Sintilimab/Axitinib Combo Shrinks FH-Deficient RCC Tumors

Xingming Zhang, MD, discusses unmet needs in fumarate hydratase–deficient renal cell carcinoma; shares key efficacy, safety, and quality of life findings from a phase 2 trial of sintilimab plus axitinib; and elaborates on the next steps for this research, including an analysis of biomarkers and potential resistance mechanisms.

Sintilimab/Axitinib Combo Shrinks 

FH-Deficient RCC Tumors | Image Credit: 

© SciePro -

Sintilimab/Axitinib Combo Shrinks

FH-Deficient RCC Tumors | Image Credit:

© SciePro -

Sintilimab plus axitinib (Inlyta) generated early evidence of clinical efficacy and tolerability in patients with fumarate hydratase (FH)–deficient renal cell carcinoma (RCC), according to Xingming Zhang, MD.

An ongoing, multicenter, phase 2 trial (NCT04387500) is investigating the combination in patients with advanced FH-deficient disease. Primary findings from this trial demonstrated an overall response rate of 65.2%, including a complete response rate of 13% and a partial response rate of 52.5%.1

“The combination treatment of sintilimab plus axitinib had a manageable safety profile and showed promising tumor response rates in the treatment of patients with FH-deficient RCC,” Zhang said in an interview with OncLive® during the 2023 American Urological Association (AUA) Annual Meeting.

In the interview, Zhang, a urologist at West China Hospital in Chengdu, Sichuan, discussed the unmet needs in FH-deficient RCC that contributed to the rationale for this trial; shared key efficacy, safety, and quality of life findings; and elaborated on the next steps for this research, including an analysis of biomarkers and potential resistance mechanisms.

OncLive: What was the rationale for this trial, and what patient population was observed?

Zhang: Non–clear cell RCC [ccRCC] is a heterogeneous tumor, [and each subtype has] unique histological features, clinical manifestations, responses to treatment, and limited evidence [to contribute to further classification]. Non–clear cell, FH-deficient RCC was initially classified as type 2 papillary RCC and was later reclassified as a new, independent subtype because of its unique characteristics.

Although several studies have explored the mechanisms and therapeutic targets in FH-deficient RCC, the efficacy of intervention against these targets is inadequate. No standard treatment strategy exists. To identify new treatment targets, we found that FH-deficient RCC was characterized by a high infiltration of immune cells with a relatively high expression of PD-L1.

Furthermore, we found that FH-deficient RCC is dependent on MRCA-mediated rapid progression driven by FH alterations. The primary tumors in FH-deficient RCC are already immune hot. However, the metastases have a more activated tumor immune microenvironment than the primary tumors. Based on these findings, we proposed for the first time this immune checkpoint inhibitor combination treatment in FH-deficient RCC, as this strategy has changed the [treatment] in metastatic RCC, especially ccRCC.

What key efficacy and safety findings from this study were presented at the 2023 AUA Annual Meeting?

This is an ongoing study. Currently, we have screened 42 patients. Among them, we have successfully enrolled 37 patients into the study [who are receiving] treatment with the combination of sintilimab plus axitinib. The objective tumor response rate in the 23 patients with available data was 65.2%, with an average tumor shrinkage rate of 48%.

Regarding safety, all patients experienced adverse effects [AEs], and only 25% of patients experienced [AEs of grade 3 or higher]. The most common AEs were proteinuria, hypertriglyceridemia, and increased blood creatinine levels. The most common [grade 3 or higher] AE was hypertriglyceridemia.

[To evaluate] patient-reported outcome measures, we used the Functional Assessment of Cancer Therapy – kidney symptom index-19 [FKSI-19] total score and the visual analogue scale [VAS] score. The mean FKSI-19 total score was stable after treatment with a slight increase in the trend after 6 months of treatment. The mean VAS score was also stable after treatment with a slight increase in the trend.

What are the next steps for this research?

We will continue to enroll potential patients into this trial. We plan to include a total of 41 patients. We will continue to collect data and confirm the efficacy and safety of [this regimen in] the included patients.

[Our next steps will include] a biomarker analysis, because the patients eventually [became] resistant to the treatment, and some patients didn’t respond to the treatment at all. We want to explore potential biomarkers to predict which patients will respond to this treatment.

We also want to find the potential mechanism of resistance to the combination treatment of the immune checkpoint inhibitor plus the TKI. [Through research regarding the] classification of FH-deficient RCC, we found that patients were classified into 3 subtypes. [One subtype] of patients responded to the immune checkpoint inhibitor–based treatment, and [another] subtype was resistant to the immune checkpoint inhibitor–based treatment. [This investigation is] ongoing.

We also have FFPE [formalin-fixed paraffin-embedded] samples from about 120 patients, as well as tissue for single-cell sequencing, [tissue for] TCR [T-cell receptor] sequencing, and PDX [patient-derived xenograft] organoids. The next step [will be to] use these samples to find potential mechanisms, especially the resistance mechanism to the immune checkpoint inhibitor–based treatment in patients with FH-deficient RCC.

What other findings were you excited to see at this year’s AUA?

I was interested in [a study presented by Jee Soo Park, MD, PhD, of the Yonsei University College of Medicine in Seoul, South Korea, that] focused on resistance to cabozantinib [(Cabometyx) in advanced ccRCC]. This research used cell lines treated with cabozantinib to detect potential targets, which may explain their resistance to cabozantinib. Unfortunately, this was just an in vitro study, not an in vivo study. More research [in this area may be warranted in] in vivo [models, such as] PDX-derived organoids.

Disclosures: Dr Zhang reports no disclosures.


Zhang X, Liu H, Zhang Y, et al. Phase II, multi-center study of sintilimab in combination with axitinib in patients with advanced fumarate hydratase-deficient renal cell carcinoma. Presented at: 2023 AUA Annual Meeting; April 28-May 1, 2023; Chicago, IL. Abstract PD24-09.

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