Osimertinib resistance strategy is fully sorted out (recommended collection~)

A situation that all patients with advanced EGFR mutant NSCLC have to face is the problem of TKI drug resistance! In the face of this difficult difficulty, all patients who have undergone first-line or second-line treatment of TKI, NCCN guidelines recommend: if the patient has a T790M mutation, three generations of TKI osimertinib are recommended; In patients without a T790M mutation or Ossim-resistant patients, standard chemotherapy is recommended
.
Unfortunately, platinum-based chemotherapy, the median PFS is only about 4 or 5 months, and the efficacy is very limited! The matter of "drug resistance" is like a sword of Damocles hanging over the heads of all patients, a dangerous blade hanging above the head, and I don't know when it will fall
.
If the drug has not been resistant, the effect is good, and the remission obtained by the patient can be maintained for a long time, and even life can be carried out as usual; Once drug resistance, the lesions begin to grow rapidly again, and the cancer returns
.
At present, the latest drug of EGFR+ is the third generation of "star" targeted drug osimertinib, although many lung cancer patients have successfully "continued their lives", but it is difficult to escape the fate
of "drug resistance".

Six strategies for osimertinib drug resistance management

EGFR IV drugs have brought a new dawn to countless patients, but so far, the FDA has not approved any new targeted drugs for osimertinib-resistant patients, and there is still a long wait
from clinical research to formal approval of drugs.
Then patients who have osimertinib resistance can first be targeted according
to the state of disease progression.

First, slow progress,

Oimertinib can be continued with topical therapy

Studies have shown that most patients with primary resistance to osimertinib have isolated progression, and these patients can benefit
from continuing osimertinib in combination with topical therapy.
Therefore, for drug-resistant patients who are asymptomatic and have slow radiographic progression, they can change their drugs
without rushing.
NCCN guidelines recommend that patients with the following three conditions may consider radical topical therapy (eg, stereotactic body radiotherapy or surgery) while continuing osimertinib:

(1) asymptomatic progression;

(2) Symptomatic brain metastasis (with brain metastasis treatment, such as whole brain radiotherapy, pemetrexel, temozolomide, intrathecal injection, etc.
);

(3) Symptomatic systemic (extracranial) isolated lesions (metastases< 3-5).
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Second, genetic testing to find out drug-resistant mutations,

Targeted combination therapy is given

If osimertinib progresses rapidly after use, prompt genetic testing and targeted therapy
according to the mutation.

1.
C797S single mutation,

Use a generation of EGFR-targeted drugs

First-line use of osimertinib, T790M mutations generally do not appear after drug resistance, but a single mutation of C797S will be found, because the early use of osimertinib can inhibit the production of T790M mutations and avoid the coexistence
of T790M with other mutations.
Mutations at this site are sensitive to either gefitinib or erlotinib in the first generation, and clinical management is relatively easy
.

2.
C797S and T790M cis-mutations,

It is still under research

T790M and C797S appear at the same time and are located on the same chromosome, which can be treated with bucatinib combined with cetuximab (Epito), and there are domestic case reports
.
A 62-year-old female patient with lung adenocarcinoma was treated with osimertinib after chemotherapy, gefitinib, and erlotinib
resistance.
After 8 months, it progressed again, and the cis-mutation of T790M-C797S was found, with bugasinib (90 mg/day) and cetuximab (600 mg/month), stable control
.

3.
Trans mutation of C797S and T790M,

1st + 3rd generation EGFR targeted drugs

T790M mutation and C797S mutation appear at the same time, located on the opposite chromosome, and the treatment method is 1st generation TKI combined with 3rd generation drug
.
Real case introduction: Professor Lu Shun of Shanghai Chest Hospital published a domestic case of trans mutation treatment in the journal JTO, a 42-year-old female lung adenocarcinoma 19Del patient was treated with osimertinib
positive after multi-line drug resistance (erlotinib, chemotherapy).
After 3 years, the drug resistance appeared C797S and T790M co-mutation, trans structure, treated with 1st generation + 3rd generation, combined with bevacizumab, maintained for 8 months
.
4.
Secondary MET amplification,

EGFR inhibitors + MET inhibitors

Whether osimertinib is used first- or later-line, the proportion of MET amplification is approximately the same, 15%-20%.

Treatment can be controlled with current MET inhibitors
.
For example, savolitinib combined with osimertinib, in a phase 1b study, osimertinib + savolitinib was used
for patients with positive MET amplification after osimertinib progression.
The ORR (objective response rate) was 25%, the DCR (disease control rate) was 69%, and the median DOR (duration of response) was 9.
7 months
.

In addition, successful cases of osimertinib combined with cabozertinib/crizotinib have been reported
.

5.
Secondary mutations in other targets

In addition to C797S and MET amplification, other bypass activations occur after osimertinib resistance, and corresponding combination therapy regimens can be used, and some literature reports have certain curative effects
.

6.
Secondary EGFR point mutation:

Back to 1/2 generation EGFR targeted drugs are available

Osimertinib resistance can secondary point mutations
on EGFR targets.
In addition to C797S is a common point mutation (solution mentioned above), EGFR L718V, G724S allele mutations will also occur, and these patients can actually overcome drug
resistance with 1/2 generation EGFR-TKI.
There have been many case reports
in the past.

Third, after genetic testing, there are no targeted drug-resistant targets,

A new combination regimen or anlotinib may be used

1.
First return to chemotherapy, flexible medication,

Osimertinib can be interspersed or tried to challenge osimertinib

In the absence of a target available, osimertinib-resistant patients should theoretically return to chemotherapy
aggressively.
Previous studies have shown chemotherapy to be 31% effective in treated T790M-positive patients and 4.
4 months
for median PFS.
In addition to conventional chemotherapy, studies have shown that interpolation therapy and re-challenge (TKI resistance after progression after other regimens, reuse of previously used TKI) target drug also have some clinical efficacy
.

2.
Anlotinib

Anlotinib is a domestic small molecule multi-target TKI (targeted drug).

In the ALTER0303 study, patients with advanced NSCLC were treated with anlotinib third-line and later
.
In the overall population, anlotinib extended overall survival (OS) by 3.
33 months, 9.
63 versus 6.
30 months
, compared with placebo.
Anlotinib extended PFS by 3.
67 months, 5.
37 months versus 1.
40 months
.
Subgroup analysis showed significant PFS and OS benefits
in patients with EGFR treated with anlotinib.
At present, it has also entered medical insurance and can be reimbursed
.

3.
Immunotherapy is not routinely recommended,

May be combined with chemotherapy or screening

PD1/PDL1 is not routinely recommended for patients with EGFR mutations because the efficacy of immunologic drugs in this population is low and prone to hyperprogression
.
However, some studies have found that EGFR mutation patients with high PDL1 expression and smoking are immune benefit groups
.
Overall, although PD-1/PD-L1 monotherapy is not recommended after EGFR resistance, immunotherapy combined with chemotherapy or antiangiogenic drugs has also achieved good efficacy
in the treatment of EGFR-resistant patients.

4.
Afatinib + cetuximab

NCCN guidelines recommend afatinib plus cetuximab as a treatment regimen for EGFR resistance
.

5.
Osimertinib addition

Generally, 80mg/day → 160mg/day are suitable for patients who have no new target and can kill tumors by increasing the concentration of drugs in vivo, especially meningeal metastases
.
The BLOOM trial included 21 patients with pia mater metastases with EGFR19/21 mutations (previous median treatment line = 3, all with EGFR targets) treated with osimertinib 160 mg/day
.
Among them, there were 8 cases of T790M mutation
.
The results showed that the confirmed pia mater ORR was 33.
33%, and the DCR reached 76.
19%.

Here's an example
.
The figures A and B below show the lesion changes of the meningalea before and after osimertinib increment (80mg→160mg), and the efficacy of the lesion reached partial remission PR
after increasing the dose.

6.
"Impulsive" Trocay

Large doses are administered in a short period of time, and there is no unified dosage regimen
in clinical practice.
NCCN guidelines recommend "pulsed" Tarcai for patients
with EGFR meneal membrane metastases.

4.
New target drugs or "fourth generation" TKI (participation in clinical trials)

1.
U3-1402 (HER3 targeted drug)

2020 WCLC reports a Phase I clinical study (NCT03260491) evaluating the safety and efficacy
of treatment with the HER3 inhibitor U3-1402 (patritumab-deruxtecan, 5.
6 mg/kg) in patients with advanced EGFR-TKIs osimertinib therapy and platinum-based chemotherapy 。 The median duration of treatment was 3.
5 months, the median follow-up was 5 months, and 55% of patients continued treatment, and the efficacy chart was shown below: one patient achieved CR, 13 patients confirmed as PR, and 3 PR patients were to be confirmed
.
2.
JNJ6372 single agent or in combination with third-generation TKI,

Strong challenge to osimertinib resistance to hope!

The Phase I clinical trial
of Amivantamab alone or in combination with Lazertinib for the treatment of patients with NSCLC with EGFR mutations was reported at the 2020 ESMO Conference.
In 45 patients with osimertinib-resistant, the overall effective rate can reach 36%, and the disease control rate can reach 60%.

It is currently the most effective regimen
after osimertinib resistance.
Therefore, once JNJ-6372 is on the market, osimertinib/ametinib combined with 6372 will address drug resistance and may impact the first and second lines
.

V.
Treatment of transformed small cell lung cancer:

In addition to conversion chemotherapy, cases with osimertinib rotation therapy also worked

Pathological type transformation is one of
the causes of osimertinib resistance.
In August 2018, Professor Geoffrey R.
Oxnard of Harvard University analyzed 41 patients after osimertinib resistance and found that 6 patients had developed transformation
of small cell lung cancer.
T790M mutations in such patients are absent (suggesting that T790M is independent of small cells), but are generally accompanied by gene mutations
that are common in small cells such as TP53, RB1, and PIK3CA.
For such people, the treatment plan needs to be combined with a chemotherapy regimen for small cell lung cancer such as EP, and such patients have encountered many times in the patient group, and the effect after symptomatic medication is good
.

Here is an example of osimertinib rotation.

A female patient, 61 years old, advanced lung adenocarcinoma with brain transfer, positive for L858R, successively treated with gefitinib, erlotinib, chemotherapy, and afatinib for 4.
2 years
.
The patient's right pleural metastases were measured with a T790M mutation (tissue as adenocarcinoma), but a pleural tumor near the right diaphragm was found to transform into small cell lung cancer
.
Patients are treated with osimertinib and chemotherapy (carboplatin + irinotecan) rotation, switching to another regimen immediately after progression of one lesion, as shown in the figure below
.

6.
Immunotherapy

1.
AK112 for the treatment of EGFR-TKI resistance

Inclusion of breakthrough therapies

On October 20, 2022, the website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration announced that the world's first bispecific antibody new drug Evoxi (PD-1/VEGF bi-antibody, AK112), which is completely independently developed by Akeso, is intended to be included in the list of breakthrough therapy varieties.
For combination chemotherapy for the treatment of transepidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for the treatment of locally advanced or metastatic non-squamous non-small cell lung cancer (NSQ-NSCLC)
with resistant EGFR mutations.

2.
Tislelizumab combined with chemotherapy

Treatment of targeted resistant EGFR+NSCLC

The study included patients who had not undergone systemic chemotherapy and had disease progression after first- or second-generation EGFR-TKI and confirmed T790M-negative, or T790M-positive patients who progressed further after third-generation EGFR-TKI treatment, or 40 patients with EGFR-sensitive mutations who progressed after third-generation EGFR-TKI as first-line therapy, 21 del 19 mutations, 17 L858R mutations, and 1 each of G719X and other EGFR mutations.
There were 8 cases (20%) of brain metastases, 92.
5% had used 1 or 2 generation EGFR-TKI, 55% had used 3rd generation EGFR-TKI, 47.
5% had used 1/2 and 3rd generation EGFR-TKI, and 37.
5% had previously used antiangiogenic drugs
.
One-year progression-free survival was given to patients with tislelizumab + albumin paclitaxel + carboplatin, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety
.

The results showed that the objective effective rate of 32 patients was 59.
4%, the DCR was 90.
6%, the median time to remission was 80 (range 41-93) days, the median progression-free survival and overall survival were still immature, and as of July 13, 2021, 26 patients continued to be treated
in the group.

3.
Atenizumab + bevacizumab + chemotherapy

Treatment driver positive NSCLC

A multicenter retrospective study
of atezolizumab + bevacizumab + paclitaxel or pemetrexed in the treatment of advanced NSCLC.

Between July 2015 and July 2021, 97 patients with advanced NSCLC, with a median age of 60 years, 95% adenocarcinoma, 47% brain metastases, 13% leptomeningeal metastases, and 36% liver metastases
, were included.
There were 68 cases of EGFR+, 4 cases of ALK fusion, 10 cases of KRAS mutation, 2 cases of RET fusion and 2 cases of METex14 skipping mutation
.
Of the 68 patients with EGFR mutations, 31 had previously received osimertinib
.
53 patients received atezolizumab + bevacizumab + carboplatin + paclitaxel, and 43 patients received atezolizumab + bevacizumab + carboplatin + pemetrexed
.

Among the 73 patients evaluable, ORR 59%, DCR 85%, median PFS 5.
4 months; ORR 57%, DCR 82%, median PFS 5.
1 months in patients with EGFR mutations (51 patients), ORR 60%, DCR 83% and median PFS 5.
8 months in patients with brain metastases (35 patients), ORR 42%, DCR 84% and median PFS 4.
3 months in patients with leptomeninge metastases (12 patients), ORR 64% in patients with liver metastases (28 patients), DCR 85.
5%, median PFS 5.
1 months
.
4.
Sindili combination regimen for the treatment of EGFR targeted drug resistance

At the 2021 European Society of Medical Oncology Asia Annual Meeting (ESMO Asia), the latest data of the ORIENT-31 study was announced, which is the first time that the interim data results have been published! The immune combination regimen in the study performed excellently, significantly prolonging the median PFS, compared with the chemotherapy group: 6.
9 months vs 4.
3 months! The meeting indicated that the phase 3 study of ORIENT-31 had reached the primary endpoint
.
This study was designed to evaluate the efficacy and safety of sindilimab with or without IBI305 and chemotherapy in patients with EGFR-positive locally advanced or metastatic nonsquamous NSCLC who have progressed through EGFR-TKI therapy
.

The study included a total of 444 patients with EGFR-positive locally advanced or metastatic non-squamous NSCLC, which were divided into three situations:

(1) The treatment of first- and second-generation EGFR TKI progressed and T790M was negative;

(2) T790M positive after the progress of first- and second-generation EGFR TKI treatment and the progression of third-generation EGFR TKI treatment;

(3) Progress in first-line treatment of third-generation TKI
.
The researchers randomized patients 1:1:1 into 3 groups:

Group A: Cindilimab + IBI305 + Pemetrexed + cisplatin;

Group B: sindilimab + placebo + pemetrexed + cisplatin;

Group C: two placebos + pemetrexed + cisplatin
.

The primary endpoints were progression-free survival (PFS) assessed by IRRC according to RECIST v1.
1, and secondary endpoints included overall survival (OS), PFS assessed by investigators according to RECIST v1.
1, objective response rate (ORR), and safety
.

In the intention-to-treat (ITT) population, sindilimab plus bevacizumab + chemotherapy versus median PFS of chemotherapy: 6.
9 months versus 4.
3 months (HR = 0.
464, 95% CI: 0.
337 to 0.
639, P<0.
0001<b10>).
The ORR of the sindilimab plus bevacizumab + chemotherapy regimen was 43.
9%, compared with only 25.
2% in the chemotherapy group; There was no significant difference in median duration of response (DoR) of 8.
3 months versus 7 months
, respectively.
In terms of security, there are no new safety signals
.
The most common (≥25%) adverse events (TEAEs) during treatment included anaemia, neutropenia, loss of appetite, leukopenia, nausea, and weakness; The most common (≥2%) immunotherapy-related adverse events (irAEs) include hypothyroidism and hyperthyroidism
.

5.
Pembrolizumab:

The Phase II clinical study of immunotherapy combined with chemotherapy to attack driver gene-positive tumors (NCT03242915) explored the efficacy of
pembrolizumab (K drug) + pemetrexed + carboplatin in patients with driver-positive NSCLC 。 The study included 33 patients with recurrent NSCLC who had previously received targeted therapy, including 26 cases with EGFR mutations (median age 68 years, 74% female, 65% white, 46% brain metastases, 61% first-line therapy, 39% received more than 2-line therapy, 85% used osimertinib), and 7 cases with ALK fusion (median age 66 years, 57% female, 86% white, 28% brain metastases, 71% received first-line therapy, and 29% received more than 2nd line therapy)
。 Patients received Pak K drug (200mg) + pemetrexed (500mg/m2) + carboplatin (AUC5) once every three weeks, and after four courses, K drug + pemetrexed maintenance therapy for two years
.
The results showed that the objective effective rate (ORR) of the EGFR subgroup was 42.
3%, the median progression-free survival (PFS) was 8.
3 months, and the median overall survival (OS) was 22.
2 months.
The ALK subgroup ORR was 28.
6%, median PFS 2.
9 months, median OS 2.
9 months
.