Case Analysis｜Clinical Application of First-line Immunization Combined with Chemotherapy for Extensive Stage Small Cell Lung Cancer

Author: Xu Jinbiao First Affiliated Hospital of Nanchang University high-tech hospital oncology article is the author's permission NMT Medical publish, please do not reprint without authorization
.

Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) according to histological characteristics, of which small cell lung cancer accounts for about 14%
.

SCLC is divided into limited-stage disease (LD) and extensive-stage disease (ED) according to the two classifications of the American Veterans Lung Cancer Association.
Limited-stage SCLC accounts for 1/3 of SCLC
.

Surgery is an important part of the comprehensive treatment of early LD-SCLC (T1-2N0M0), but only 5% of patients can be operated on
.

In recent years, breakthroughs have been made in immunotherapy for SCLC, and combined immunotherapy has become the first-line treatment recommended by the guidelines
.

A recently admitted patient with extensive-stage small cell lung cancer was treated with immune-combined chemotherapy in the first line.
The lesions were significantly reduced and the quality of life was significantly improved
.

Now I share this patient's diagnosis and treatment experience and my own experience, hoping to bring some help to patients with small cell lung cancer
.

The general condition of the patient is a 54-year-old female patient
.

In August 2021, coughing and sputum recurring began to occur, occasionally with blood in the sputum
.

The past history is nothing special
.

Come to our hospital on August 22, 2021 to complete the inspection: tumor markers: carcinoembryonic antigen 125ng/mL; neurospecific enolase 37.
59ng/mL
.

Chest and abdomen CT: 1.
Right lower lung Ca and mediastinal lymph node metastasis, right pleura and interlobular pleura metastasis, right pleural effusion
.

The two lungs are scattered with tiny nodules, except for metastasis
.

Brain MRI: No obvious abnormalities
.

Pleural effusion pathology: malignant tumor cells were found.
Right lower lung mass puncture biopsy pathology: (right lung) small cell carcinoma
.

Final diagnosis: extensive stage small cell lung cancer
.

Treatment decision (1) Thoracic puncture and drainage, relieve cough and resolve phlegm
.

(2) Drug selection for anti-tumor therapy: immune combined chemotherapy
.

Therapeutic effect The patient had 2 courses of immunization combined with chemotherapy on August 30 and September 23, specifically: etoposide 140 mg d1-3 + cisplatin 30 mg d1-2 40 mg d3 + tislelizumab 200 mg d1
.

Re-examination after 2 courses, the curative effect assessment is big PR
.

The symptoms of cough and sputum disappeared
.

Experience 2018 can be said to be a turning point in the treatment of extensive-stage small cell lung cancer
.

Before 2018, the first-line standard was etoposide/irinotecan combined with platinum
.

In view of the IMpower133 study and the CASPIAN study, NCCN and CSCO guidelines listed atelizumab, duvalizumab combined with EP regimen as the first-line treatment recommendation for extensive-stage small cell lung cancer
.

There is no standard recommendation for third-line treatment before 2018.
In view of the CheckMate 032 study, KEYNOTE-028 study, KEYNOTE-158 study, and ALTER1202 study, the CSCO guidelines list PD-1 inhibitors and anlotinib as the third-line treatment for extensive-stage small cell lung cancer Recommended
.

 The progress of first-line immunotherapy for extensive-stage small cell lung cancer is summarized as follows: 1PD-L1 inhibitor combined with chemotherapy IMpower133 study [1] is a randomized, double-blind, multi-center phase III clinical study, including 403 newly-treated ED-SCLC patients , One group received 4 cycles of atezizumab + EP regimen induction, and then followed by atilizumab maintenance treatment; the other group was treated with EP + placebo, followed by placebo maintenance treatment
.

The primary endpoints of the study are overall survival (OS) and progression-free survival (PFS)
.

The final results of the study showed that the median OS of the atilizumab group and the placebo group were 12.
3 months and 10.
3 months respectively (P=0.
007); the median PFS were 5.
2 months and 4.
3 months, respectively (P=0.
02 )
.

The toxicity of the atilizumab combination group was controllable
.

IMpower133 is the first phase III study that has achieved OS benefit in the first-line treatment of ED-SCLC in 30 years
.

IMpower133 study OS results CASPIAN study[2] randomly divided 805 newly-treated ED-SCLC patients into 3 groups at 1:1:1: (1) Immunization + chemotherapy group: Duvalizumab combined with EP three-week program Treatment for 4 cycles, the sequential 4-week regimen of Vallizumab maintains treatment until the disease progresses; (2) Chemotherapy group: EP three-week regimen for 6 cycles; (3) Double immunity + chemotherapy group: Duvalizumab Anti-Tremelimumab combined with EP three-week regimen was treated for 4 cycles, followed by a four-week regimen of Vallizumab to maintain treatment until the disease progressed
.

The primary study endpoint was OS.
The median OS of the immune+chemotherapy group and the chemotherapy group were 12.
9 months and 10 months, respectively (P=0.
0032)
.

The updated data from ASCO in 2020 show that the dual-immune combination chemotherapy does not bring about the improvement of OS and PFS compared with chemotherapy
.

The CASPIAN study further confirms that the first-line treatment of ED-SCLC by immunotherapy combined with chemotherapy has the benefit of OS
.

CASPIAN study OS results 2PD-1 inhibitor combined with chemotherapy KEYNOTE-604 [3] is a randomized, double-blind, placebo-controlled phase III study, 453 newly diagnosed ED-SCLC patients were randomly assigned to receive pembrolizol Anti-combined chemotherapy or placebo combined with chemotherapy
.

The primary endpoints of the study are OS and PFS
.

The results showed that the median PFS in the pembrolizumab group and the placebo group were 4.
8 months and 4.
3 months, respectively (P=0.
0023); the median OS was 10.
8 months and 9.
7 months, respectively (P=0.
0164, unsatisfied P=0.
0128 preset); objective response rate (ORR) was 70.
6% and 61.
8%, respectively; median duration of response (DOR) was 4.
2 months and 3.
7 months, respectively
.

Pembrolizumab combined with chemotherapy improved the PFS of ED-SCLC patients.
The OS did not reach the critical value of the designed statistical hypothesis, but there was a trend of benefit
.

KEYNOTE-604 study OS results ECOG-ACRIN EA5161 [4] is a phase II clinical study, 160 patients with newly-treated SCLC were randomly divided into nivolumab combined with EP group and EP group, the main study endpoint is OS
.

The results showed that the PFS of nivolumab and EP groups were 5.
5 months and 4.
6 months, respectively (P=0.
012); OS were 11.
3 months and 8.
5 months, respectively (P=0.
038); the two groups were ≥3 level treatment related The incidence of adverse events (TRAE) was 77% and 62%, respectively
.

ECOG-ACRIN EA5161 study OS results 3CTLA-4 inhibitor combined with chemotherapy CA184-041 study [5] 1132 patients with ED-SCLC were included and randomly divided into EP+ipilimumab group and EP+placebo group.
The main study endpoint is OS The final study results showed that the median OS of the ipilimumab group and the placebo group were 11 months and 10.
9 months, respectively (P=0.
3775); the median PFS were 4.
6 months and 4.
4 months, respectively
.

Diarrhea, rash, and colitis occurred more frequently in the EP+ipilimumab group, and the incidence and severity of other adverse events were similar in the two groups
.

Compared with EP chemotherapy alone, the first-line EP+ipilimumab group did not bring survival benefits to ED-SCLC patients
.

Some studies are currently exploring the value of ipilimumab group combined with PD-1 inhibitors in the first-line treatment of ED-SCLC
.

4 Exploration of domestic immunologic drugs in the first-line treatment of ED-SCLC The RATIONALE 206 study is a phase II clinical study of tislelizumab combined with chemotherapy in the first-line treatment of Chinese patients with advanced lung cancer.
This study covers various tissue types of lung cancer, including non- Squamous NSCLC, squamous NSCLC and SCLC, preliminary evaluation of the effectiveness and safety of tislelizumab combined with chemotherapy in the treatment of lung cancer
.

The median follow-up time for the small cell lung cancer cohort was 15.
5 months, the median OS was 15.
6 months, the ORR of the primary study endpoint reached 77%, and there were no new AEs
.

RATIONALE 206 study curative effect summary Etoposide + cisplatin has been unchanged for more than 20 years as the first-line chemotherapy regimen for extensive-stage small cell lung cancer.
The effective rate can reach 60%~65%, but the median survival time of patients is only 10 Month
.

At present, in view of the IMpower133 study and the CASPIAN study, the NCCN and CSCO guidelines list atilizumab and duvalizumab combined with EP regimens as the first-line treatment recommendation for extensive-stage small cell lung cancer
.

For PD-1 inhibitors combined with chemotherapy, PFS reached the end point in the dual-endpoint of the KEYNOTE-604 study.
OS did not reach the critical value of the designed statistical hypothesis, but there was a trend of benefit
.

In addition to statistical assumptions, this result is also related to the inclusion of a higher proportion of patients with brain metastases with worse prognosis and patients with high tumor burden in the pembrolizumab combined chemotherapy group
.

In the RATIONALE 206 study based on the Chinese population, the primary endpoint ORR was as high as 77%, and the median OS was as high as 15.
6 months
.

The randomized, double-blind, placebo-controlled phase III clinical trial RATIONALE 312 of tislelizumab combined with chemotherapy for the first-line treatment of extensive-stage small cell lung cancer is underway
.

Based on the above knowledge, we chose the domestic PD-1 inhibitor tislelizumab combined with EP regimen, and achieved good therapeutic effects
.

References: [1] Horn L, Mansfield AS, Szczęsna, Aleksandra, et al.
First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer[J].
New England Journal of Medicine,2018, 379(23) :2220-2229.
[2]Paz-Ares L,Dvorkin M,Chen Y, et al.
Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial [J].
Lancet, 2019 ,394(10212):1929-1939.
[3]Rudin CM, Awad MM, Navarro A, et al.
KEYNOTE-604: Pembrolizumab (pembro ) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC)[J].
Journal of Clinical Oncology, 2020, 38(15_suppl):9001-9001.
[4]9000-Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161.
2020 ASCO.
[5]Martin R, Alexander L, Aleksandra S, et al.
Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.
J Clin Oncol, 2016, 34(31 ): 3740-3748.