Shine! Axitinib combined with immune second-line treatment for advanced kidney cancer with PFS for up to 29 months

*For medical professionals only

How to choose a more appropriate treatment plan for patients with advanced kidney cancer that recurs after surgery?

In recent years, the diagnosis and treatment of advanced kidney cancer has developed rapidly, and targeted therapy drugs have become increasingly abundant, which has significantly improved the survival time and quality of life of patients, and has become an important treatment method
for advanced kidney cancer.
At the same time, with the rapid development of immunotherapy in the field of kidney cancer, clinical treatment methods are more diversified
.
In clinical practice, how to formulate appropriate treatment plans for different patients with advanced kidney cancer has become a hot spot
in clinical attention.
In this paper, a case of clear cell carcinoma of left kidney (ccRCC) with multiple metastases (IMDC high-risk) after surgery and multiple metastases of both lungs, thoracolumbar spine (IMDC) brought by Professor Lu Cuiping from the team of Director Zhan Ying of the Department of Medical Oncology of Longyan First Hospital shared the diagnosis and treatment process, related basis and clinical ideas, in order to provide reference and reference
for the individualized comprehensive treatment and whole process management of advanced kidney cancer.

[Disclaimer: The case sharing and discussion involved in the meeting is for educational and communication purposes only, and does not involve consultation and intervention
.
The decision to treat is made independently by the physician according to the
patient's condition.
】

• Basic information

General: male, 53 years old, no family history
of tumors.

Complaint: In February 2020, the patient was admitted to the hospital
in a wheelchair due to "increased low back pain, inability to stand in both lower limbs, difficulty urinating and defecating".

History of present illness:

In May 2018, the patient was diagnosed with Guangzhou Zhujiang Hospital for concurrent surgical resection due to repeated gross hematuria and found "left kidney mass", and the postoperative pathological "clear cell carcinoma of the kidney" was not treated after surgery
.

In April 2019, CT of the chest and abdomen of our hospital: 1.
After left kidney cancer surgery, multiple nodules and mass shadows in the left kidney area (involving the left diaphragm, psoas muscle and erector spinal muscle); 2.
Multiple nodules and mass shadows in the lower lobe of the right lung: metastasis is possible
.

Figure 1.
Results of chest and abdominal CT examination in April 2019

Physical examination: KPS score < 70 points, obvious percussion pain in the left kidney area, chest 11-L3 vertebral tenderness, positive percussion pain; Grade 3 muscle strength of both lower extremities, normal muscle tone, and dissociative sensory impairment
of both lower extremities.

Ancillary examinations:

Blood routine: white blood cells (WBC) 5.
6g/L, hemoglobin (HGB) 94g/L↓, neutrophils (N) 2.
18g/L, platelets (PLT) 359g/L
.

Biochemistry: calcium (Ca) 2.
65mmol/L↑, alkaline phosphatase (ALP) 155IU/L
.

Chest and abdominal CT: multiple metastases in both lungs, increasing and enlarging compared with the front; The renal mass is further enlarged
.

Head + thoracolumbar MR: thoracic 11-lumbar 3 vertebral body and adnexal bone metastasis, involving paravertebral soft tissue, partial invasion of spinal canal and left intervertebral foramen, corresponding nerve root invasion, spinal cord compression and abnormal signal; There are no abnormalities
in the skull.

Figure 2.
Imaging results in February 2020

• diagnosis

Clear cell carcinoma of the left kidney (T1N0M0 stage I) recurred after surgery and multiple metastases of both lungs, thoracolumbar spine (IMDC prognostic score: high risk); Spinal cord compression syndrome
.

• First-line therapy: sunitinib plus immunotherapy, PFS 4 months

Treatment regimen: On February 20, 2020, the patient started oral "sunitinib 50mg QD (4/2 regimen)" targeted therapy, and from February 18 to May 5, 2020, combined with carrelizumab immunotherapy for 4 courses; On March 3, 2020, local palliative radiotherapy for thoracolumbar metastases was started, and GTV-P 3000CGY/10F was given; Low back pain is obvious, with oral oxycodone sustained-release tablets 80mg Q12H to relieve pain
.

Adverse reactions: grade 1 diarrhea, grade 3 thrombocytopenia, PLT 47g/L
during treatment.

Review of contrast-enhanced CT (June 21, 2020): 1.
After surgery for malignant tumor of the left kidney, multiple nodules and clumps in the left kidney area, considering the possibility of recurrence, are similar to before; 2.
Multiple metastases in both lungs, enlarged compared with the front; 3.
Left pleural effusion with incomplete expansion of the lower lobe of the left lung, which is more obvious than before; 4.
The bone of the lower thoracic spine and upper lumbar spine is destroyed and the surrounding soft tissues are swollen, which is similar to before; 5.
There was no abnormality
on non-contrast head CT scanning.

Efficacy assessment: PD.

Figure 3.
Imaging results on June 21, 2020

• Second-line therapy: axitinib plus immunotherapy, PFS > 29 months

Treatment regimen: The patient started oral axitinib 5 mg bid-targeted therapy on June 20, 2020, and continued to cooperate with PD-1 immunotherapy
.

Efficacy evaluation: After 2 months of treatment (August 28, 2020), CT re-examination showed that lung lesions and left kidney lesions were smaller than before, and the efficacy was evaluated for PR
.
The dose of oxycodone sustained-release tablets is gradually reduced, and oral painkillers
are stopped after 4 months of treatment.
Patients can stand and walk, urinate and defecate normally
.

Adverse reactions: increased blood pressure during treatment, oral antihypertensive drugs can be controlled; No adverse reactions
such as proteinuria were seen.

Figure 4.
Imaging findings before and during second-line therapy

Case summary

Kidney cancer is a common malignant tumor of the urinary system in China, and the incidence is increasing year by year
.
In recent years, the diagnosis and treatment of kidney cancer has developed rapidly, from the era of cytokines to the era of targeted therapy, and now it has entered the era of
immune combination therapy.
At the same time, the diagnosis and treatment model of stratified treatment of patients with advanced kidney cancer has become more and more important
.
In this case, the patient with clear cell carcinoma of the left kidney recurred after surgery and multiple metastases to both lungs, thoracolumbar spine (IMDC is high-risk), how to develop an individualized and precise comprehensive treatment strategy for him in clinical practice?

• IMDC high-risk groups, how to choose first-line treatment?

Studies have shown that anti-angiogenic therapy can normalize the abnormal tumor vascular system to increase the infiltration of immune effector cells, that is, the immunosuppressed tumor microenvironment into an immune-enhanced tumor microenvironment
.
In other words, vascular normalization can enhance the efficacy of immunotherapy, which lays a theoretical foundation
for immunity combined with antiangiogenesis.
Moreover, JAVELIN Renal 101, KEYNOTE-426 and other international large-scale randomized controlled studies have shown that compared with vascular endothelial growth factor receptor (VEGFR) TKI monotherapy, immune checkpoint inhibitor (ICI) + TKI combined with first-line therapy significantly improves the survival benefit of advanced kidney cancer.
In particular, in high-risk groups of IMDC, the survival benefit of targeted combination therapy is greater ^[1,2].

A real-world study presented at the 2022 American Society of Clinical Oncology Annual Meeting on Genitourinary Oncology (ASCO-GU) analyzed the survival benefits of dual free (IO-IO), target immunity (TKI+IO), and single target (TKI) treatment modes, and found that TKI+IO first-line therapy had a greater survival benefit and better improved treatment outcomes ^[3].

The 2022 V3 edition of the National Comprehensive Cancer Network (NCCN) pointed out that advanced kidney cancer has entered the era of immune combination, and first-line target-free combination therapy for high-risk groups has obtained the preferred recommendation of the guidelines ^[4].

。 In addition, the 2022 edition of the Chinese Society of Clinical Oncology (CSCO) guidelines pointed out that metastatic kidney cancer is divided into low-risk, medium-risk, and high-risk according to the MSKCC or IMDC prognosis model, and the corresponding population has different biological characteristics, and more and more evidence shows that stratified therapy is required, low-risk groups are more suitable for targeted therapy, and medium- and high-risk groups are difficult to treat and may require combined immunotherapy ^[5].

Accordingly, the combination of PD-1 inhibitor + sunitinib was used first-line in patients with clear cell carcinoma of the left kidney who recurred after surgery and multiple metastases of both lungs, thoracolumbar spine (IMDC high risk
).
In addition, although the traditional concept of kidney cancer is not sensitive to radiotherapy and chemotherapy, with the development of radiotherapy technology, the value of radiotherapy in kidney cancer has also been reflected, especially in patients with brain metastasis and vertebral body metastasis, local palliative radiotherapy combined with targeted can obtain better remission
.
Therefore, the patient received local palliative radiotherapy
for thoracolumbar metastases during first-line target-free combination therapy.
Unfortunately, after 4 months, re-examination found that the case had multiple metastases in both lungs that were larger than before, and the left pleural effusion with incomplete expansion of the lower lobe of the left lung was more obvious than before, and the tumor PD
.

It should be pointed out that although targeted combination therapy has been recommended by foreign guidelines, ICI has not been approved for first-line treatment of kidney cancer in China, which has brought certain restrictions
to the formulation of clinical treatment plans.
What is the real-world research status of first-line target-free combination therapy in China, and more exploration
is needed in the future.

• After the progress of first-line target immunity therapy, what option is more appropriate for the second line?

The occurrence of renal cancer is related to the loss of function of the VHL gene, which leads to abnormal regulation of the VEGF pathway, making advanced kidney cancer a vascular tumor
.
Preclinical studies have shown that advanced kidney cancer that progresses after TKI treatment still has continuous angiogenesis, and the tumor is still sensitive to the inhibition of VEGF signaling pathway, and VEGFR is an important therapeutic target
.

THE INTERNATIONAL MULTICENTER PHASE III INTORSECT STUDY SHOWED THAT SEQUENTIAL VEGFR-TKI SIGNIFICANTLY PROLONGED OS (16.
6 VERSUS 12.
3 MONTHS) COMPARED WITH MTOR INHIBITORS IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA AFTER DISEASE PROGRESSION WITH SUNITINIB ^[6].

。 A Czech real-world study (RENIS) of 745 patients with metastatic renal cell carcinoma using common sequential regimens (including sunitinib-axitinib, sunitinib-everolimus, pezopanib-everolimus, and pezopanib-sunitinib between June 2007 and February 2018) found that other sequential regimens had less OS than sunitinib first-line resistant sequential axitinib treatment regimens ^[7].

。 Moreover, the SWITCH study showed no toxic accumulation with sequential TKI-TKI treatment, and no increase
in the incidence of major grade 3/4 adverse events.
In addition, the latest results of KEYNOTE-426 and other studies presented at the 2022 American Society of Clinical Oncology (ASCO) Congress suggest that immunotherapy or immune combination therapy is an important choice after TKI treatment failure, while TKI continues to benefit as sequential therapy after immunotherapy failure ^[8,9].

Axitinib is a new generation of oral VEGFR inhibitor with stronger inhibition of VEGFR-2; Moreover, axitinib has high selectivity for VEGFR-2, low off-target effect, and is not easy to cause related adverse events
.
After comprehensive consideration, the patient was treated with axitinib in combination with PD-1 inhibitors on the second line
.
After 2 months of treatment, the lung lesions and left kidney lesions were reduced by re-examination, and the efficacy was evaluated as PR.
After 4 months of treatment, the patient stopped taking oral painkillers, was able to stand and walk, and urinate and defecate returned to normal
.
As of November 2022, the case has reached a near-clinical complete response (CR) with PFS for up to 29 months and is expected to have a longer survival benefit
.
Moreover, during treatment, the patient can tolerate only the increase in blood pressure, which can be controlled
by oral antihypertensive drugs.
It can be seen that in the real world, axitinib + PD-1 inhibitor second-line therapy can significantly improve the survival time and quality of life of patients with advanced kidney cancer, and has good safety and is the preferred treatment plan in clinical practice
.

Although the current second-line treatment options for advanced kidney cancer are gradually enriched, there are still many clinical issues that need to be further explored, such as whether genetic testing needs to be added to find effective biomarkers and guide treatment choices
.
In the future, it is expected that with the development of more clinical studies and the accumulation of clinical drug experience, the comprehensive benefits
of patients with advanced kidney cancer will be continuously improved.