January 21, 2022

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Lung cancer丨EGFR mutation targeted therapy series research summary

Lung cancer丨EGFR mutation targeted therapy series research summary

 

Lung cancer丨EGFR mutation targeted therapy series research summary.  The median PFS of the osimertinib group was 15.8 months, and the median PFS of the combination group was 14.6 months (HR 1.09, 95% CI: 0.51-2.32, P = 0.83). The median OS was not reached (HR 2.42 (95% CI: 0.82-7.15), P = 0.10).


The formation of non-small cell lung cancer (NSCLC) is closely related to a variety of oncogenic mutations, such as EGFR mutation, ALK/ROS1 rearrangement, MET14 exon skipping, and RET rearrangement. Targeted drugs have therefore begun to show up. Because of their significant advantages of high efficiency, low toxicity, and strong specificity, they have basically occupied the throne of the first-line treatment of NSCLC.

In 2019, we launched the “Lung Cancer丨Precision Medicine” series of articles. Due to the rapid development of targeted drugs, we will update targeted therapies to make it easier for everyone to find them.

 


EGFR article summary

Lung Cancer丨Precision Medicine, Targeted Therapy for Sensitive EGFR Mutations (2019)

1st generation EGFR-TKIs

1. IPASS study: Gefitinib vs chemotherapy, PFS is 9.6 vs 6.3 months

2. ENSURE study: Erlotinib vs chemotherapy, PFS is 11.0 vs 5.5 months

3. A study: brain metastases, erlotinib pulse therapy

4. CONVINCE study: Icotinib vs chemotherapy, PFS is 11.2 vs 7.9 months

5. INCREASE study: increased icotinib, prolonged PFS in L858R subgroup

2nd generation EGFR-TKIs

6. LUX-LUNG series research: Afatinib prolongs PFS and has anti-rare mutation activity

7. ARCHER 1050 study: dacomitinib vs gefitinib, the OS was 34.1 vs. 27.0 months, and the dose reduction did not reduce the effect

3rd generation EGFR-TKIs

8. ADAURA study: Osimitinib postoperative adjuvant treatment reduces the risk of disease recurrence or death by 80%

9. AURA3 study: advanced second-line, osimertinib vs chemotherapy, PFS 10.1 vs 4.4 months, respectively

10. FLAURA study: Late first-line, osimertinib vs first-generation targeted drugs, OS 38.6 vs 31.8 months, respectively

11. Brain metastasis: AURA3 study, FLAURA study subgroup analysis, osimertinib can significantly prolong PFS

12. APOLLO study: late second-line, ametinib ORR reached 68.9%, PFS was 12.3 months; brain transfer prolonged PFS

13. A study: Late second-line, vometinib ORR was 74.1%, PFS was 9.6 months; brain transfer prolonged PFS

EGFR-TKIs+ anti-vascular

14. A+T (first-generation targeted drugs): RELAY, NEJ026, ARTEMIS research, A+T prolongs PFS

15. A+T (Osimertinib): No matter the first line or the second line, PFS cannot be significantly prolonged

EGFR-TKIs+ chemotherapy

16. JMIT study: Gefitinib + chemotherapy vs gefitinib, PFS is 15.8 vs 10.9 months

17. NEJ009 study: Gefitinib + chemotherapy vs gefitinib, OS 52.5 vs 38.8 months

18. NEJ032A study: osimertinib + chemotherapy vs osimertinib, PFS is 14.6 vs 15.8 months

Drug resistance treatment strategies

19. See text for details

 

 

1st generation EGFR-TKIs

 

Gefitinib, Erlotinib

Phase III clinical study (IPASS):

Compared with traditional chemotherapy regimens, gefitinib targeted therapy for patients with advanced NSCLC with EGFR-sensitive mutations has a better effect (ORR: 71.2% vs 47.3%, median PFS: 9.6 months vs 6.3 months, medium Bit OS: 21.6 months vs 21.9 months), toxic side effects (such as bone marrow suppression) were significantly reduced. The study identified gefitinib as the first-line treatment for patients with EGFR-mutant NSCLC. The latest IPASS results show that regardless of the EGFR mutation status, the overall survival rates of the two groups of patients are similar.

Phase III clinical study (ENSURE):

The median PFS of the erlotinib group and the chemotherapy group were 11.0 months and 5.5 months, respectively, the median OS was 26.3 months and 25.5 months, and the ORR was 62.7% and 33.6%, respectively.

Brain metastases

Lung cancer EGFR mutation brain metastases, you might as well try erlotinib pulse therapy

Lcotinib (China)

Randomized, double-blind, parallel controlled clinical trial (ICOGEN):

It shows that icotinib has similar efficacy to gefitinib in the treatment of stage IIIB/IV NSCLC, but its tolerability and safety are better than gefitinib. A subsequent phase IV trial further confirmed this.

Phase III open randomized clinical trial (CONVINCE):

The first-line use of icotinib and traditional chemotherapy (“cisplatin + pemetrexed” combined with pemetrexed maintenance therapy) for the treatment of NSCLC patients with stage IIIB/IV EGFR sensitive mutations were compared. The results showed that the median PFS of the icotinib group was significantly longer than that of the chemotherapy group (11.2 months vs. 7.9 months) and the former was significantly better in safety and tolerability than the latter, but there was no significant difference in the median OS between the two groups .

INCREASE research:

Icotinib, a targeted drug for lung cancer, can increase the dose to increase the efficacy?

 

 

2nd generation EGFR-TKIs

Although the first-generation EGFR-TKIs showed clinical efficacy in the treatment of advanced NSCLC, the median OS did not show a significant advantage compared with traditional chemotherapy, and it is easy to resist drug resistance.

Afatinib

Phase III clinical trials (LUX-LUNG3, LUX-LUNG6):

All showed that afatinib as the first-line treatment for patients with EGFR-mutant NSCLC adenocarcinoma, compared with traditional standard chemotherapy, the median PFS and ORR were significantly improved, but there was no significant difference in median OS. In the latest LUX-LUNG6 subgroup analysis, afatinib showed a significant improvement in the median OS of patients with EGFR 19del mutation compared with chemotherapy group (median OS: 31.6 vs 16.3 months), but in patients with L858R mutation There is no such difference.

Phase ⅡB clinical trial (LUX-LUNG7):

The efficacy of afatinib and gefitinib in patients with EGFR mutations (19del, L858R) were compared, the ORR of afatinib and gefitinib (70% vs 56%), the median PFS (11.9 months vs. 10.9 months) and treatment failure time (TTF: 13.7 months vs 11.5 months) were statistically significant, but the median OS was not statistically significant, and the difference in efficacy between the 19del and L858R subgroups was also No statistical significance. However, for patients with non-classical EGFR mutations (such as L861Q, G719S, etc.), the efficacy of the first and third generation EGFR-TKIs is not ideal, and afatinib can significantly improve the survival benefits of such patients.

Rare mutations

How to treat lung cancer with uncommon EGFR mutations, try afatinib

 

Dacomitinib

ARCHER 1050 is a global multicenter, randomized, open phase III clinical study, which aims to compare the efficacy and safety of dacomitinib and gefitinib in the first-line treatment of patients with advanced NSCLC with EGFR-sensitive mutations. The second-generation EGFR TKI dacomitinib is a pan-HER (EGFR/HER1, HER2 and HER4) inhibitor that can selectively and irreversibly bind to its HER family receptor target, providing long-term inhibition.

Lung cancer丨EGFR mutation targeted therapy series research summary
Study design (brain transfer excluded)

Lung cancer丨EGFR mutation targeted therapy series research summary
Patient baseline characteristics

 

The ARCHER 1050 study data released by the 2018 American Society of Clinical Oncology (ASCO) annual meeting showed that compared with the gefitinib group, the dacomitinib group had prolonged progression-free survival (PFS) and OS [1], Dacotinib became the first EGFR TKI to provide clinically meaningful OS improvement. Based on the results of the ARCHER 1050 research, Dacotinib has been listed globally, and it was also approved for domestic listing in May 2019.

At ESMO Asia 2019, after 47.9 months of follow-up, the OS data of the ARCHER 1050 study was updated [2]. The OS in the dacomitinib group and the gefitinib group were 34.1 months vs. 27.0 months, respectively. In Asian patients, the median OS of the two groups was 37.7 months vs. 29.1 months, an increase of 8.6 months (two-sided test P=0.0457).

 

Total populaLung cancer丨EGFR mutation targeted therapy series research summarytion OS

Lung cancer丨EGFR mutation targeted therapy series research summary

Subgroup analysis

According to the analysis of the patient’s gene mutation type, the median OS of the 19del mutation patients, the dacomitinib group and the gefitinib group were 36.7 months vs. 30.8 months, respectively; in the 21 L858R mutation patients, the median OS of the two groups were respectively 32.5 months vs. 23.2 months. In addition, the study also found that after the dose of dacomitinib was reduced, it did not affect the patient’s OS benefit.

Lung cancer丨EGFR mutation targeted therapy series research summary

Dose reduction vs OS in Asian population

Lung cancer丨EGFR mutation targeted therapy series research summary

OS in patients at various dose levels

In 2021, Lung Cancer announced the updated results of the Phase III ARCHER 1050 study [3]: In the Chinese population, dacomitinib compared with gefitinib, the ORR of the two groups was 77.1% vs. 72.7%, and the PFS was 16 respectively. Months vs. 9.2 months, the OS was 32.5 months and 24.9 months, respectively, and the OS benefit was consistent with the overall population of the study and the Asian population.

Lung cancer丨EGFR mutation targeted therapy series research summary

PFS assessed by IRC

Lung cancer丨EGFR mutation targeted therapy series research summary

Chinese crowd OS

According to the analysis based on the patient’s gene mutation type, in patients with 19del mutation, the median OS of the dacomitinib group and the gefitinib group were 33.2 months vs. 25.9 months, respectively; in the patients with 21 L858R mutation, the median OS of the two groups were respectively 26.7 months vs. 23.2 months.

Lung cancer丨EGFR mutation targeted therapy series research summary

Chinese population PFS: 19del (top), L858R (bottom)

Lung cancer丨EGFR mutation targeted therapy series research summary

Chinese OS: 19del (top), L858R (bottom)

 

Safety:

In the Asian population, the most common adverse events (AE) in the dacomitinib group were diarrhea (90.6%), paronychia (64.7%), acnoid dermatitis (56.5%), stomatitis (51.2%), and gemfibrillary The most common adverse events in the tinib group were diarrhea (56.8%), elevated alanine aminotransferase (ALT) (46.0%), and elevated aspartate aminotransferase (AST) (42.6%). In all patients receiving dacomitinib dose reduction treatment, after the first and second dose reduction, the incidence of grade 3 diarrhea, stomatitis, skin rash, dry skin, etc. generally decreased.

 

 

3rd generation EGFR-TKIs

At present, the clinical use of EGFR-TKIs to treat advanced NSCLC is effective, but most patients develop drug resistance after 6-13 months of treatment, which is manifested as tumor progression. This phenomenon is called “secondary drug resistance.” The most common drug resistance mechanism of the first and second generation EGFR-TKIs is the T790M mutation in exon 20 (40%-55%), and the third generation EGFR-TKIs are drugs specifically designed for the T790M mutation.

Osimertinib

Postoperative adjuvant treatment

NEJM丨Lung cancer, osimertinib postoperative adjuvant treatment reduces the risk of recurrence by 83%

NSCLC丨EGFR-TKI has sounded the clarion call for adjuvant treatment of early NSCLC, are you clinically ready?

NSCLC|Osimitinib gets a new indication: FDA approves the first postoperative adjuvant targeted therapy for NSCLC!

AURA3 research

The AURA-3 study [4] is a randomized, prospective, phase III clinical study that includes patients with locally advanced or metastatic non-small cell lung cancer who have received a first-generation TKI-like drug treatment and have T790M mutations, and those who meet the enrollment criteria , Receive osimertinib 80mg in a 2:1 ratio, orally, once a day or chemotherapy, the chemotherapy regimen is pemetrexed (500 mg/m2), combined with cisplatin 75 mg/m2 or carboplatin (AUC=5 ), chemotherapy is performed every three weeks, and the upper limit of treatment is 6 cycles. Treatment should be continued until the disease progresses, intolerable toxicity occurs or the informed consent is withdrawn.

When patients are screened, they need to provide peripheral blood and perform T790M testing based on the Cbas method. Patients who have not progressed after receiving dual platinum-containing dual-drug chemotherapy are allowed to receive pemetrexed maintenance therapy. At the same time, this part of patients is allowed to receive osimertinib treatment, but the combined application of pemetrexed and osimertinib is not allowed. If the researcher believes that the patient can continue to benefit from the treatment of osimertinib after the disease progresses, the patient is allowed to continue to receive the drug treatment.

The primary endpoint of AURA-3 is the PFS assessed by the investigator, and OS and safety lines are secondary endpoints. All patients who received randomization constituted a complete analysis set, and patients who received at least one chemotherapy or osimertinib treatment constitute a safety analysis and set. OS is defined as the time from the start of randomization to the death of the patient from all causes, and the efficacy evaluation is performed every 6 cycles. The study uses the RPSFTM method to correct for the crossover effect.

At the end of the final data, 415 patients had received at least one study drug treatment. There were 279 and 136 patients in the osimertinib group and 136 patients in the chemotherapy group, respectively. 73% of the patients who received platinum-containing dual-drug chemotherapy were cross-received on osimertinib after progression. The baseline characteristics between the two groups were balanced and comparable. The median treatment exposure time was 13.8 months and 4.3 months, respectively. At the time of data analysis, 10% and 0% of patients in the two groups were still receiving study drug treatment. In the final data analysis, 67% and 66% of the patients in the osimertinib group and the chemotherapy group had deaths. 21% and 19% of patients in the two groups were still undergoing survival follow-up.

Lung cancer丨EGFR mutation targeted therapy series research summary

Lung cancer丨EGFR mutation targeted therapy series research summary

Lung cancer丨EGFR mutation targeted therapy series research summary

 


Previously published AURA3 results reported [5], median PFS (10.1 months vs 4.4 months), ORR (71% vs 31%) in the osimertinib group and chemotherapy group, and median PFS of 144 cases of CNS metastasis ( 8.5 months vs 4.2 months), ADR (23% vs 47%).

In 2020, “Ann Oncol” released the final OS, and the median follow-up time of the two groups was 23.5 months and 20.3 months, respectively. The median OS of the osimertinib group and the chemotherapy group were 26.8 months and 22.5 months, respectively, HR=0.87, P=0.277, the difference was not statistically significant. The 12-month OS rates of the two groups were 83% and 78%, the 24-month OS rates were 55% and 43%, and the 36% monthly OS rates were 37% and 30% (Figure 2).


OS analysis of the two groups


OS subgroup analysis

 

 

Subgroup analysis:

In the vast majority of subgroups, osimertinib showed better efficacy, but in men and the subgroup with central nervous system metastasis at baseline, the first to receive chemotherapy showed a better trend of benefit . Based on the analysis of peripheral blood, the median OS of patients with negative T790M mutation in peripheral blood was 34.9 months, which was numerically better than the 23.9 months of positive patients. After adjusting for cross-effects, the OS of the two groups was 26.8 months and 15.9 months, respectively.

Safety:

The safety analysis results are consistent with previous reports, and there are no new safety signals. In the two groups, 85% and 89% of patients had adverse reactions, among which the incidence of adverse reactions above grade 3 was 9% and 34%, respectively. The incidence of interstitial lung disease and pneumonia in the osimertinib group were 2% and 3%, respectively. Among them, 1% and 2% of interstitial lung disease and pneumonia were considered related to the study drug. There were 4% and 1% of patients in the two groups, respectively, who died due to adverse reactions.


FLAURA research

556 untreated patients with advanced lung cancer (EGFR mutation: exon 19 del. or L858R) were randomly assigned to two groups of treatment: osimertinib group and other EGFR-TKIs. The study does not exclude patients with stable symptoms of CNS metastasis. All patients were given the trial drug treatment until the disease progressed or the side effects could not be tolerated or the patient voluntarily withdrew from the trial. Control patients with confirmed disease progression or T790M mutation are allowed to cross over to unblinded osimertinib treatment.

The data as of June 12, 2017 analysis of the previous FLAURA study showed that [6], the ORR of the osimertinib group and the first-generation EGFR-TKIs group were similar (80% vs 76%), and the median PFS (18.9 months vs. 10.2 months), ADR (34% vs 45%).

In January 2020, “N Engl J Med” announced the final research results[7], The median overall survival of osimertinib in the first-line treatment of NSCLC was 38.6 months (95% CI, 34.5-41.8), and the median overall survival of the control group was 31.8 months (95% CI, 26.6-36.0), (Risk of death [HR]=0.80; 95.05% CI, 0.64-1.00; P=0.046). After 3 years of treatment, 79/279 cases (28%) in the osimertinib group and 26/277 cases (9%) in the control group continued to receive the trial medication, with a median time of 20.7 months vs 11.5 months, respectively. 42% of patients in the osimertinib group reported adverse events of grade 3 or higher, compared with 47% in the control group.


OS


Subgroup analysis

Discussion: The patients included in FLAURA were all untreated EGFR mutation-positive advanced NSCLC. These patients received longer PFS and longer OS after receiving osimertinib treatment. The two groups were followed up for at least 39 months. Even if there was a crossover from the control group to the ositinib group, the median overall survival of the ositinib group was 6.8 months longer than that of the control group, reducing the risk of death by 20%. In addition, the number of patients in the ossitinib group who continued to receive the trial drug treatment at 36 months was three times that of the control group. Even though patients in the osimertinib group took longer to take the drug, the incidence of adverse events was still similar.

In the stratified analysis, most subgroups observed a survival benefit with osimertinib, and an overall survival benefit with osimertinib was observed. Moreover, the survival benefit of each subgroup is different. In Asian patients and the L858R mutation subgroup, the hazard ratio is close to 1.0 [2020ESMO丨Lung cancer, summary of the latest progress in targeted therapy, Chinese data shows prolonged OS] Asian patients’ KM survival The curve shows that there is an early benefit trend of osimertinib and it has continued for about 3 years. As the second end point of the study, the subgroup analysis data of the Asian population in this study is not sufficient for the analysis of OS. In other words, it is not known whether the first-line use of NSCLC for overall survival in Asian populations will benefit.


Previous studies have confirmed that osimertinib in patients with EGFR T790M mutations is more effective than other EGFR-TKIs treatments. Therefore, the study allowed the control group to cross over to the ositinib group, which may lead to prolonged mOS in the control group (31.8mo). Previous studies have shown that the mOS of first-line or second-line treatment with EGFR-TIKs is between 18-28 months. The recent ARCHER 1050 study showed that the mOS of gefitinib and dacomitinib was 26.8mo vs 34.1mo, respectively. But the ARCHER 1050 study is different from FLAURA in that it did not include patients with CNS metastasis, and CNS metastasis means a shorter survival period.


The FLAURA study allowed patients who were confirmed to be positive for the EGFR T790M mutation to cross over to the ossitinib group for second-line treatment after their disease progressed. After the disease progresses, nearly 50% of patients who use the first and second generation EGFR-TKIs will develop EGFR T790M, which creates a biological driving factor for the second-line treatment of osimertinib. In the real world, it has been reported that 25-39% of patients receive first- and second-generation EGFR-TKIs treatment and continue to receive osimertinib as a second-line treatment. In the control group of the FLAURA study, 31% (85/277) of patients were cross-used with osimertinib as the first follow-up treatment.


The follow-up treatment received in the two groups was basically consistent with the recommendations of the treatment guidelines. The first follow-up treatment for most patients in the osimertinib group was chemotherapy, while the cross-use of osimertinib in the control group was the most common follow-up treatment. The proportion of the two groups receiving another regimen containing EGFR-KTIs (excluding osimertinib) was similar. The proportion of patients who received the second follow-up treatment in the two groups was similar, and the types of treatment received were also similar.


In these two groups, about 30% of patients discontinued the trial drug and did not receive the first follow-up treatment, because about 70% of them died. The data is consistent with the results of previous studies of EGFR-KTIs treatment.


Among NSCLC patients with EGFR mutations, approximately 25% of patients have CNS metastases at the time of diagnosis, and nearly 50% of patients have CNS metastases within 3 years of diagnosis. The results of FLAURA’s previous study showed that osimertinib is also active for CNS metastasis. The progression-free survival rate at 18 months was 58% vs 40% in the oscitinib group and the control group (risk of disease progression [HR], 0.48; 95% CI, 0.26-0.86).


To understand the resistance mechanism after first-line treatment and determine the appropriate treatment method, molecular tolerance mechanism is an important consideration. Preliminary data indicate that the resistance mechanism of osimertinib in the first-line treatment is similar to that of patients receiving osimertinib as the second-line treatment of T790M mutation. This resistance mechanism is also similar to the rare mutations (except T790M) that use first and second generation EGFR-KTIs to resist. A phase II ELIOS study is undergoing a more in-depth study (NCT03239340). Two studies based on the best treatment model for resistance after receiving first-line osimertinib therapy-the ORCHARD study and SAVANNAH-are also ongoing.


In conclusion, the use of osimertinib in the first-line treatment of EGFR-mutant NSCLC can achieve longer overall survival and similar safety than other EGFR-TKIs.

 

Brain metastases

AURA3 subgroup analysis:

The median PFS (11.7 months vs 5.6 months) and ORR (70% vs 31%) of CNS metastasis in the osimertinib and chemotherapy groups;

FLAURA subgroup analysis:

The median PFS (not reached vs 13. 9 months) and ORR (66% vs 43%) in the osimertinib group were significantly better than the standard treatment group.
Don’t be afraid of brain and meningeal metastases from lung cancer, you might as well try osimertinib

 

Ametinib

Blockbuster丨The domestic third-generation EGFR-TKI Ametinib, with amazing curative effect appeared on AACR
“Excellence in China, the era of Merlot”-the first-line treatment of NSCLC, Ametinib has achieved a major breakthrough in targeted therapy of lung cancer!

Vometinib

The 2020 American Society of Clinical Oncology (ASCO) annual meeting announced the results of the phase IIb study of vomitinib[8]. The objective response rate (ORR) of vomitinib in the treatment of EGFR T790M mutation-positive locally advanced or metastatic NSCLC is 74.1 %, disease control rate (DCR) is 93.6%, disease progression-free survival (PFS) is 9.6 months, and it also shows a strong effect on brain metastases with poor prognosis.

At the 21st World Conference on Lung Cancer (WCLC 2020) held this year, the analysis results of vomitinib in the treatment of CNS metastasis NSCLC were announced [9]. This result comes from the Phase I-II dose expansion study of vomitinib in the treatment of EGFR T790M mutation-positive locally advanced or metastatic NSCLC. The results showed that the CNS ORR of 80 mg vomitinib treatment of NSCLC patients with CNS metastasis was 60.0%, and the CNS ORR of 160 mg vomitinib treatment of NSCLC patients with CNS metastasis was 84.6%, and the DCR was 100%.

Efficacy results of patients with CNS metastasis in different dose groups (data cut-off date: 2020-01-29)



Abbreviations: CNS, central nervous system; cEFR, CNS assessable efficacy set; cFAS, CNS full analysis set; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; NR, not reached

In terms of safety, 26% of patients in the vometinib treatment group observed ≥3 grade adverse events (AE), 11% of which were treatment-related, and each single ≥3 grade treatment-related adverse event was not higher than 1%; The incidence of treatment-related diarrhea and rash is relatively low, at 5% and 7%, respectively, and both are grade 1 to 2. The most common treatment-related adverse reactions of grade ≥3 were mainly aspartate aminotransferase elevation (1%), alanine aminotransferase elevation (1%), and gamma glutamyl transpeptidase elevation (1%). No unexpected events were found Special adverse events.

On March 3, 2021, the State Food and Drug Administration approved vomitinib conditionally based on the above research results during or after previous treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have had disease progression and confirmed the presence of EGFR T790M mutation-positive.

 

EGFR-TKIs+ anti-vascular

A+T (1st generation targeted drug)

Lung cancer丨EGFR mutation treatment A+T regimen, the efficacy is comparable to osimertinib
Lung cancer丨targeted combined anti-vascular therapy efficacy and drug resistance mechanism
A+T (3rd generation targeted drugs)

Osimertinib + Bevacizumab

WJOG-8715L research[12]:

This is a phase II randomized controlled study to observe the efficacy of osimertinib combined with bevacizumab in the treatment of T790M-positive patients(Second-line treatment). A total of 81 patients were enrolled, 40 patients and 41 patients were enrolled in the combination therapy group and osimertinib single-agent group, respectively. However, multiple parameters were worse in the combination treatment group.

The median PFS in the combination therapy group and the single-agent osimertinib group was 9.4 months and 13.5 months, respectively (HR1.44, 95%CI, 1.00-2.08, P=0.20), that is, in the osimertinib group Combining bevacizumab therapy on the basis of treatment actually increased the risk of disease progression by nearly 1.5 times. The OS data of the two groups were similar, not reached and 22.1 months (P=0.96), only ORR was better in the combined treatment group, with 68% and 54% in the two groups, respectively.



PFS


OS

 

A study: 

A phase 1/2 clinical study that explores the efficacy and safety of first-line osimertinib combined with bevacizumab(First-line treatment).  A total of 49 patients were enrolled in the study, and the median PFS was only 19.0 months. Although there is no control group, we know based on the FLAURA study that the first-line treatment of patients with 19del or 21L858R mutations, even if osimertinib alone has PFS It has reached 18.9 months, and the combined bevacizumab does not seem to have a substantial increase in data. In addition, studies suggest that the detection of EGFR mutations in ctDNA at week 6 is associated with shorter median PFS and OS.

ctDNA and OS, PFS

 

Osimertinib + ramucirumab

Another study:

The clinical study of combined osimertinib in the treatment of patients with advanced NSCLC with T790M mutation. A total of 25 patients were enrolled in the group. During the dose anti-climbing phase, no dose-limiting toxicity was observed in the 3 included patients. Therefore, during the cohort expansion phase, 22 additional patients were included and a total of 25 patients received at least treatment. Based on the Phase I dose exploration, the patient’s subsequent dose was determined to be ramucirumab 10mg/kg, once every two weeks, combined with osimertinib 80mg, orally, once a day.

The confirmed ORR of the entire group of patients was 76%, and another 16% of patients were assessed as SD, and the median duration of response was 13.4 months. The ORRs of patients with and without brain metastases at baseline were 87% and 60%, respectively. The median PFS of the entire group was 11 months, and the PFS rates at 6 months, 12 months, and 24 months were 67%, respectively. , 50% and 20%. For patients with and without brain metastases at baseline, the median PFS was 14.7 months and 10.9 months, respectively.

 


EGFR-TKIs+ chemotherapy

JMIT Research (Phase II):

The median PFS of untreated patients with advanced NSCLC with EGFR sensitive mutations treated with gefitinib combined with pemetrexed and gefitinib were 15.8 months and 10.9 months, respectively.

NEJ009 Research:

Based on the results of the JMIT study, a phase III study was carried out. Enrolled 345 patients with advanced NSCLC who were newly treated with EGFR sensitive mutations. The results showed that compared with the gefitinib group (n=173), the gefitinib+carboplatin+pemetrexed group (n=172) showed superior efficacy, with a median PFS of 11.2 months and 20.9, respectively Months, ORR was 67% and 84%, and median OS was 38.8 months and 52.2 months, respectively. The incidence of grade 3 and above adverse reactions in the combination group was higher (31.4% vs 65.1%), mainly bone marrow Inhibition, the overall tolerance is better.

NEJ032A Study (2020WCLC)

For the first-line treatment of T790M mutation, osimertinib alone is better than combination chemotherapy

Osimertinib has been approved for the first-line treatment of EGFR+ advanced NSCLC, as well as the second-line treatment of T790M mutation after initial treatment, but the safety of osimertinib combined with chemotherapy is still unknown. NEJ032A is a randomized phase II study to compare osimertinib single agent vs osimertinib + carboplatin + pemetrexed first-line treatment of patients with EGFR-TKI progression. A total of 62 patients were enrolled in the study, and they were randomly divided into osimertinib single-agent group and combined chemotherapy group at 1:1.


Research design


PFS

 

Research results:


1) The median PFS of the osimertinib group was 15.8 months, and the median PFS of the combination group was 14.6 months (HR 1.09, 95% CI: 0.51-2.32, P = 0.83). The median OS was not reached (HR 2.42 (95% CI: 0.82-7.15), P = 0.10). The response rate of the osimertinib group was 71.4%, and the response rate of the combination group was 53.6%. In the osimertinib group, the incidence of treatment-related adverse events (G) ≥ grade 3 was 45.2%, and in the combination group it was 83.9%.


2)This is the first randomized study on the efficacy and safety of osimertinib combined with chemotherapy in NSCLC patients with EGFR sensitizing mutations. The study did not reach the primary endpoint. 
From the current data, the efficacy of single-agent and combination chemotherapy groups is not much different, and even osimertinib is more effective as a single agent and has fewer side effects. Research further supports the clinical effect of osimertinib as a single agent.


Targeting + anti-vascular/chemotherapy summary

Judging from the existing data, the combined treatment strategy for patients with advanced NSCLC does not seem to be suitable for osimertinib; in the field of postoperative adjuvant therapy, combined chemotherapy seems to be better, but it still needs to wait for the NeoADAURA study to give a confirming conclusion.

Although the first-generation EGFR-TKI combined chemotherapy and anti-angiogenesis therapy have been supported by numerous phase II and phase III clinical research data, at present, the third-generation drug osimertinib-based combination therapy strategy has not yielded significant positive results.

Therefore, if you consider combination therapy, the current generation of drugs may still be the first choice.

 

 

(source:internet, reference only)


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