended 600 mg orally twice a day as the final dosage. Among the 20 patients who received the recommended dose, there were 16 NSCLC patients, of which 15 could be evaluated for efficacy. The ORR of the patients was 53.3%, the median DOR was 16.4 months, the median PFS was 11.1 months, the 12-month PFS rate reached 50%, the median OS was not reached, and the 12-month OS rate was 66.7%.
3, EGFR exon 20 insertion mutation
In May this year, Cancer Discovery magazine published the efficacy and safety data of the domestic compound-DZD9008 in treating these patients[3]. Based on preliminary research data, the maximum tolerated dose of the drug is 400 mg, taken orally, once daily. For patients who received ≥100 mg treatment, the ORR was 41.1%. Among the patients who received 200 mg or 300 mg treatment, the ORR was 45.5% and 48.4% respectively, showing good efficacy and safety.
Another treatment strategy - increasing the dosage of third-generation drugs also released relevant research data this year [4] . The results showed that 25 patients were enrolled to receive osimertinib 160 mg. After once-daily drug treatment, the ORR was 28%. There was no difference in the efficacy of patients receiving this treatment strategy in the first or second line, with ORRs of 31% and 25% respectively, P=0.464. The median PFS was 6.8 months and the median OS was 15.2 months. There was no significant difference in the efficacy of C-helical zone or loop zone.
4, RET fusion
In September this year, Selpercatinib announced its long-term and larger sample research data on the treatment of RET fusion-positive NSCLC patients [5]. The results showed that among 69 treatment-naïve patients, the ORR assessed by the independent review committee was 84%, the median PFS was 22.0 months, and the median OS was not reached; in 247 previously treated patients, the ORR was 61%, the median PFS was 24.7 months, and the median OS was not reached. Selpercatinib demonstrated a good effect in entering the brain. Among 106 patients with brain metastases at baseline, the median PFS was 19.4 months. In 26 patients with measurable lesions, the ORR was 85%. The incidence of all-cause adverse reactions of grade 3 or above was 71.9%.
Another specific inhibitor for RET fusion, platinib, also has relevant data updates [6]. In this study, 281 NSCLC patients carrying RET fusion were enrolled. The ORR for treatment-naive and treatment-experienced patients was 72% and 59%, respectively, and the median PFS was 13.0 months and 16.5 months, respectively. Median duration of response was not reached and 22.3 months, respectively. The two drugs
bring very important treatment options for first-line and later-line treatment of NSCLC patients with RET fusion.
2. Targeted therapy of classic mutations
1, EGFR pathway
In addition to osimertinib, this year, three third-generation EGFR-TKIs have successively announced their efficacy and safety data in the first-line treatment of patients with EGFR mutated advanced NSCLC.In the AENEAS study [7], the median PFS in the ametinib group and gefitinib treatment for patients with previously untreated advanced stages and carrying 19del or 21L858R mutations were 19.3 months and 9.9 months respectively, H R=0.46, P<0.0001;>EGFR mutations show [8], and fumetinib's first-line treatment of patients carrying 19del or 21L858R mutations has demonstrated better efficacy. The median PFS assessed by the independent review committee was 20.8 months and 11.1 months, respectively, HR=0.44 (95% CI: 0.34–0.58; P0.0001). For patients with brain metastasis, HR=0.50; for patients without brain metastasis, HR=0.42; for patients carrying 19del, HR=0.35; for patients carrying 21L858R, HR=0.54.
Nazartinib is a new third-generation targeted therapy drug. Its Phase II recommended dosage is 150 mg, taken orally, once a day. Clinical research data for first-line applications show that the median PFS and median OS are 18 months and have not reached [9] respectively. However, it should be noted that this study is a single-arm clinical study with a sample size of only 45 cases.
Although new progress continues to be made in the first-line single drug field, third-generation drugs frequently encounter Waterloo in the first-line combination field. A randomized controlled study published in June this year showed that adding bevacizumab to osimertinib alone failed to bring further benefit to patients.[10]. The median PFS of the two groups were 20.2 months and 22.1 months respectively, HR=0.86, P=0.21. The 12-month PFS rates were 63.7% and 73.8%, respectively, and the 24-month PFS rates were 44.5% and 49.8%, respectively. The differences were not statistically significant. The release of the 5-year follow-up data of the NEJ-009 study also brought some uncertainty to the combination treatment. The updated PFS2 of the two groups were 18.0 months and 20.9 months respectively, HR=0.77, P=0.027. The median OS of the single-drug group and the combination group were 38.5 months and 49.0 months, respectively, HR=0.822, P=0.127. The 5-year OS rates were 34% and 39% respectively.
In the field of late-line treatment of secondary T790M mutations, domestic drugs continue to perform successfully, and a number of third-generation targeted therapy drugs have announced key phase II clinical research data. Limertinib is a third-generation TKI drug [12] targeting the EGFR pathway. Its recommended dosage is 160 mg, orally, twice a day. Phase IIb expanded html The 6-cohort study showed that after a median follow-up of 10.4 months, the ORR assessed by the independent review committee was 68.8%, the median DOR was 11.1 months, the median PFS was 11.0 months, and 91.7% of patients experienced tumor shrinkage. The intracranial ORR was 56.1%, the DCR was 100%, and the intracranial median PFS was 10.6 months. The incidence rate of adverse reactions of grade 3 or above was 49.8%. Another drug, befortinib, may also provide patients with a new choice.[13]. This study set up a dynamic ramp (75 mg orally for 1 cycle, and further ramped to 100 mg when tolerated). 73.1% (212/290) of patients successfully ramped up to 100 mg for subsequent treatment. At the time of data analysis, nearly one-third (29.7%) of patients were still receiving treatment. The ORR and median PFS assessed by the independent review committee were 67.6% and 16.6 months, respectively. For patients with and without brain metastases at baseline, the ORR of befortinib treatment was 68.6% and 67.0%, respectively.
In February this year, JTO magazine published the efficacy and safety of osimertinib combined with durvalumab in patients with EGFR mutations[14]. result. Similar to the first generation EGFR-TKI, this combination demonstrated major security issues and was terminated early. The study was divided into Cohort A (progress in TKI drug treatment) and Cohort B (patients who were new to treatment) based on their previous treatment status. The results found that 48% and 82% of patients in Cohort A and Cohort B respectively experienced grade 3 or above adverse reactions. Pooled analysis found that 35% of patients in both groups experienced adverse reactions related to interstitial lung disease. The ORR of cohort A was 43.5%, and the median duration of response was 20.4 months; the ORR of cohort B was 82%, the DCR was 100%, and the median PFS was 9.0 months. The study was terminated early based on observed safety concerns. The alternate application of
first- and second-generation drugs has given some new clinical enlightenment. In vitro studies have found that C797S mutation and T790M mutation did not appear in cell lines treated with second- and third-generation drugs at the same time, suggesting that rotation of the two treatments may prolong patient resistance.However, judging from clinical research data, it seems that more support for [15] is needed. In a prospective, single-arm, phase II clinical study, the researchers gave patients 80 mg of osimertinib, orally, once a day, and after 8 weeks, they switched to afatinib, 720 mg, orally, once a day, alternating every 8 weeks. However, the study narrowly missed its primary endpoint. At the time of the first data analysis, the median follow-up time was 14.5 months, 30.4% of patients experienced end-point events, the 12-month PFS rate was 70.2%, and the lower limit of the 60% confidence interval was 63.9%. Although it was very close to the primary study endpoint of 64%, the study missed the primary study endpoint. At the second lockout, the median follow-up time of the entire group was 25.7 months, and the median PFS reached 21.3 months.
In the field of postoperative adjuvant treatment, this year’s EVAN study released long-term follow-up data. The results found that the median OS of the targeted therapy and chemotherapy groups were 84.2 months and 61.1 months respectively, the 5-year OS rates were 84.8% and 51.1% respectively, and HR=0.373 (ITT population) and 0.375 (PP population), thus providing additional evidence-based medical basis for postoperative adjuvant treatment [16].
2, ALK fusion pathway
At present, the treatment of ALK pathway is the most mature, the prognosis of patients is the best, and drug development is also the most intense. This year, several drugs have successively announced relevant research data on the Chinese population and research results on translational medicine . In March this year, Clinical Cancer Research magazine published the accompanying research results of the ALEX study-cf-DNA levels and the prognosis of ALK-positive patients[17]. Among 276 patients with evaluable tumor marker , the average cf-DNA level was 11.53ng/ml. For patients with lower than average levels, the median PFS of the two groups were not reached and 14.8 months, respectively, HR=0.38; for the group with greater than average levels, the median PFS of the two groups were 14.8 months and 8.6 months, respectively, with HR=0.43. Elevated cf-DNA was associated with a 1.94-fold increase in the risk of disease progression in the alectinib group and a 2.1-fold increase in the crizotinib group. Demonstrated the possibility of dynamically judging patient prognosis based on cf-DNA. In addition, aletinib has also explored related combination treatments and published it in the ESMO Open magazine [18] in March this year. The main purpose of the study was to explore the appropriate dosage of alectinib and bevacizumab. The results showed that aletinib 600 mg, orally, twice daily combined with bevacizumab, 15 mg/kg, every 3 weeks did not cause dose-limiting toxicity. The ORR and DCR of 11 patients were 81.8% and 100% respectively.
In addition, part of the phase III clinical study has released long-term follow-up data. In July this year, the ESMO Open magazine published the long-term follow-up data of the J-ALEX study [19]. The results showed that the median OS of both groups was not reached, HR=1.03, P=0.91, and the 5-year OS rates of the two groups were 60.9% and 64.1% respectively.
3. Patterns after drug resistance Exploring
how to establish new treatment strategies in patients with drug resistance to standard TKIs has been an important direction of clinical research in recent years. At the beginning of the year, Cancer Discovery published a phase I clinical study exploring the efficacy and safety of Patritumab Deruxtecan, an antibody-conjugated drug targeting HER-3, in patients with EGFR-TKI resistance.[20]. The study enrolled 36 patients in the ramp-up phase, with doses including 3.2 mg/kg (n=4), 4.8 mg/kg (n=15), 5.6 mg/kg (n=12), and 6.4 mg/kg (n=5). Among the 36 patients in the dose escalation phase, 5 patients experienced dose-limiting toxicities, including 1 patient with grade 3 agranulocytosis fever and grade 4 thrombocytopenia in the 5.6 mg/kg group; 1 patient with grade 3 neutropenia and grade 4 thrombocytopenia in the 4.8 mg/kg group, and 3 patients with grade 4 thrombocytopenia in the 6.4 mg/kg group. Based on ramping data, the recommended subsequent dosage is 5.6 mg/kg, Q3W. The subsequent cohort expansion was divided into three independent cohorts. Among them, cohort 1 included 45 patients with EGFR gene mutations who had progressed after previously receiving TKI drugs and platinum drug resistance, and received recommended doses of drug treatment.Although this group of patients showed relatively refractory characteristics, including: multiple lines of treatment (the median number of previous lines of treatment was 4 lines), a high proportion of brain metastases (53% of patients had stable brain metastases at the time of enrollment), 89% of patients had previously received osimertinib treatment, 80% of the patients had previously received platinum-based treatment, and 78% of the patients had known gene mutations related to EGFR-TKI resistance based on tissue or peripheral blood, but the patients still showed a certain efficacy. At 10.2 months of follow-up, the ORR assessed by the independent review committee was 39%, and the median DOR was 6.9 months. Even among patients with brain metastases, the ORR reached 32%. The median PFS and OS of the entire group of patients were 8.2 months and not reached, respectively.
In areas such as HER-2 mutations, antibody drug conjugates represented by DS-8201 have shown certain effects. In an open-label, dual-cohort, phase II clinical study [21], researchers included 91 NSCLC patients with HER-2 mutations. The median number of lines of treatment was 2 lines. The ORR of the entire group of patients was 55%. 92% of patients were assessed as stable and had varying degrees of tumor shrinkage. The median PFS was 8.2 months. Median OS was 17.8 months. Among 33 patients with central nervous system metastases at baseline, the median PFS and OS were 7.1 months and 13.8 months, respectively. The
antibody-conjugated drug is very likely to represent the next important direction in lung cancer drug research and development, especially in the fields of refractory mutations and drug resistance. It has great application prospects. However, it is necessary to pay attention to the higher incidence of interstitial lung changes caused by treatment, insufficient linker stability, premature cleavage in the blood so that the drug cannot be stable, precise delivery, and a low antibody-drug ratio. These problems are all problems that need to be overcome in the development of next-generation antibody-conjugated drugs.
small
knot
Although targeted therapy has made some progress overall this year, still has many problems to be solved:
First of all, including KRAS Targeted therapy in areas such as G12C and EGFR exon 20 insertion mutations is still in its infancy. The ORR of targeted drugs is generally within 50% and the PFS is about 6 months. Compared with the efficacy of targeted drugs such as EGFR classic mutations and ALK pathways, there is still a lot of room for improvement. At the same time, the serious adverse reactions of some drugs may also limit their use. Widely used in clinical practice, the research on the resistance mechanisms of these rare mutations is currently basically blank; at the same time, although there is some evidence-based medical evidence for the standard treatment strategy after resistance to targeted drugs, the corresponding diagnosis and treatment path has not yet been established; finally, how to make targeted and immunotherapy more precise, elucidate the molecular mechanism of differential drug response, and enable different patients to receive individualized targeted drug treatment, remains to be further studied.
Author introduction
Han Baohui Professor
Professor, doctoral supervisor, chief physician
Honorary Director of the Department of Respiratory Medicine, Shanghai Chest HospitalHonorary Director of the Department of Respiratory Medicine
Shanghai's leading talent, Shanghai's outstanding subject leader, State Council Special Allowance Winner
Former Chairman of the CSCO Vascular Targeting Special Committee
Deputy Chairman of the CSCO Non-Small Cell Lung Cancer Special Committee
Deputy Chairman of the Precision Cancer Treatment Committee of the Chinese Anti-Cancer Association
Chairman of the Cancer Branch of the Asia-Pacific Society of Biology and Immunology
Executive President of the Chinese Lung Cancer College
Vice President of the Respiratory Medicine Physician Branch of Shanghai Medical Doctors Association
Progress in Targeted Treatment of Non-Small Cell Lung Cancer in 2022
Han Baohui
(Shanghai Chest Hospital, Department of Respiratory Medicine, Shanghai, 200030)
Corresponding author : Han Baohui
E-mail: [email protected]
Abstract: Lung cancer is the most common malignant tumor, non-small cell lung cancer accounts for about 75% of the total number of lung cancers, and most patients have metastasized at the time of diagnosis and are inoperable. With the deepening understanding of the molecular biological behavior of lung cancer, the application of targeted therapeutic drugs has not only improved the prognosis of patients, but also improved the quality of life of patients. Therefore, it has become the first-line standard treatment for these patients. This review systematically takes stock of the progress in the field of targeted therapy for non-small cell lung cancer in 2022.
Keywords: non-small cell lung cancer; targeted therapy; 2022
Targeted therapy for non-small cell lung cancer (NSCLC) is a representative of modern precision cancer treatment. Targeted therapy drugs given for different driver mutations not only greatly improve the patient's survival time, but also improve the patient's quality of life.
In 2022, the field of targeted therapy for lung cancer will continue to make important progress. Generally speaking, it is reflected in the following aspects:
First of all, the research and development of drugs for rare and difficult-to-treat targets continues to flourish. Due to the large population base of lung cancer patients, even a low mutation ratio still represents a larger patient group. Against the background of fierce competition in traditional classic pathways such as EGFR/ALK, drug development for rare/refractory mutations has become an important direction, including EGFR insertion mutations, HER-2 mutations, mutations, and RET fusions. There have been important research progresses;
Secondly, the establishment of treatment models after drug resistance is still being explored. Whether it is mechanism-based targeted drugs or other treatment methods based on new theories, relevant explorations and promising data have been obtained;
Third, national enterprise drug research and development continues to flourish. This is especially evident in the EGFR pathway. At present, a number of third-generation EGFR-TKIs have successively announced their first-line and later-line efficacy and safety data, which is expected to bring new options for the treatment of these patients in the near future.
Finally, antibody drug conjugates are developing rapidly and are expected to open up a new track for the diagnosis and treatment of lung cancer. Overall, the release of relevant evidence-based medicine data provides a more sufficient basis for the optimization of clinical diagnosis and treatment strategies.
1. The arduous exploration of rare targets
The development of highly efficient and low-toxic targeted drugs for rare and difficult-to-treat targets has always represented an unmet clinical need. Starting in 2020, drug research and development targeting rare/difficult-to-treat targets has continued to make breakthroughs and progress. This year, the release of multiple research data in this field is expected to provide new treatment options for patients. Although
1, HER-2 pathway
belongs to the same family as the EGFR pathway, the drug development progress of the HER-2 pathway lags far behind that of the EGFR pathway, and the efficacy is even inferior to that of the EGFR pathway.
In January this year, JCO magazine published the efficacy and safety data of trastuzumab , pertuzumab combined with docetaxel in the treatment of HER-2 mutated NSCLC patients [1].In this open-label, phase II clinical study , researchers included patients with HER-2 exon 20 point mutations and insertion mutations who had disease progression after receiving at least one platinum-based drug. Finally, a total of 45 patients were enrolled, and the proportions of patients who had received first-line, second-line, and third-line treatment were 74%, 22%, and 4% respectively. The ORR of the entire group of patients was 29%, the DCR was 58%, the median PFS was 6.8 months, and the median OS was 17.6 months. The presence of brain metastases significantly affects the patient's efficacy. For patients with and without brain metastases at baseline, the ORR was 14.3% and 35.5%, respectively. The safety of this combination needs to be taken seriously. In the study, the incidence rate of grade 3 or above adverse reactions in the entire group of patients reached 64%. The most common grade 3 or above treatment-related adverse reaction was neutropenia of 33%. The release of clinical research data related to
2, KRAS G12C mutation
AMG-510 ended the history of KRAS G12C being undruggable, and thus opened up competition for a series of subsequent compounds in this field. In February this year, JCO magazine announced the efficacy and safety of Adagrasib (MRTX849), the second drug targeting KRASG12C mutation, in treating patients with solid tumors carrying KRAS G12C mutation[2]. The study used 150 mg orally once a day as the initial dosage, and ultimately recommended 600 mg orally twice a day as the final dosage. Among the 20 patients who received the recommended dose, there were 16 NSCLC patients, of which 15 could be evaluated for efficacy. The ORR of the patients was 53.3%, the median DOR was 16.4 months, the median PFS was 11.1 months, the 12-month PFS rate reached 50%, the median OS was not reached, and the 12-month OS rate was 66.7%.
3, EGFR exon 20 insertion mutation
In May this year, Cancer Discovery magazine published the efficacy and safety data of the domestic compound-DZD9008 in treating these patients[3]. Based on preliminary research data, the maximum tolerated dose of the drug is 400 mg, taken orally, once daily. For patients who received ≥100 mg treatment, the ORR was 41.1%. Among the patients who received 200 mg or 300 mg treatment, the ORR was 45.5% and 48.4% respectively, showing good efficacy and safety.
Another treatment strategy - increasing the dosage of third-generation drugs also released relevant research data this year [4] . The results showed that 25 patients were enrolled to receive osimertinib 160 mg. After once-daily drug treatment, the ORR was 28%. There was no difference in the efficacy of patients receiving this treatment strategy in the first or second line, with ORRs of 31% and 25% respectively, P=0.464. The median PFS was 6.8 months and the median OS was 15.2 months. There was no significant difference in the efficacy of C-helical zone or loop zone.
4, RET fusion
In September this year, Selpercatinib announced its long-term and larger sample research data on the treatment of RET fusion-positive NSCLC patients [5]. The results showed that among 69 treatment-naïve patients, the ORR assessed by the independent review committee was 84%, the median PFS was 22.0 months, and the median OS was not reached; in 247 previously treated patients, the ORR was 61%, the median PFS was 24.7 months, and the median OS was not reached. Selpercatinib demonstrated a good effect in entering the brain. Among 106 patients with brain metastases at baseline, the median PFS was 19.4 months. In 26 patients with measurable lesions, the ORR was 85%. The incidence of all-cause adverse reactions of grade 3 or above was 71.9%.
Another specific inhibitor for RET fusion, platinib, also has relevant data updates [6]. In this study, 281 NSCLC patients carrying RET fusion were enrolled. The ORR for treatment-naive and treatment-experienced patients was 72% and 59%, respectively, and the median PFS was 13.0 months and 16.5 months, respectively. Median duration of response was not reached and 22.3 months, respectively. The two drugs
bring very important treatment options for first-line and later-line treatment of NSCLC patients with RET fusion.
2. Targeted therapy of classic mutations
1, EGFR pathway
In addition to osimertinib, this year, three third-generation EGFR-TKIs have successively announced their efficacy and safety data in the first-line treatment of patients with EGFR mutated advanced NSCLC.In the AENEAS study [7], the median PFS in the ametinib group and gefitinib treatment for patients with previously untreated advanced stages and carrying 19del or 21L858R mutations were 19.3 months and 9.9 months respectively, H R=0.46, P<0.0001;>EGFR mutations show [8], and fumetinib's first-line treatment of patients carrying 19del or 21L858R mutations has demonstrated better efficacy. The median PFS assessed by the independent review committee was 20.8 months and 11.1 months, respectively, HR=0.44 (95% CI: 0.34–0.58; P0.0001). For patients with brain metastasis, HR=0.50; for patients without brain metastasis, HR=0.42; for patients carrying 19del, HR=0.35; for patients carrying 21L858R, HR=0.54.
Nazartinib is a new third-generation targeted therapy drug. Its Phase II recommended dosage is 150 mg, taken orally, once a day. Clinical research data for first-line applications show that the median PFS and median OS are 18 months and have not reached [9] respectively. However, it should be noted that this study is a single-arm clinical study with a sample size of only 45 cases.
Although new progress continues to be made in the first-line single drug field, third-generation drugs frequently encounter Waterloo in the first-line combination field. A randomized controlled study published in June this year showed that adding bevacizumab to osimertinib alone failed to bring further benefit to patients.[10]. The median PFS of the two groups were 20.2 months and 22.1 months respectively, HR=0.86, P=0.21. The 12-month PFS rates were 63.7% and 73.8%, respectively, and the 24-month PFS rates were 44.5% and 49.8%, respectively. The differences were not statistically significant. The release of the 5-year follow-up data of the NEJ-009 study also brought some uncertainty to the combination treatment. The updated PFS2 of the two groups were 18.0 months and 20.9 months respectively, HR=0.77, P=0.027. The median OS of the single-drug group and the combination group were 38.5 months and 49.0 months, respectively, HR=0.822, P=0.127. The 5-year OS rates were 34% and 39% respectively.
In the field of late-line treatment of secondary T790M mutations, domestic drugs continue to perform successfully, and a number of third-generation targeted therapy drugs have announced key phase II clinical research data. Limertinib is a third-generation TKI drug [12] targeting the EGFR pathway. Its recommended dosage is 160 mg, orally, twice a day. Phase IIb expanded html The 6-cohort study showed that after a median follow-up of 10.4 months, the ORR assessed by the independent review committee was 68.8%, the median DOR was 11.1 months, the median PFS was 11.0 months, and 91.7% of patients experienced tumor shrinkage. The intracranial ORR was 56.1%, the DCR was 100%, and the intracranial median PFS was 10.6 months. The incidence rate of adverse reactions of grade 3 or above was 49.8%. Another drug, befortinib, may also provide patients with a new choice.[13]. This study set up a dynamic ramp (75 mg orally for 1 cycle, and further ramped to 100 mg when tolerated). 73.1% (212/290) of patients successfully ramped up to 100 mg for subsequent treatment. At the time of data analysis, nearly one-third (29.7%) of patients were still receiving treatment. The ORR and median PFS assessed by the independent review committee were 67.6% and 16.6 months, respectively. For patients with and without brain metastases at baseline, the ORR of befortinib treatment was 68.6% and 67.0%, respectively.
In February this year, JTO magazine published the efficacy and safety of osimertinib combined with durvalumab in patients with EGFR mutations[14]. result. Similar to the first generation EGFR-TKI, this combination demonstrated major security issues and was terminated early. The study was divided into Cohort A (progress in TKI drug treatment) and Cohort B (patients who were new to treatment) based on their previous treatment status. The results found that 48% and 82% of patients in Cohort A and Cohort B respectively experienced grade 3 or above adverse reactions. Pooled analysis found that 35% of patients in both groups experienced adverse reactions related to interstitial lung disease. The ORR of cohort A was 43.5%, and the median duration of response was 20.4 months; the ORR of cohort B was 82%, the DCR was 100%, and the median PFS was 9.0 months. The study was terminated early based on observed safety concerns. The alternate application of
first- and second-generation drugs has given some new clinical enlightenment. In vitro studies have found that C797S mutation and T790M mutation did not appear in cell lines treated with second- and third-generation drugs at the same time, suggesting that rotation of the two treatments may prolong patient resistance.However, judging from clinical research data, it seems that more support for [15] is needed. In a prospective, single-arm, phase II clinical study, the researchers gave patients 80 mg of osimertinib, orally, once a day, and after 8 weeks, they switched to afatinib, 720 mg, orally, once a day, alternating every 8 weeks. However, the study narrowly missed its primary endpoint. At the time of the first data analysis, the median follow-up time was 14.5 months, 30.4% of patients experienced end-point events, the 12-month PFS rate was 70.2%, and the lower limit of the 60% confidence interval was 63.9%. Although it was very close to the primary study endpoint of 64%, the study missed the primary study endpoint. At the second lockout, the median follow-up time of the entire group was 25.7 months, and the median PFS reached 21.3 months.
In the field of postoperative adjuvant treatment, this year’s EVAN study released long-term follow-up data. The results found that the median OS of the targeted therapy and chemotherapy groups were 84.2 months and 61.1 months respectively, the 5-year OS rates were 84.8% and 51.1% respectively, and HR=0.373 (ITT population) and 0.375 (PP population), thus providing additional evidence-based medical basis for postoperative adjuvant treatment [16].
2, ALK fusion pathway
At present, the treatment of ALK pathway is the most mature, the prognosis of patients is the best, and drug development is also the most intense. This year, several drugs have successively announced relevant research data on the Chinese population and research results on translational medicine . In March this year, Clinical Cancer Research magazine published the accompanying research results of the ALEX study-cf-DNA levels and the prognosis of ALK-positive patients[17]. Among 276 patients with evaluable tumor marker , the average cf-DNA level was 11.53ng/ml. For patients with lower than average levels, the median PFS of the two groups were not reached and 14.8 months, respectively, HR=0.38; for the group with greater than average levels, the median PFS of the two groups were 14.8 months and 8.6 months, respectively, with HR=0.43. Elevated cf-DNA was associated with a 1.94-fold increase in the risk of disease progression in the alectinib group and a 2.1-fold increase in the crizotinib group. Demonstrated the possibility of dynamically judging patient prognosis based on cf-DNA. In addition, aletinib has also explored related combination treatments and published it in the ESMO Open magazine [18] in March this year. The main purpose of the study was to explore the appropriate dosage of alectinib and bevacizumab. The results showed that aletinib 600 mg, orally, twice daily combined with bevacizumab, 15 mg/kg, every 3 weeks did not cause dose-limiting toxicity. The ORR and DCR of 11 patients were 81.8% and 100% respectively.
In addition, part of the phase III clinical study has released long-term follow-up data. In July this year, the ESMO Open magazine published the long-term follow-up data of the J-ALEX study [19]. The results showed that the median OS of both groups was not reached, HR=1.03, P=0.91, and the 5-year OS rates of the two groups were 60.9% and 64.1% respectively.
3. Patterns after drug resistance Exploring
how to establish new treatment strategies in patients with drug resistance to standard TKIs has been an important direction of clinical research in recent years. At the beginning of the year, Cancer Discovery published a phase I clinical study exploring the efficacy and safety of Patritumab Deruxtecan, an antibody-conjugated drug targeting HER-3, in patients with EGFR-TKI resistance.[20]. The study enrolled 36 patients in the ramp-up phase, with doses including 3.2 mg/kg (n=4), 4.8 mg/kg (n=15), 5.6 mg/kg (n=12), and 6.4 mg/kg (n=5). Among the 36 patients in the dose escalation phase, 5 patients experienced dose-limiting toxicities, including 1 patient with grade 3 agranulocytosis fever and grade 4 thrombocytopenia in the 5.6 mg/kg group; 1 patient with grade 3 neutropenia and grade 4 thrombocytopenia in the 4.8 mg/kg group, and 3 patients with grade 4 thrombocytopenia in the 6.4 mg/kg group. Based on ramping data, the recommended subsequent dosage is 5.6 mg/kg, Q3W. The subsequent cohort expansion was divided into three independent cohorts. Among them, cohort 1 included 45 patients with EGFR gene mutations who had progressed after previously receiving TKI drugs and platinum drug resistance, and received recommended doses of drug treatment.Although this group of patients showed relatively refractory characteristics, including: multiple lines of treatment (the median number of previous lines of treatment was 4 lines), a high proportion of brain metastases (53% of patients had stable brain metastases at the time of enrollment), 89% of patients had previously received osimertinib treatment, 80% of the patients had previously received platinum-based treatment, and 78% of the patients had known gene mutations related to EGFR-TKI resistance based on tissue or peripheral blood, but the patients still showed a certain efficacy. At 10.2 months of follow-up, the ORR assessed by the independent review committee was 39%, and the median DOR was 6.9 months. Even among patients with brain metastases, the ORR reached 32%. The median PFS and OS of the entire group of patients were 8.2 months and not reached, respectively.
In areas such as HER-2 mutations, antibody drug conjugates represented by DS-8201 have shown certain effects. In an open-label, dual-cohort, phase II clinical study [21], researchers included 91 NSCLC patients with HER-2 mutations. The median number of lines of treatment was 2 lines. The ORR of the entire group of patients was 55%. 92% of patients were assessed as stable and had varying degrees of tumor shrinkage. The median PFS was 8.2 months. Median OS was 17.8 months. Among 33 patients with central nervous system metastases at baseline, the median PFS and OS were 7.1 months and 13.8 months, respectively. The
antibody-conjugated drug is very likely to represent the next important direction in lung cancer drug research and development, especially in the fields of refractory mutations and drug resistance. It has great application prospects. However, it is necessary to pay attention to the higher incidence of interstitial lung changes caused by treatment, insufficient linker stability, premature cleavage in the blood so that the drug cannot be stable, precise delivery, and a low antibody-drug ratio. These problems are all problems that need to be overcome in the development of next-generation antibody-conjugated drugs.
small
knot
Although targeted therapy has made some progress overall this year, still has many problems to be solved:
First of all, including KRAS Targeted therapy in areas such as G12C and EGFR exon 20 insertion mutations is still in its infancy. The ORR of targeted drugs is generally within 50% and the PFS is about 6 months. Compared with the efficacy of targeted drugs such as EGFR classic mutations and ALK pathways, there is still a lot of room for improvement. At the same time, the serious adverse reactions of some drugs may also limit their use. Widely used in clinical practice, the research on the resistance mechanisms of these rare mutations is currently basically blank; at the same time, although there is some evidence-based medical evidence for the standard treatment strategy after resistance to targeted drugs, the corresponding diagnosis and treatment path has not yet been established; finally, how to make targeted and immunotherapy more precise, elucidate the molecular mechanism of differential drug response, and enable different patients to receive individualized targeted drug treatment, remains to be further studied.
References
[1] Julien Mazieres, Claire Lafitte, Charles Ricordel, et al. Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non-Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial. J Clin Oncol. 2022;40(7):719-728. doi: 10.1200/JCO.21.01455.
[2] Sai-Hong Ignatius Ou, Pasi A Jänne, Ticiana A Leal et al. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530-2538.doi: 10.1200/JCO.21.02752.
[3] Mengzhao Wang, James Chih-Hsin Yang, Paul L Mitchell. et al. Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. Cancer Discov. 2022;12(7):1676-1689.doi: 10.1158/2159-8290.CD-21-1615.
[4] Fenneke Zwierenga, Bianca van Veggel, Lizza E L Hendriks, et al. High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial. Lung Cancer. 2022;170:133-140.doi: 10.1016/j.lungcan.2022.06.012.
[5] Alexander Drilon, Vivek Subbiah, Oliver Gautschi, et al. Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial. J Clin Oncol. 2022;JCO2200393.doi: 10.1200/JCO.22.00393.
[6] F Griesinger, G Curigliano, M Thomas, et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol. 2022;33(11):1168-1178.doi: 10.1016/j.annonc.2022.08.002.
[7] Shun Lu, Xiaorong Dong, Hong Jian, et al, AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or MetastaticNon-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol. 2022;40(27):3162-3171. doi: 10.1200/JCO.21.02641.
[8] Yuankai Shi, Gongyan Chen, Xiang Wang, et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomized phase 3 study. Lancet Respir Med. 2022;10(11):1019-1028.doi: 10.1016/S2213-2600(22)00168-0.
[9] Daniel S W Tan, Sang-We Kim, Santiago Ponce Aix, et al. Nazartinib for treatment-naive EGFR-mutant non-small cell lung cancer: Results of a phase 2, single-arm, open-label study. Eur J Cancer. 2022;172:276-286.doi: 10.1016/j.ejca.2022.05.023.
[10] Hirotsugu Kenmotsu, Kazushige Wakuda, Keita Mori, et al. Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study. J Thorac Oncol. 2022;17(9):1098-1108.doi: 10.1016/j.jtho.2022.05.006.
[11] Eisaku Miyauchi, Satoshi Morita, Atsushi Nakamura, et al. Updated Analysis of NEJ009: Gefitinib-Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated EGFR. J Clin Oncol. 2022;40(31):3587-3592.doi: 10.1200/JCO.21.02911.
[12] Yuankai Shi, Baolan Li, Lin Wu, et al. Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study. J Thorac Oncol. 2022;17(10):1205-1215. doi: 10.1016/j.jtho.2022.05.011.
[13] Shun Lu, Yiping Zhang, Guojun Zhang, et al. Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study. J Thorac Oncol. 2022;17(10):1192-1204. doi: 10.1016/j.jtho.2022.06.002.
[14] Myung-Ju Ahn, Byoung Chul Cho, Xiaoling Ou, et al. Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial. J Thorac Oncol. 2022;17(5):718-723. doi: 10.1016/j.jtho.2022.01.012.
[15] Hidetoshi Hayashi, Kimio Yonesaka, Atsushi Nakamura, et al. Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). Lung Cancer. 2022;168:38-45. doi: 10.1016/j.lungcan.2022.04.004.
[16] Dongsheng Yue, Shidong Xu, Qun Wang, et al. Updated Overall Survival and Exploratory Analysis From Randomized, Phase II EVAN Study of Erlotinib Versus Vinorelbine Plus Cisplatin Adjuvant Therapy in Stage IIIA Epidermal Growth Factor Receptor+ Non-Small-Cell Lung Cancer. J Clin Oncol. 2022;JCO2200428.doi: 10.1200/JCO.22.00428.
[17] Rafal Dziadziuszko, Solange Peters, Tony Mok, et al. Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non-small Cell Lung Cancer in the Global Phase III ALEX Trial. Clin Cancer Res. 2022;28(9):1800-1808.doi: 10.1158/1078-0432.CCR-21-2840.
[18] J J Lin, A Muzikansky, E Kennedy, et al. Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study. ESMO Open. 2022;7(1):100342. doi:10.1016/j.esmoop.2021.100342.
[19] K Hotta, T Hida, H Nokihara, et al. Final overall survival analysis from the phase III J-ALEX study of alectinib versus alectinib crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive non-small-cell lung cancer. ESMO Open. 2022;7(4):100527. doi:10.1016/j.esmoop.2022.100527.
[20] Pasi A Jänne, Christina Baik, Wu-Chou Su, et al. Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer. Cancer Discov. 2022;12(1):74-89.doi: 10.1158/2159-8290.CD-21-0715.
[21] Bob T Li, Egbert F Smit, Yasushi Goto, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022 Jan 20;386(3):241-251.doi: 10.1056/NEJMoa2112431.
Editor｜Ye Wenjie
Editor｜High Health
Review｜Ye Wenjie
Source: Oncology WeChat public account
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The content published on this platform cannot replace professional medical guidance in any way, nor should it be regarded as diagnosis and treatment advice. If such information is used for purposes other than understanding medical information, this platform does not bear relevant responsibilities. The content published on this platform does not mean that you agree with its descriptions and opinions. If there are any copyright issues, please contact us and we will handle it as soon as possible.
