Camrelizumab plus Famitinib in Patients with Advanced or Metastatic Renal Cell Carcinoma: Data from an Open-label, Multicenter Phase II Basket Study

This article is featured in Highlights of This Issue, p. 5731

Renal cell carcinoma (RCC) comprises a heterogeneous group of cancers derived from the renal tubular epithelial cells (1). It encompasses several subtypes with unique characteristics, with clear cell carcinoma being the most common one (2).

Tyrosine kinase inhibitors (TKI) targeting VEGF pathway and mTOR are standards of care for advanced or metastatic RCC and have been widely used over the past decade. First-line sunitinib and pazopanib and second-line axitinib, everolimus, and cabozantinib improve the clinical outcomes of patients (3–9), but development of drug resistance is inevitable.

It has been reported that RCC tumors are heavily infiltrated by immune-inhibitory cells such as regulatory T cells (T_reg) and myeloid-derived suppressor cells (MDSC; refs. 10, 11), providing the scientific rational for immunotherapeutic approaches to restore antitumor immunity by targeting negative regulators such as programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and CTL-associated protein-4 (CTLA-4). On the basis of the superiority in overall survival (OS) over everolimus, nivolumab was approved in patients with RCC after failure of one or two anti-angiogenic TKIs, but no progression-free survival (PFS) benefit was observed (12). In subsequent clinical studies for untreated advanced or metastatic RCC, a single immune checkpoint inhibitor (ICI) including atezolizumab and pembrolizumab also displayed antitumor activity (13–15). However, there was still a substantial proprotion of patients who did not respond to ICI monotherapy.

To further improve the prognosis of patients with RCC, combination of an ICI and TKI targeting VEGF pathway represents a potential effective strategy, on the basis of the interaction between immunosuppression and angiogenesis in tumor development (16). Actually, several clinical trials have proven the effectiveness of this combinatorial approach and supported the approval of avelumab plus axitinib, pembrolizumab plus axitinib, and nivolumab plus cabozantinib in treatment-naïve patients with advanced or metastatic RCC (17–20), leading to a paradigm shift in front-line treatment. But evidence of this combinatorial strategy in previously treated patients is very scarce.

Camrelizumab, a humanized monoclonal antibody that selectively blocks the binding of PD-1 to PD-L1 and eventually inhibits the immune escape of tumor cells (21), has shown activity across a wide range of malignant carcinomas. Famitinib is a structural analog of sunitinib with improved inhibition activities. The targets of famitinib include VEGFR-2 and -3, platelet-derived growth factor receptor β (PDGFRβ), stem-cell factor receptor (c-kit), FMS-like tyrosine kinase-3 receptor (FLT3), proto-oncogene tyrosine-protein kinase receptor (RET), and TAM family of kinases (AXL and MER; data on file, Jiangsu Hengrui Pharmaceuticals). In the multicenter, randomized, positive-controlled, double-blind, phase II trial (ClinicalTrials.gov Identifier: NCT01829841), famitinib monotherapy achieved a noninferiority objective response rate (ORR) to sunitinib in advanced or metastatic RCC (36.0% vs. 28.0%; data on file, Jiangsu Hengrui Pharmaceuticals). Hence, we initiated a basket phase II study to assess the preliminary efficacy and safety of camrelizumab and famitinib. Here we report the results of camrelizumab plus famitinib in an RCC cohort regardless of lines of prior systemic therapy.

This is an open-label, multicenter, basket phase II study of camrelizumab and famitinib as monotherapy or combination therapy in patients with advanced genitourinary or gynecologic cancers (Supplementary Fig. S1; Clinicaltrials.gov registration: NCT03827837). Here, we report the data from cohort 1, in which patients aged 18 to 75 years with histologically or cytologically confirmed advanced or metastatic RCC, clear cell, or predominantly clear cell subtype, with no prior anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies were recruited to receive camrelizumab in combination with famitinib. Prior systemic treatments (except ICIs and famitinib) were allowed but not required. Other key eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease by RECIST version 1.1, a life expectancy of at least 12 weeks, and adequate hematologic, hepatic, and renal function. Key exclusion criteria included untreated central nervous system metastases; poorly controlled hypertension; radiological evidence of tumor invading major blood vessels; known active or a history of autoimmune disorder; use of immunosuppressant or systemic hormone within 2 weeks before study; abnormal coagulation function, bleeding susceptibility, or receiving thrombolysis or anticoagulation therapy; prior chemotherapy within 4 weeks before study; prior surgery or systemic therapy for advanced or metastatic disease within 2 weeks; less than 5 half-life interval after discontinuation of molecular targeted therapies; and active infection.

The protocol and all amendments were approved by the ethics committee of each participating site. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and local laws and regulatory requirements. All patients provided written informed consent.

For combination therapy, camrelizumab 200 mg by intravenous infusion every 3 weeks on day 1 of each 21-day cycle and oral famitinib 20 mg once daily were set as the initial doses. Tolerability was assessed during the period from first administration to two treatment cycles of the first 12 patients recruited in cohorts 1 to 5, in which camrelizumab plus famitinib were given to patients with no prior anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies. If clinically significant toxicity (see Supplementary Materials and Methods for definition) was observed in 4 or more of the first enrolled 12 patients or a famitinib dose reduction due to adverse events (AE) was required in more than 30% of the patients enrolled during the tolerability observation period, the initial doses would be changed to camrelizumab 200 mg every 3 weeks plus famitinib 15 mg once daily. As of June 1, 2019, only 1 of the first 12 patients had clinically significant toxicities and 2 of the enrolled 49 patients (4.1%) experienced a dose reduction of famitinib due to AEs (22). Thus, camrelizumab 200 mg every 3 weeks plus famitinib 20 mg once daily was well tolerated and used as initial doses for subsequently enrolled patients. Study treatment was continued until confirmed disease progression, unacceptable toxicity, patient decision or withdrawal of consent, withdrawal by the investigator, or loss to follow-up, whichever occurred first. Treatment beyond confirmed disease progression was allowed only if the patients were in clinically stable condition according to the investigator's discretion. The total camrelizumab exposure could not exceed 2 years. Treatment interruption was permitted to manage toxic events, but dose reductions of camrelizumab were not permitted.

Primary endpoint was ORR per RECIST version 1.1, defined as the percentage of patients whose best overall response was confirmed complete response (CR) or partial response (PR). Secondary endpoints included duration of response (DoR), disease control rate (DCR), time to response (TTR), PFS, OS, 6-month OS rate, and safety. Exploratory endpoints included the associations between efficacy of study treatment and PD-L1 expression or other biomarkers.

Tumor response assessments were done at baseline and then every 3 cycles by the investigator according to RECIST version 1.1. For patients who discontinued study treatment without radiological disease progression, tumor response assessments were done every 3 months. CRs or PRs were required to be confirmed with a repeat scan at least 4 weeks later. Disease progression was required to be confirmed 4 to 6 weeks beyond progression, except quick radiological progression and clinical progression. Survival status was assessed every 2 months during follow-up.

Safety assessments included 12-lead electrocardiograms, vital signs, laboratory tests, echocardiography, and AEs. AEs were monitored until 30 days after the last dose [data on serious events and treatment-related adverse events (TRAE) were collected until 90 days after the last dose], and were graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0).

The PD-L1 combined positive score (CPS) was centrally tested using archival or fresh tumor tissues by PD-L1 IHC 22C3 pharmDx test (Dako) and was calculated as the number of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) out of the total number of tumor cells, multiplied by 100. PD-L1 positivity was defined as a CPS of 1 or more.

An adaptive two-stage design (23) was used for cohorts 1 to 5 to minimize the sample size if study treatment was deemed ineffective for a specific tumor type. For cohort 1 reported here, an ORR of 15% was considered ineffective, 25% was considered low response rate, and 35% was considered high response rate. Assuming ORR as specified, a power of 80% for a high response rate and 70% for a low response rate, and a two-sided α level of 0.1, the number of patients required would be 22, 33, or 53 depending on the level of antitumor activity observed. At stage 1, 22 patients would be enrolled. Of the 22 patients, if there were 2 or less responders, study treatment was considered ineffective and enrollment would be terminated. If there were 3 to 6 responders, enrollment would be extended to 53 at stage 2; if there were 7 or more responders, enrollment would be extended to 33 at stage 2. Study treatment was considered effective if at least 12 responders of 53 patients or at least 8 responders of 33 patients were observed.

In cohort 1, 13 of the 22 patients enrolled at stage 1 achieved objective responses, and thus enrollment of stage 2 was initiated. Because the actual number of patients screened was more than the planned enrollment number, a total of 38 eligible patients were enrolled in cohort 1.

Efficacy was assessed in the full-analysis set, including all patients with at least one dose of the study treatment. Safety was assessed in all patients who received at least one dose of study treatment and had at least one post-baseline assessment. The 95% confidence intervals (CI) for ORR and DCR were calculated with the Clopper–Pearson method. Time-to-event endpoints were estimated with the Kaplan–Meier method; the 95% CIs for median were calculated with the Brookmeyer and Crowley method and the 95% CIs for survival rates were calculated by means of log–log transformation (on the basis of normal approximation) with back transformation to CIs on the untransformed scale.

Totally, 38 patients with advanced or metastatic clear cell RCC were recruited between February 20, 2019 and April 28, 2020 from nine study sites in China, and all received the study treatment. Table 1 shows the baseline characteristics. Median age was 58.5 years (range, 35.0–73.0). The majority of patients had an ECOG performance status of 1 (81.6%), and at least two sites of metastases (71.1%). Sixteen (42.1%) patients were categorized as International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk, and 22 (57.9%) as intermediate or poor risk. Thirteen (34.2%) patients were treatment naïve for advanced or metastatic disease, while 25 (65.8%) had previous systemic treatment [15 (39.5%) received one prior treatment, 6 (15.8%) received two, and 4 (10.5%) received three or more], and 24 of these 25 patients had disease progression on at least one prior anti-angiogenesis regimen.

As of October 31, 2020, the median duration from enrollment to data cutoff was 16.5 months (range, 6.1–20.4). Totally, 24 (63.2%) patients were still on treatment; of these, most patients [22 (91.7%)] were receiving camrelizumab plus famitinib. One (2.6%) patient was receiving camrelizumab only, and 1 (2.6%) patient was receiving famitinib only. Fourteen (36.8%) patients discontinued study treatment due to radiographic disease progression (n = 9, 23.7%), patient's decision (n = 2, 5.3%), AEs (n = 1, 2.6%), poor compliance (n = 1, 2.6%), and death (n = 1, 2.6%).

Totally, 23 of the 38 patients achieved a confirmed objective response (Table 2), and ORR was 60.5% (95% CI, 43.4–76.0). Stable disease was observed in 11 (28.9%) patients, and DCR was 89.5% (95% CI, 75.2–97.1). Best changes in target lesion from baseline are shown in Fig. 1A. Among the 36 patients who had at least one post-baseline target lesion assessment, most patients (n = 35, 97.2%) showed tumor shrinkage, and median best reduction in target lesions from baseline was 39.8% (range, 1.9–100). Substantial and durable reductions in tumor burden were observed (Fig. 1B). Responses in 18 of the 23 (78.3%) responders were still ongoing, and Kaplan–Meier estimated median DoR had not been reached yet (range, 1.0⁺–14.8⁺ months). DoR rate at 6 months was 88.9% (95% CI, 61.8–97.2) and at 9 months was 68.8% (95% CI, 40.0–85.8). Twelve of the 23 (52.2%) responses occurred approximately 2 months after first dose and 9 (39.1%) occurred approximately at 4 months (Fig. 2), and median TTR was 2.2 months (range, 1.6–8.5).

As of cutoff date, 16 (42.1%) of 38 patients had disease progression or death. The Kaplan–Meier estimated median PFS was 14.6 months (95% CI, 6.2–not reached; Fig. 3A). The PFS rates at 6, 9, and 12 months were 75.5% (95% CI, 58.1–86.4), 62.4% (95% CI, 43.8–76.4), and 58.2% (95% CI, 39.2–73.2), respectively. Only 4 (10.5%) deaths occurred. Twelve-month OS rate was as high as 92.1% (95% CI, 77.5–97.4).

Efficacy outcomes by prior systemic therapies for advanced or metastatic disease are summarized in Table 2. Of the 13 treatment-naïve patients, camrelizumab plus famitinib as first-line therapy achieved an ORR of 84.6% (95% CI, 54.6–98.1; Table 2). Kaplan–Meier estimated median DoR had not been reached yet (range, 2.0–14.5⁺ months) in treatment-naïve patients; 6-month DoR rate was 90.9% (95% CI, 50.8–98.7) and 9-month DoR rate was 72.7% (95% CI, 24.1–93.1). Of the 25 previously treated patients, camrelizumab plus famitinib as second- or later-line therapy achieved an ORR of 48.0% (95% CI, 27.8–68.7; Table 2). Median DoR had not been reached yet (range, 1.0⁺–14.8⁺ months) in previously treated patients; 6-month DoR rate was 88.9% (95% CI, 43.3–98.4) and 9-month DoR rate was 66.7% (95% CI, 28.2–87.8).

As of cutoff date, only 3 (23.1%) of the treatment-naïve patients had disease progression or death, and the median PFS had not been reached yet (Fig. 3B). Thirteen (52.0%) of the previously treated patients had disease progression or death, and the median PFS was estimated to be 13.4 months (95% CI, 4.1–not reached; Fig. 3B).

In our analysis of biomarkers, 6 (30.0%) of 20 evaluable tumor biospecimens were positive for PD-L1 CPS. The ORR was 83.3% (95% CI, 35.9–99.6) in patients with positive PD-L1 and 57.1% (95% CI, 28.9–82.3) in patients with negative PD-L1.

The median number of cycles of camrelizumab delivered was 14 (range, 1–30), and the relative dose intensity was 96.1% (range, 8.0–100). The median exposure of famitinib was 40.4 weeks (range, 3.0–90.0), and the relative dose intensity was 77.5% (range, 38.1–100). Of the 38 patients who received study treatment, 19 (50.0%) had at least one reduction in the dose of famitinib.

All 38 patients experienced at least one TRAE (Table 3). The most frequent TRAEs of any grade included proteinuria (n = 27, 71.1%), hypertension (n = 26, 68.4%), palmar-plantar erythrodysesthesia (PPE) syndrome (n = 21, 55.3%), and diarrhea (n = 19, 50.0%). TRAEs of grade 3 or 4 occurred in 25 (65.8%) of the 38 patients (Table 3). The most common occurring in more than 10% of patients were proteinuria (n = 7, 18.4%), hypertension (n = 7, 18.4%), decreased neutrophil count (n = 5, 13.2%), PPE syndrome (n = 4, 10.5%), and hypertriglyceridemia (n = 4, 10.5%). Reactive cutaneous capillary endothelial proliferation (RCCEP, the most common AE attributable to camrelizumab monotherapy) was reported in 18.4% of patients (n = 7) with study treatment of camrelizumab plus famitinib. Majority of the events were grade 1 or 2 in severity (n = 6, 15.8%), and grade 3 RCCEP occurred in 1 (2.6%) patient.

Serious TRAEs occurred in 8 (21.1%) patients (Supplementary Table S1). All serious TRAEs were improved or resolved, except grade 2 pneumonitis in 2 patients. No treatment-related deaths occurred.

Three (7.9%) patients discontinued camrelizumab because of TRAEs of liver injury, pneumonitis, and proteinuria (n = 1, 2.6% each). Only 1 (2.6%) patient discontinued famitinib owing to hypertension. Supplementary Table S2 shows TRAEs leading to dose modification. TRAEs led to dose interruption of camrelizumab in 10 (26.3%) patients, with increased aspartate aminotransferase (AST; n = 2, 5.3%) and increased blood bilirubin (n = 2, 5.3%) occurring in more than 1 patient. Twenty (52.6%) patients experienced at least one TRAE leading to famitinib interruption, mainly including proteinuria (n = 7, 18.4%), hypertension (n = 4, 10.5%), PPE syndrome (n = 4, 10.5%), and decreased neutrophil count (n = 3, 7.9%). TRAEs led to dose reduction of famitinib in 14 (36.8%) patients, with proteinuria (n = 5, 13.2%) and PPE syndrome (n = 4, 10.5%) occurring in more than 1 patient.

Immune-related AEs (Supplementary Table S3) of any cause occurred in 7 (18.4%) of 38 patients, including pneumonitis (n = 2, 5.3%), and skin plaque, rash, drug eruption, dermatitis acneiform, secondary hypothyroidism, hypothyroidism, proteinuria, and enteritis (n = 1 for each; 2.6%).

In this phase II study, camrelizumab plus famitinib demonstrated notable clinical efficacy, with a response rate of 60.5%, substantial and sustained reductions in tumor burden, and median PFS of 14.6 months in patients with advanced or metastatic RCC.

Totally, 57.9% of enrolled patients had IMDC intermediate or poor risk, similar to other studies of ICI plus antiangiogenic combinations. In treatment-naïve population, camrelizumab plus famitinib resulted in tumor shrinkage in all patients and exhibited an ORR of 84.6% and a DCR of 100%, which were comparable with other combinations including avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus cabozantinib, atezolizumab plus bevacizumab, and pembrolizumab plus lenvatinib (ORR, 32%–73%; DCR, 73%–92%; refs. 13, 17–20, 24, 25). Our findings demonstrated the promising activity of camrelizumab in combination with famitinib in untreated advanced or metastatic RCC; but due to a small simple size, further clinical trials are warranted.

In the era of immunotherapy, treatment landscape for untreated advanced or metastatic RCC has been changed. An ICI in combination with TKI including avelumab plus axitinib, pembrolizumab plus axitinib, and nivolumab plus cabozantinib are standard treatment options, and double checkpoint immunotherapy with nivolumab and ipilimumab is approved for patients at poor or intermediate risk. However, antiangiogenic TKI is still an indispensable first-line treatment option, such as pazopanib and sunitinib for patients at favorable risk and cabozantinib for those at poor or intermediate risk. In this context, effective therapeutic approaches are needed for patients after antiangiogenic TKI failure. But the current second-line standard of care including VEGFR TKIs, mTOR inhibitor, and ICI monotherapy are far from satisfactory, with an ORR of 1% to 25% and median PFS of 4.6 to 7.4 months (6–9, 12, 26). In our study, 65.8% of enrolled patients were heavily pretreated, and camrelizumab plus famitinib exhibited an ORR of 48.0%, a DCR of 84.0%, and a median PFS of 13.4 months in this population, which were in line with other investigative combinations (nivolumab plus pazopanib: ORR of 45%, DCR of 80%, median PFS of 7.2 months; nivolumab plus tivozanib: ORR of 62%, DCR of 100%; refs. 27, 28). Our results indicated camrelizumab in combination with famitinib as a promising second- and later-line treatment choice.

The encouraging antitumor function of camrelizumab plus famitinib could be explained, in part, by enhanced antitumor immune response through blockage of VEGF pathway (29, 30). In addition, other targets of famitinib are also involved in immune suppression, such as c-kit in MDSC accumulation and T_reg development and PDGF pathway in inhibiting dendritic cell maturation and inducing formation of T_regs (31, 32). For patients previously treated with TKIs, AXL expression is increased and acts as an important factor mediating resistance to VEGFR inhibitors (33), which may partly explain the robust response of camrelizumab plus famitinib in the relapsed or refractory setting. On the basis of these speculations, specific molecular mechanisms that contribute to the synergistic/additive effect of camrelizumab and famitinib could be further investigated.

Safety profile of camrelizumab and famitinib was consistent with previous reports of each component as a single agent, and no new safety signals were identified. The most common TRAEs of study combination were similar to those of famitinib alone (34–36) and sunitinib (3, 18), including proteinuria, hypertension, PPE syndrome, diarrhea, and hematologic toxicities. Occurrence of camrelizumab-related RCCEP was very low when combined with famitinib in this trial, consistent with other studies involving camrelizumab in combination with a VEGFR TKI (37, 38). Hepatotoxicity attracted the investigators' attention due to the high incidences of liver function test abnormalities reported in patients treated with nivolumab plus sunitinib, nivolumab plus pazopanib, and pembrolizumab plus pazopanib [grade 3 or 4 increased alanine aminotransferase (ALT), 18.2%, 20.0%, and 50%–70%, respectively; grade 3 or 4 increased AST, 9.1%, 20.0%, and 50%-60%, respectively; refs. 27, 39]. In our study, only 2.6% of patients had grade 3 or 4 increased ALT and 5.3% of patients experienced grade 3 or 4 increased AST. Furthermore, camrelizumab 200 mg every 3 weeks plus famitinib 20 mg once daily were tolerable and the AEs were manageable. With median duration from enrollment of 16.5 months, only 36.8% of patients required a dose reduction of famitinib to 15 mg due to TRAEs. The proportion of treatment discontinued owing to TRAEs was quite low (camrelizumab, 7.9%; famitinib, 2.6%).

A limitation of this study is that DoR and survival data were immature at the time of data cutoff. Longer follow-up will aid describing long-term antitumor response and survival of camrelizumab and famitinib combination in patients with RCC. Another limitation is lack of a control arm. But our findings supported further investigation of this combination compared with standard of care in large-scale studies, and a company-sponsored, international, multicenter, randomized, active-controlled phase III clinical trial is being planned to compare camrelizumab plus famitinib versus sunitinib in patients with advanced or metastatic RCC who have progressed on or are intolerant to anti-PD-(L)1–based regimens (monotherapy or in combination with TKIs). No more than two lines of prior systemic treatment are allowed.

In conclusion, this study demonstrated the substantial antitumor activity and manageable safety of camrelizumab combined with famitinib in patients with advanced or metastatic RCC, whether they had received prior TKI agents or not, probably providing another choice for these patients.

J. Cai is an employee of Jiangsu Hengrui Pharmaceuticals. X. Zhang is an employee of Jiangsu Hengrui Pharmaceuticals. Q. Wang is a full-time employee of Jiangsu Hengrui Pharmaceuticals Co., Ltd. No disclosures were reported by the other authors.

Y.-Y. Qu: Data curation, investigation, methodology, writing–original draft, data interpretation. H.-L. Zhang: Data curation, investigation, methodology, writing–original draft, data interpretation. H. Guo: Data curation, investigation, methodology, writing–review and editing, data interpretation. H. Luo: Data curation, investigation, methodology, writing–review and editing, data interpretation. Q. Zou: Data curation, investigation, methodology, writing–review and editing, data interpretation. N. Xing: Data curation, investigation, methodology, writing–review and editing, data interpretation. S. Xia: Data curation, investigation, methodology, writing–review and editing, data interpretation. Z. Sun: Data curation, investigation, methodology, writing–review and editing, data interpretation. X. Zhang: Data curation, investigation, methodology, writing–review and editing, data interpretation. C. He: Data curation, investigation, methodology, writing–review and editing, data interpretation. J. Cai: Resources, methodology, writing–original draft, data interpretation. X. Zhang: Resources, formal analysis, methodology, writing–original draft, data interpretation. Q. Wang: Conceptualization, resources, supervision, funding acquisition, methodology, writing–original draft, project administration, data interpretation. D.-W. Ye: Conceptualization, resources, data curation, supervision, investigation, methodology, project administration, writing–review and editing, data interpretation.

The study was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd. (formerly Jiangsu Hengrui Medicine Co., Ltd). We thank all patients and their families, investigators, and research personnel for participating in this study. We would also like to acknowledge Hui Dong (a Medical Writer from Jiangsu Hengrui Pharmaceuticals) for medical writing support according to Good Publication Practice Guidelines.

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