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Case sharing | exploration of the efficacy and safety of albumin paclitaxel + apatinib in the third-line treatment of SCLC and above

 Last Update: 2022-10-20
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Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer subtypes, with high recurrence, early metastasis, rapid proliferation of tumor cells, and high degree of malignancy, which makes clinical treatment difficult
.
Despite the high sensitivity of SCLC to first-line chemotherapy, relapse
occurs in most patients.
The efficacy of post-line therapy for extensive-stage small cell lung cancer is poor, and even with third-line therapy recommended by NCCN guidelines, the effective rate and survival are still not ideal
.
Data from a real-world study showed an objective response rate (ORR) of 10 to 21.
3 percent, a median duration of response (DOR) of 2.
6 months, a median overall survival (OS) of 4.
4 months, and a one-year OS rate of only 11 percent in patients with SCLC who received various regimens (third-line and above) regimens [^1].
。

Therefore, it is necessary to continue to find and explore new therapeutic drugs or therapeutic strategies to further improve the survival
of patients treated with small-cell lung cancer in the afterline.
According to the drug development trend and clinical practice accessibility of small cell lung cancer in recent years, the use of albumin paclitaxel combined with apatinib in the back line of our center has achieved good efficacy and good
safety.
The efficacy of a patient with extensive-stage small cell lung cancer using this protocol in fourth-line therapy is shared
.

Author: Xu Jinbiao The First Affiliated Hospital of Nanchang University This article is authorized by the author to be published by Yimaitong, please do not reprint
without authorization.

Patient situation

The patient is male, 70 years old
.
In November 2020, abdominal pain began to appear, and on January 14, 2021, after completing imaging and pathological examination, he was finally diagnosed as extensive-stage small cell lung cancer with metastases
in the right lung, liver and bone.

From January 22, 2021 to May 11, 2021, the first-line EC+D regimen (duvanomab 1500mg d1 + etoposide 150mg d1-3 + carboplatin 400mg d1, q3w) was administered for 5 cycles of chemotherapy, and the efficacy was assessed as partial remission (PR) after 2 courses and the efficacy was assessed as stable (SD) after 4 stages, This is followed by immunomaintenance therapy
with duvalumab (1500 mg).

On July 13, 2021, the reexamination of the head MRI showed multiple small nodules of brain metastases, and the whole brain radiotherapy was performed on July 22, 2021, specifically DT=30Gy/3Gy/10F
.
In September 2022, reexamination showed that the intracranial metastases had basically disappeared, and the lesions in the lungs were more and larger than before, so from September 20, 2022 to November 13, 2022, three courses of second-line treatment were performed, specifically: duvalumab 1500mg D1 + irinotecan 240mg D1 + lopplatin 35mg D1 Q3W, severe poor appetite and fatigue occurred during second-line chemotherapy, and chemotherapy was not performed again.
Continue to be treated with duvalumab 1500mg D1 monotherapy, last on February 28, 2022
.

In April 2022, re-examination CT showed that the para-oblique fissure nodule in the lower lobe of the left lung was smaller than before, the nodule in the remaining lung was enlarged, and soft tissue nodules were added to the right adrenal area, considering metastasis, and the remaining liver, bone and cranial lesions were stable
.
Third-line therapy was given on 18 April 2022, specifically: duvalumab 1500mg D1 + Anlotinib 10mg D1-14
.
Review for full disease progression (PD)
on 9 May.

Fourth-line treatment decisions – relevant progress

The growth and metastasis of tumor cells depend on the formation of new blood vessels, and inhibition of angiogenesis is one of the important strategies for
tumor treatment.
Apatinib, as a tyrosine kinase inhibitor (TKI) that selectively targets vascular endothelial growth factor receptor 2 (VEGFR-2), has the main mechanism of action is to competitively bind to the intracellular tyrosine ATP binding site of this receptor, highly selectively inhibit VEGFR-2 tyrosine kinase activity, block signaling after VEGFR binding, and thus strongly inhibit tumor angiogenesis
.
When the VEGF molecule binds to VEGFR-2, several different molecular pathways are activated
simultaneously.
Although the binding characteristics of VEGF and VEGFR-2 are lower affinity compared to VEGFR-1, it produces significantly stronger kinase activity
.
Apatinib has no treatment recommendation in SCLC guidelines, but there are still many retrospective studies and prospective studies ^[2-7] exploring the use of apatinib in the later line therapy of SCLC, and the results of the study also show that apatinib monotherapy has good efficacy and safety in the later line treatment of ES-SCLC patients, with an ORR of 18% to 37.
5%.
Progression-free survival (PFS) is around 5 months and OS is around
8 months.

Studies have found that antiangiogenic therapy can "normalize" tumor blood vessels over a period of time, and that vascular normalization helps deliver chemotherapy drugs
.
In addition, sequential chemotherapy with antiangiogenic drugs improves the permeability
of chemotherapy drugs within tumors.
That is, antivascular drugs have a synergistic effect with chemotherapy and can enhance the therapeutic effect
.
The chemotherapy drugs recommended for the later line of extensive-stage small cell lung cancer include topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, etc
.
However, totetecan, gemcitabine, etc.
have greater side effects and poor
accessibility in clinical application.
Studies have confirmed that paclitaxel-based regimens have some activity, but because ordinary paclitaxel is insoluble in water and requires the use of organic solvent solubilization and hormonal drugs for pretreatment, the dosage and clinical efficacy
are greatly limited.
Albumin-bound paclitaxel (NAB-P) exhibits better toxicity profiles than conventional paclitaxel, and more and more clinical studies have attempted to explore the use
of albumin paclitaxel in extensive-phase small cells.

At ESMO 2018, Francesco Gelesomino et al.
^[8]. A phase II study of NAB-P for sensitive or refractory relapsed SCLC was announced, in which 72 patients with small cell lung cancer received NAB-P second-line after first-line EP/IP progression, and the primary endpoint ORR reached 17.
64% (refractory subgroup 16%, sensitivity 18.
6%)
。 A phase II prospective clinical study reported by ASCO in 2022 explored the efficacy and safety of albumin paclitaxel in the first-line treatment of extensive-stage small cell lung cancer, and the results showed that the ORR of carrelizumab combined with albumin-bound paclitaxel and carboplatin as the first-line treatment of ES-SCLC was as high as 81.
8%, and the median PFS was 7.
27 months (95% CI: 4.
7-9.
8 months).

Fourth-line treatment decision: apatinib + albumin paclitaxel

In summary, a number of retrospective studies and prospective studies have shown that apatinib has good efficacy and safety in the back-line treatment of patients with extensive-stage small cell lung cancer, and more and more clinical studies have shown that albumin-bound paclitaxel has a good effect as a post-line treatment for extensive-stage small cell lung cancer, and even moves albumin paclitaxel to first-line treatment
.
Considering the synergistic effect of antivascular drugs and chemotherapy to enhance the efficacy of treatment, we finally gave the patient a four-line treatment regimen of albumin paclitaxel 150 mg D1 D8 + apatinib 250 mg QD
.

Initial response to fourth-line therapy

The patient underwent two courses of fourth-line chemotherapy on May 10 and June 8, 2022, specifically: albumin paclitaxel 150mg D1 D8 + apatinib 250mg QD
.
After 2 stages of efficacy evaluation PR, the original four-line antitumor therapy was continued on July 2 and July 28, specifically: albumin paclitaxel 150mg D1 d8 + apatinib 250mg qd.

SD after 4 stages, the original four-line anti-tumor therapy continued on August 31 and September 29, specifically: albumin paclitaxel 150mg d1 d8 + apatinib 250mg qd.

The main treatment-related adverse reactions of patients throughout the fourth-line treatment period were mild fatigue and moderate anaemia
.

Experience

Research progress in the field of small cell lung cancer treatment is slower than that of non-small cell lung cancer, but in recent years, the exploration of immunotherapy in the field of SCLC has made significant progress, giving patients more choices
.

There is no standard recommendation for third-line therapy before 2018, and in view of the CheckMate 032 study, the KEYNOTE-028 study, and the KEYNOTE-158 study, and the ALTER1202 study, the CSCO guidelines include PD-1 inhibitors and anlotinib as third-line treatment recommendations
for extensive-stage small cell lung cancer.
In the CheckMate 032 study ^[9], patients with SCLC who received nivolumab had 11.
9% ORR, PFS, and OS treated with nivolumab, respectively, for 1.
4 months and 5.
6 months
.
The results of the pooled analysis of the KEYNOTE-028 study and the KEYNOTE-158 study ^[10], the ORR, PFS, and OS of patients with SCLC who received pembrolizumab on the third line or above were 19.
3%, 2.
0 months, and 7.
7 months
, respectively.
The ALTER1202 study ^[11] showed that patients with SCLC who had received at least two lines of chemotherapy continued to use anlotinib for 4.
1 months and 7.
3 months
, respectively.

For patients with extensive-stage small cell lung cancer, efficacy and survival are not ideal
, even if they are taken according to NCCN guidelines as recommended for third-line therapy.
Therefore, it is necessary to continue to find and explore new therapeutic drugs or treatment strategies
.
In addition to the cases described herein, we enrolled two additional patients (1 with 3rd line and 1 with 5-line), and the first efficacy assessment of apatinib combined with albumin paclitaxel was PR and the safety was tolerated
.
Based on the excellent performance of this protocol in the early observations, we believe that it is necessary to further explore the efficacy and safety of apatinib combined with albumin paclitaxel in the post-line treatment of extensive-stage small cell lung cancer to verify the clinical value of this treatment model, so we initiated an IIT study to hope that this treatment mode can improve patient survival
.

Expert profiles

Dr.
Xu Jinbiao

physician
Member of the Communist Party of China
Attending physician, Department of Oncology, High-tech Campus, The First Affiliated Hospital of Nanchang University
Member of the Tumor Immunotherapy Branch of Jiangxi Integrative Medicine Association
Member of the Oncology Precision Diagnosis and Treatment Branch of Jiangxi Integrative Medicine Association
He presided over 1 provincial project and 1 municipal project
5 articles published at home and abroad (1 SC1, 3 core of Peking University, 1 core of China Science and Technology)
Work on thoracic tumors

References:

[1] Coutinho AD,Shah M,Lunacsek OE,et al.
Real-world treatment patterns and outcomes of patients with small cell lung cancer progressing after 2 lines of therapy[J].
lung cancer，2019,127:53-58.

[2] CT083 - Camrelizumab plus apatinib in extensive-stage small-cell lung cancer （PASSION): A multicenter, two-stage,phase 2 trial.
Presented at the ASCO, 2020.

[3] Wei H , Hui L , Jin X , et al.
P1.
07-053 Apatinib for Chemotherapy-Refractory Extensive Stage SCLC: Results from a Single-Center Retrospective Study[J].
Journal of Thoracic Oncology, 2017, 12（1):S729.

[4] XU Y, HUANG Z, LU H, et al.
Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study[J].
Br J Cancer, 2019, 121（8):640-646.

[5] LIU Y, HU X, JIANG J, et al.
A Prospective Study of Apatinib in Patients with Extensive-Stage Small Cell Lung Cancer After Failure of Two or More Lines of Chemotherapy[J].
Oncologist, 2020, 25（5):e833-e842.

[6] LUO H, ZHANG L, YANG B, et al.
A randomized phase 2 trial of apatinib vs observation as maintenance treatment following first-line induction chemotherapy in extensive- stage small cell lung cancer [J].
Invest New Drugs, 2020, 38（1):148-159.

[7] HE Z, ZHOU H, WANG J, et al.
Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial[J].
Transl Lung Cancer Res, 2021, 10（2): 889-899.

[8]2018 EMSO poster/Phase II study of NAB-paclitaxel in sensitive and refractory relapsed SCLC （NABSTER TRIAL) .

[9] Antonia S J , López-Martin, José A, Bendell J , et al.
Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer （CheckMate 032): a multicentre, open-label, phase 1/2 trial[J].
Lancet Oncology, 2016:883-895.

[10] Chung HC,Piha-Paul SA,Lopez-Martin J,et al.
Pembrolizumab after two or more lines of prior therapy in patients with advanced small-cell lung cancer （SCLC):results from the KEYNOTE-028 and KEYNOTE-158 studies[R/OL].
AACR 2019,abstract CT073.

[11] Cheng Y , Wang Q , Li K , et al.
P2.
12-26 The Impact of Anlotinib for Relapsed SCLC Patients with Brain Metastases: A Subgroup Analysis of ALTER 1202[J].
Journal of Thoracic Oncology, 2019, 14（10):S823-S824.

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