SCLC patients receive metformin combined with nivolumab, the tumor shrinks significantly?

*For medical professionals to read only, what should I do if small cell lung cancer has acquired resistance to PD-1 inhibitors? Come look at this case! Metformin is widely used in the treatment of type 2 diabetes due to its hypoglycemic effect.

In recent years, due to its ability to reduce the immune failure of CD8+ tumor infiltrating lymphocytes (TIL), its anti-cancer effects have also been extensively studied.

Metformin can reduce the apoptosis of CD8+TIL, thereby enhancing the immune response to tumor cells.

Previously reported a case of non-small cell lung cancer (NSCLC) patients.
The addition of metformin to the nivolumab regimen significantly reduced the tumor lesions.
This article reports a case of small cell lung cancer (SCLC) patients who received nivolumab treatment for two years Progress, and then received metformin combined with nivolumab treatment, within six months, the patient's efficacy reached a partial remission (PR).

The Medical Oncology Channel invited Professor Zhang Zhenfa, the administrative director of the Department of Pulmonary Oncology Surgery, Tianjin Medical University Affiliated Tumor Hospital, to take you to analyze this new treatment strategy! Patient information A 64-year-old female patient has an unknown medical history.
She was seen in the emergency department of the hospital because of symptoms of acute dyspnea.

Chest CT showed: mediastinal mass with a size of 5.
6 cm, multiple lymph nodes in the middle of the neck and supraclavicular swelling.

Lower lung biopsy revealed: stage IIIB poorly differentiated small cell lung cancer.

Immunohistochemical staining showed that cytokeratin AE1/AE3, chro-mogranin, and CD56 were positive.

1Small cell lung cancer patients relapsed after one year of radiotherapy and chemotherapy, and nivolumab brings the patients 2 years of PFS.
The patients first receive radiotherapy (54Gy) for 5 weeks, and use cisplatin 60 mg/m2 on the first day of every 3 weeks.
Use etoposide 120 mg/m2 for 1, 2, and 3 days.

After the fourth cycle of cisplatin and etoposide treatment, the size of the mediastinal mass decreased from 5.
6 to 0.
7 cm.

One year after the chemotherapy, the follow-up CT examination showed that the patient had an enlarged cystic solid mass on the left ovary, with enhanced nodular components and partitions in the lesion, which was highly suspected of being a malignant tumor.

Therefore, the patient underwent laparoscopic left salpingo-oophorectomy to remove a lesion of about 10.
5 × 9.
0 × 3.
5 cm.
The pathological results of the excised specimens showed that they were consistent with metastatic SCLC with extensive necrosis.

After repeating the CT scan twice a few months after the operation, a new soft tissue nodule with a size of 1.
8 cm was found on the parachain of the left aorta, and a cystic lesion of 5.
6 cm was observed.

 The patient subsequently received intravenous injection of nivolumab (3 mg/kg every two weeks) and combined radiotherapy for para-aortic lesions (55 Gy).
When the radiotherapy was completed 5 weeks later, the para-aortic nodular lesions were found to have resolved.
.

Using nivolumab monotherapy, the patient's condition was stable for more than two years, and the cystic lesions continued to shrink to 1.
5 cm.

  2 Metformin combined with nivolumab brings new opportunities after PD-1 resistance.
Re-examination 2 years later, CT revealed two new small nodules in the lungs, 0.
9 cm and 0.
4 cm respectively.

At this time, for the purpose of the trial, it was decided to try to use metformin combined with nivolumab (3 mg/kg every two weeks) for the patient.
The dose of metformin was 1000 mg/kg in the first week and increased to 1500 mg/day in the second week.
, Then increased to 2000 mg/day, administered in divided doses.

A follow-up CT scan 2 months later showed that after several months of combined treatment with metformin and nivolumab, the 15.
5 mm cystic lesions in the para-aortic area were relieved, and the total number of pulmonary nodules was reduced from 13 to 11.

The target lesion on the parachain of the left aorta was completely remitted (CR), and the non-target lung disease was stable (SD) (RECIST 1.
1).

 Figure 1 CT changes of metformin combined treatment of target lesions Figure 2 Discussion of CT changes of metformin combined treatment of non-target lesions This case is the first reported case of metformin + nivolumab treatment after resistance to SCLC PD-1 treatment, showing After 6 months of continuous anti-tumor activity, the curative effect reached PR.

Before metformin treatment, the patient's condition showed progress in many aspects after surgery, chemoradiation therapy and immunotherapy.

In recent years, immune checkpoint inhibitors (ICIs) have shown good efficacy in the treatment of various cancers, but the mechanism of drug resistance needs further exploration.
The current research focus is to determine new combination methods to improve tumor immunogen And overcome the resistance of ICIs.

 A large number of retrospective and pre-clinical studies have proved the anti-cancer properties of metformin and may reduce the risk of cancer.

Tumor hypoxia is one of the reasons for drug resistance, and the signal of tumor hypoxia environment activation is related to the reduced sensitivity of PD-1 blockade.

Metformin can inhibit the oxygen consumption of mouse tumor cells and reduce intratumor hypoxia, which also shows that metformin can increase the sensitivity of PD-1 inhibitors.

Professor Zhang Zhenfa's comment: 1 Metformin's anti-tumor effect needs to be further verified.
Metformin is a miraculous drug that has been widely used in the treatment of type 2 diabetes.
Recently, many scholars have also discovered its anti-tumor effect.

The anti-tumor mechanism of metformin is mainly to activate the AMPK signaling pathway, which leads to the phosphorylation of serine at position 195 of the PD-L1 protein, thereby degrading PD-L1, which indirectly plays an anti-tumor effect.

At present, many cases of metformin have been observed to show good efficacy.
Some patients have prolonged PFS, and some patients have reduced tumor lesions.
However, there are no significant statistical differences in the anti-tumor effects of metformin in clinical studies.
.

In general, the number of cases included in the current study is relatively small, and further large-sample clinical studies are needed to determine the anti-tumor effect of metformin.

  2 Immunotherapy breaks through the benefits of chemotherapy OS and reshapes the new standard of SCLC first-line treatment.
Immunotherapy has been widely used in the field of tumors in recent years, including the diagnosis and treatment of SCLC.

There are two well-known studies of immunotherapy in the field of SCLC diagnosis and treatment.
The first is the IMpower133 study, which compared the efficacy of atelizumab combined with chemotherapy and chemotherapy alone.
The results showed that the combined treatment group had a prolonged OS by 2 months and the risk of death.
Reduced by 30%.

The IMpower133 study is the first milestone study in the field of SCLC diagnosis and treatment to obtain OS benefits in the past 30 years.
Based on this study, the US FDA and the State Food and Drug Administration approved ateliizumab as the first-line treatment for SCLC.

 The second is the CASPIAN study, exploring the efficacy of anti-PD-L1 antibody duvalimab and anti-CTLA-4 antibody Tremelimumab combined with chemotherapy in the first-line treatment of patients with extensive-stage SCLC.

Compared with chemotherapy alone, the duvalimab combined with chemotherapy group prolonged OS by nearly 3 months (13.
0 months vs 10.
3 months), and reduced the risk of death by 27%.

The 12-month OS rate in the chemotherapy alone group was 39.
8%, while that in the duvalizumab combined chemotherapy group was 53.
7%, an increase of 13.
9%.

The ORR of the chemotherapy alone group was 57.
6%, and that of the duvalizumab combined chemotherapy group was 67.
9%, an increase of 10.
3%.

The results of these two studies show that immunotherapy has greater application value for the first-line treatment of SCLC.

 At the same time, the IMpower133 study showed that immune drugs compared with chemotherapy also showed the benefits of PFS and OS in the maintenance treatment of SCLC.
The results of the PASSION study of carrelizumab combined with apatinib in the second-line treatment of extensive-stage small cell lung cancer showed an objective response rate (ORR).
) Is 34.
0%, the median PFS is 3.
6 months, the median overall survival (OS) is 8.
4 months, and the toxicity is controllable, and it will provide the next step for the study of immunotherapy combined with anti-angiogenic drugs in the second-line treatment of SCLC The basis.

  3 Anti-angiogenic drugs can be tried after further resistance.
This patient may be able to try anlotinib follow-up treatment after metformin combined with nivolumab treatment fails.
Currently, anlotinib has been approved for the third-line treatment of SCLC.
It was recommended by the Chinese Society of Clinical Oncology (CSCO) guidelines and included in medical insurance.

 References: [1] Kim, Y.
, Vagia, E.
, Viveiros, P.
et al.
Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC).
Cancer Immunol Immunother 70, 961–965 (2021).
https://doi.
org/10.
1007/s00262-020-02703-8