Resistance to EGFR-TKI!

At 7 pm on November 19th, Beijing time, at the 2021 European Society for Medical Oncology Asia Annual Meeting (ESMO Asia) Plenary, Professor Lu Shun from the Chest Hospital of Shanghai Jiaotong University reported the first mid-term study of ORIENT-31 Analyze the results

Eternal resistance and progress problems

Targeted therapy represented by EGFR-TKIs is an important treatment for advanced NSCLC, which significantly prolongs the survival period of patients with EGFR mutations and has fewer adverse reactions

At present, after the first-line and second-generation EGFR TKI treatment fails, the second-line use of the third-generation TKI osimertinib for patients with T790M mutation through genetic testing has become the standard; but for the second-line biopsy of T790M mutation negative or third-generation patients For patients with failed TKI treatment, platinum-based chemotherapy is still the standard treatment.

Source: CSCO Lung Cancer Diagnosis and Treatment Guidelines 2021

Source: ESMO ASIA 2021, the same below

Significantly reduce the risk of disease progression or death by 54%

The ORIENT-31 study is a comparison of Sintilimab with or without IBI305 (bevacizumab biosimilar) and chemotherapy for EGFR-positive locally advanced or metastatic non-squamous NSCLC patients who have progressed through EGFR-TKI therapy A randomized, double-blind, multi-center phase III study on the effectiveness and safety of the drug (NCT03802240)

The study plans to enroll 480 patients with EGFR-positive locally advanced or metastatic non-squamous NSCLC

The subjects were randomly enrolled in the group according to 1:1:1, and received:

Group A: Sintilimab + IBI305 + Pemetrexed + Cisplatin;

Group B: Sintilimab + placebo 2 + pemetrexed + cisplatin;

Group C: placebo 1 + placebo 2 + pemetrexed + cisplatin;

After 4 cycles of combined treatment, the three groups continued to receive Sintilizumab + IBI305 + Pemetrexed, Sintilizumab + Placebo 2 + Pemetrexed, Placebo 1 + Placebo 2 + Pemetrexed Maintain treatment until the disease progresses, toxicity is intolerable, or other conditions that require termination of treatment

The primary research endpoint is the PFS assessed by the Independent Imaging Evaluation Committee (IRRC) according to the RECIST v1.

As of the first interim analysis on July 31, 2021, a total of 444 subjects were enrolled, and the baseline characteristics of the three groups were balanced

The first interim analysis showed that in the intention-to-treat (ITT) population, based on the blinded independent imaging evaluation committee (BIRRC) evaluation, sintilimab combined with bevacizumab and chemotherapy (group A), compared with chemotherapy (C Group) obtained a significant and clinically significant PFS extension (median PFS: 6.

Subgroup analysis showed that regardless of whether the baseline was accompanied by brain metastases, the trend of benefit of the quadruple regimen was observed

In terms of secondary endpoints, compared with the chemotherapy group, although the ORR of the four-drug combination regimen was higher (43.

In addition, in the preset invalidity analysis, Sintilizumab combined with bevacizumab and chemotherapy (group A) compared with Sintilizumab combined with chemotherapy (group B) did not cross the invalidity threshold.

In terms of safety, the results are consistent with previous reports and there is no new safety signal

The most common (≥25%) treatment period adverse events (TEAE) include anemia, neutropenia, loss of appetite, leukopenia, nausea, weakness, elevated aspartate aminotransferase, vomiting, alanine amino group Elevated transferase, decreased platelets, constipation, high blood pressure, proteinuria

The most common (≥2%) immunotherapy-related adverse events (irAE) include hypothyroidism, hyperthyroidism, elevated blood thyroid-stimulating hormone, elevated amylase, elevated aspartate aminotransferase, and alanine amino groups Increased transferase, skin rash, decreased blood thyroid stimulating hormone, increased blood creatinine, pneumonia, increased free thyroxine, increased blood creatine phosphokinase, immune-mediated lung disease

Unanswered questions

Since 2018, with the wide application of immunotherapy in different tumor types, researchers have tried to apply immunotherapy to people with EGFR mutations.

People with EGFR mutations were once considered to be "immune-exempt" groups
.
Clinical trials and meta-analysis also indicate that single-agent immunotherapy has limited benefits for people with EGFR mutations, and the efficacy is inferior to EGFR wild-type patients
.

Therefore, patients with EGFR mutations are excluded from most first-line clinical trials of immuno-oncology drugs, with the exception of IMpower130 and IMpower150
.

In the IMpower130 study, compared with chemotherapy alone, the addition of atelizumab to chemotherapy in the EGFR mutation subgroup did not show any benefit
.
In the IMpower150 study, the addition of atilizumab and bevacizumab to chemotherapy (ABCP regimen) is currently the only immune combination regimen that has proven benefits in the EGFR mutation subgroup
.

This international multi-center study overturned the previous "EGFR mutation immune exemption" theory and increased confidence in the application of immunotherapy in EGFR mutation populations
.

Based on this, the European Union approved ativizumab combined with bevacizumab and paclitaxel combined with carboplatin for the subsequent treatment of patients with EGFR-TKI resistance in March 2019
.
The FDA has also approved atelizumab for the second-line treatment of EGFR/ALK mutant metastatic NSCLC patients after TKI resistance
.

The ORIENT-31 study published this time is similar to the IMpower150 medication regimen.
The four-drug combination therapy is used, but the PD-1 monoclonal antibody is used, and the chemotherapy regimen is pemetrexed + cisplatin
.
According to the analysis of on-site discussion experts, compared with the IMpower150 study, the PFS and ORR of the ORIENT-31 study are relatively low in value, which may be due to the fact that 30% of the latter's enrolled population received both the first/second and third generation TKIs.
Heavier), and 35.
8% of patients had brain metastases at baseline
.

Following IMpower150, the ORIENT-31 study undoubtedly further increases confidence in the exploration of immunotherapy in the EGFR-mutant NSCLC population
.
However, only the results of the first interim analysis are disclosed at present.
How does the four-drug regimen compare to the three-drug regimen (A vs B)? Is it necessary to superimpose anti-angiogenic drugs on the basis of chemotherapy (B vs C)? What is the long-term safety of subsequent maintenance treatment? Can the benefits of PFS translate into benefits of OS? How to more accurately identify the beneficiaries? How to measure the benefits and risks of the four-drug regimen? ….
.
These questions still need to be answered by further follow-up data
.

It is worth looking forward to, similar to the ORIENT-31 study, multiple phase III clinical studies (KEYNOTE-789, CheckMate 722, ATTLAS) are exploring the status of chemotherapy + immunotherapy ± anti-angiogenesis therapy in patients with EGFR-TKI resistance
.
In addition to the immunization combination program, the four-generation EGFR-TKI, the combination program that simultaneously targets EGFR and other targets (MEK, PARP, CDK4/6, JAK), bispecific antibodies, and HER2-ADC are also being explored Among
.

How big is the cake of secondary EGFR resistance? How to cut? What role does immune checkpoint inhibitor play? More exciting, please look forward to the follow-up report of Med
.

Reference materials:

1.
ESMO Asia VirtualPlenary-ORIENT-31: Phase III study of sintilimab with or without IBI305 pluschemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy

2.
Ma Li, Qin Na, Zhang Xinyong, et al.
Analysis of the efficacy of immunotherapy in patients with advanced non-small cell lung cancer with EGFR mutations[J].
Chinese Journal of Lung Cancer, 2021, 24(5):7.