OS Super 59 months! Lung cancer brain metastasis recurred 3 degrees, and immunotherapy brought amazing results

Brain metastases (BM) are very common in non-small cell lung cancer (NSCLC) and the prognosis is quite poor, with median survival of less than 6 months
in untreated patients.
The mainstay of treatment for patients with NSCLC and BM is surgical resection and radiation therapy (RT) (category 2A recommended evidence), but the risk of neurotoxicity is as high as 35 percent [1].

Immunotherapy (or combination chemotherapy) has become an important treatment for NSCLC, and while there have been many clinical trials of PD-1 monoclonal antibodies for patients with metastatic NSCLC, most have excluded these untreated BM patients
.

How to choose treatment for patients with NSCLC who have not treated BM? This issue of the tumor channel brings a miracle case
of NSCLC combined with BM that has been completely remitted after fourth-line treatment.

Medical record information

Patient, male, 60 years old

Complaints: repeated cough and sputum for more than several months

Cardiopulmonary physical examination is normal, smoking for 40 pack years
.

CT: right mid-lobe mass (2.
7 cm×2.
1 cm), right inferior hilar metastases (5.
0 cm× 6.
2 cm) with mediastinal lymphadenopathy
.

Mediastinal lymph node biopsy: lung adenocarcinoma, CK7(+), TTF1(+) and Napsin A(+)

MRI: multiple incunar brain injuries in the frontopatrietal lobe

Immunohistochemistry: PD-L1>95%.

Genetic testing: EGFR(-), ROS1(-), ALK(-), BRAF(-), C-MET(-).

Clinical diagnosis: NSCLC stage IIIB (T4N2M0).

ECOG score: 1 point

After diagnosis and treatment

First-line treatment:

After careful consideration of the risks and benefits of concurrent chemoradiotherapy, patients refuse to receive radiotherapy
.

What treatment will you choose?

answer

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The patient was given first-line chemotherapy
with pemetrexed plus cisplatin (PP) with informed consent in February 2017.

After 4 cycles of combination chemotherapy, a partial remission (PR)
was obtained.
Discuss with a radiation oncologist to determine if chest radiation therapy
should be started immediately.
Due to poor lung function and increased tumor burden, we considered two additional chemotherapy regimens
.
Unfortunately, after the fifth cycle of chemotherapy, radiological evaluation showed PD.

Second-line treatment:

PP regimen is not effective, what treatment will you choose?

answer

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Beginning in June 2017, the regimen was changed to gemcitabine plus cisplatin (GP) as second-line chemotherapy
.

However, after 1 cycle, the patient developed hemoptysis and imaging showed PD (Figure 1A).

(Figure 1A imaging data shows PD)

Third-line therapy:

With cisplatin combined with antifolic acid (PP), pyrimidine antitumor (GP) drugs have failed one after another

What treatment will you choose?

answer

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Since July 2017, pembrolizumab plus docetaxel has been given as third-line therapy
.

After 2 cycles, a decrease in the size of the right inferior hilar mass was rapidly confirmed by chest CT (Figure 1B).

(Figure 1B Mass reduction)

MRI of the brain in September 2017 showed multiple metastases in the left frontal lobe and cerebellum, with a maximum diameter of 2.
1 cm × 1.
5 cm (Figure 1C, 1D).

(Figure 1C, 1D left frontal lobe and cerebellar multiple metastases)

Fourth-line treatment:

In October 2017, the patient's hemoptysis was significantly relieved and there were no obvious symptoms
of brain metastasis.

How would you choose a treatment plan?

answer

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Doctors subsequently changed the regimen to pembrolizumab plus temozolomide (132 mg/m2/day) for 5 days
.

After 1 cycle of treatment with temozolomide combined with pembrolizumab, the left frontal lobe and cerebellum of craniocerebral metastases continued to shrink (Fig.
2, 2b), but brain MRI showed new metastases in the right occipital lobe with a maximum diameter of 1.
3 cm × 1.
0 cm (Figure 2).

(Fig.
2 After one cycle of combination therapy with temozolomide and pembrolizumab, new metastases
in the right occipital lobe were found.
) ）

Temozolomide combined with pembrolizumab regimen has a significant efficacy, and lung lesions and BM continue to shrink, (Fig.
3A-3D).

In January 2018, both the primary lung and brain metastases reached CR (Figure 3E-3H).

(Fig.
3A-3D Lung lesions and persistent reduction of BM)

Consolidation therapy:

From February to August 2018, pembrolizumab was reduced to 100 mg per month and temozolomide 250 mg
per month.
Maintained for 24 months
.

The patient is still alive with CR
in both primary lesions and BM.
The last follow-up visit was in January 2022
.

Following initial treatment with docetaxel and pembrolizumab in September 2017, exudative inflammation of the left lower lobe of the lung was relieved
with antibiotics instead of corticosteroids.
The patient experiences slight numbness on both sides of the foot, which does not interfere with his daily life
.

The clinical history and course of
treatment are summarized in Figure 4.

(Fig.
4 PP: pemetrexed plus cisplatin, GP: gemcitabine plus cisplatin, ICIs: immune checkpoint inhibitors, TMZ: temozolomide)

Pembrolizumab may be effective against BM

This case [2] is stage IIIB lung adenocarcinoma
.
No driver gene mutations, platinum-based chemotherapy
is given.
Severe cough with hemoptysis and chest CT scan show progression (PD).

Immunotherapy was considered, and after pembrolizumab combined with docetaxel, two brain metastases
were found.
After 1 month of switching to temozolomide in combination with pembrolizumab, there was a new metastasis in the right occipital lobe, but the other 2 lesions continued to shrink
.
After 3 cycles of continued treatment, complete remission (CR)
was achieved in both the primary lung and BM.
Currently, the patient has been OS for 59 months
.

In an analysis of pembrolizumab in NSCLC and BM, the activity of pembrolizumab in brain tumors was similar to that observed in extracranial tumors [3].

Patients with BM with tumors between 5-20 mm are treated with pembrolizumab 10 mg/kg every 2 weeks until PD (13).

In Cohort 1, patients >1% of patients PD-L1, achieving an objective response rate of 29.
7%; In contrast, patients in Cohort 2 had PD-L1 <1% and BM did not respond.
<b11> The median time to BM response was 1.
8 months[3].

In this case, both BM and pulmonary lesion reactions occurred 2 months after pembrolizumab treatment, consistent
with the above study.

A recent first-line immunotherapy trial of NSCLC showed that 35 cycles of pembrolizumab at 200 mg every 3 weeks (nearly 2 years) were beneficial to 39 patients, and 82.
1% of patients had OS for more than 5 years without adverse reactions related to grade 5 treatment; However, patients with untreated BM were excluded from the trial [4].

A reduced dose of pembrolizumab (100 mg every 21 days) was used as maintenance therapy for more than 2 years in this case, suggesting that lower doses may also be effective
.

Temozolomide + WBRT failed to significantly improve OS

Temozolomide is an oral alkylating agent with small molecular weight, broad anti-tumor spectrum, lipophilicity, etc
.
Due to its superior ability to cross the blood-brain barrier, temozolomide is used in glioblastoma patients
.

Although previous clinical trials have shown that temozolomide is associated with higher CR rates in patients with BM than whole-brain radiotherapy (WBRT) (38% vs.
33%; P = 0.
017), but the incidence of vomiting was higher
in the combined group.
For patients with NSCLC and BM, objective response rate (ORR) and progression-free survival (PFS) were significantly improved in the temozolomide + WBRT group (6.
0 vs.
3.
5 months; P = 0.
038), but the difference in OS was not significant [5].

In this case, the patient has no central nervous system symptoms and the primary lung focus is effectively controlled, so temozolomide plus pembrolizumab is recommended instead of WBRT
.

ICIs are active against BM after pembrolizumab therapy

An analysis of the efficacy of immunotherapy in 27 patients with NSCL expressing PD-L1 > found that two of the three patients with BM had primary PR but BM progression and survival time exceeded two years [6].

Also observed in this case, the primary lung shrinkage
after treatment with pembrolizumab plus docetaxel.
We hypothesize that the effects of immunotherapy by altering immune cell balance and enhancing immune monitoring may have a synergistic effect, but the specific mechanism is not well understood
.

ICIs combined with temozolomide deserve further exploration

A growing body of clinical data suggest that immunotherapy works well with radiotherapy alone or in combination, but further evaluation
of the efficacy and safety of this regimen is needed.

There are risks associated with the combination of ICIs and temozolomide, which may affect DNA repair and lead to mismatch repair, and the combination of ICIs may produce neoantigens and increase the mutational load
of human colorectal cancer.
In addition, temozolomide may also reduce regulatory T cells, leaving a large number of activated effector T cells in the tumor microenvironment [7].