Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma
by
, , , , , , , , ,
Shuzo Hamamoto
1,*,†
,
Yoshihiko Tasaki
2,†,
Toshiharu Morikawa
1,
Taku Naiki
1,
Toshiki Etani
1,
Kazumi Taguchi
1,
Shoichiro Iwatsuki
1,
Rei Unno
1
,
Tomoki Takeda
1,
Takashi Nagai
1,
Kengo Kawase
1,
Yoshihisa Mimura
2,
Yosuke Sugiyama
2,
Atsushi Okada
1,
Yoko Furukawa-Hibi
2 and
Takahiro Yasui
1
1
Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
2
Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2024, 13(12), 3365; https://doi.org/10.3390/jcm13123365
Submission received: 13 May 2024
/
Revised: 30 May 2024
/
Accepted: 5 June 2024
/
Published: 7 June 2024
(This article belongs to the Special Issue Urological Oncology: New Insights into Diagnosis and Treatment)
Abstract
:Background/Objectives: Immuno-oncology plus tyrosine kinase inhibitor (IO+TKI) combination therapy is an essential first-line therapy for advanced renal cell carcinoma (RCC). However, reports of its efficacy and safety as late-line therapy are lacking. This study aimed to examine the efficacy and safety of IO+TKI combination therapy as a late-line therapy for patients with RCC. Methods: We retrospectively examined 17 patients with RCC who received IO+TKI combination therapy as a second-line therapy or beyond (pembrolizumab plus axitinib, n = 10; avelumab plus axitinib, n = 5; nivolumab plus cabozantinib, n = 2). Results: The overall response and disease control rates of IO+TKI combination therapy were 29.4% and 64.7%, respectively. The median overall survival was not attained. Progression-free survival was 552 days, and 94.1% of patients (n = 16) experienced adverse effects (AEs) of any grade; moreover, 41.2% of patients (n = 7) experienced grade ≥ 3 immuno-related AEs. Conclusions: IO+TKI combination therapy may be a late-line therapy option for RCC.
1. Introduction
Advanced renal cell carcinoma (RCC) is a rare and refractory cancer. Large-scale cancer statistics, which estimate new cancer cases and deaths in the United States, showed that approximately 4% (83,190 of 2,001,140 cases) of all cancer cases diagnosed each year were RCC [1]. The estimated 5-year survival rates for RCC between 2014 and 2019 were 93% for localized cases, 74% for regional cases, and 17% for distant cases [1]. According to the National Cancer Center Japan, approximately 3% (30,458 of 999,075 cases) of all cancer cases diagnosed each year in Japan were RCC. Additionally, the estimated 5-year survival rates for RCC in Japan were 94.3% for localized cases, 53.6% for regional cases, and 12.4% for distant cases. These statistical data indicate that RCC is a rare cancer that is associated with a poor prognosis. One reason for its poor prognosis is the lack of efficient therapy for RCC. However, recently, immuno-oncology (IO) therapy was approved for RCC, thus dramatically changing the treatment strategy and prognosis of such patients [2,3,4,5,6,7,8].
The European Association of Urology and the National Comprehensive Cancer Network (NCCN) guidelines strongly recommend IO plus tyrosine kinase inhibitor (IO+TKI) combination therapy or IO combination therapy as the standard first-line therapy for RCC [2,3,4,5,6,7,8]. Patients who cannot tolerate IO therapy receive TKI monotherapy as the first-line therapy for RCC [8]. There is no consensus regarding whether IO+TKI combination therapy or IO combination therapy is the optimal treatment for patients with RCC. Based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category, histological subtype, and patient condition, physicians can use several treatments as first-line therapy for RCC. Patients with disease progression after IO+TKI combination therapy or IO combination therapy as the standard first-line therapy for RCC require a new treatment modality as late-line therapy. However, although physicians can choose from many treatments as first-line therapy, the available late-line therapies may not be sufficiently effective.
IO+TKI combination therapy is a rational immunological treatment option. TKI can impose anti-tumor effects alone and also support the effects of IO through the suppression of regulatory T cells [9,10]. Large-scale clinical trials have shown that IO+TKI combination therapy is associated with better clinical outcomes [2,3,4,5,7,8]. For instance, the median progression-free survival (mPFS) of nivolumab plus cabozantinib is significantly longer than that of sunitinib (16.6 months vs. 8.3 months) [2]. Compared with sunitinib, pembrolizumab plus axitinib significantly decreases the risk of disease progression or death (hazard ratio: 0.69) [4]. Therefore, IO+TKI combination therapies, such as cabozantinib plus nivolumab, pembrolizumab plus lenvatinib, pembrolizumab plus axitinib, and avelmab plus axitinib, were approved and used as first-line therapy for RCC in Japan in 2019 [2,3,4,5]. Additionally, the NCCN guidelines describe the use of IO+TKI combination therapy after late-line therapy, regardless of whether the patient has received IO therapy [7]. However, the NCCN guidelines do not strongly recommend IO+TKI combination therapy after late-line therapy. One reason for this is the lack of reports on the efficacy and safety of IO+TKI combination therapy as late-line therapy. Therefore, this study aimed to investigate the efficacy and safety of IO+TKI combination therapy as late-line therapy for patients with advanced RCC.
2. Materials and Methods
2.1. Patients and Treatment
Seventeen patients were retrospectively analyzed at Nagoya City University Hospital between April 2020 and September 2023. We enrolled patients with RCC who received IO+TKI combination therapy as late-line therapy after one or more regimens of TKI monotherapy (sunitinib, axitinib, pazopanib, and sorafenib), nivolumab monotherapy, ipilimumab plus nivolumab, and mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus). IO+TKI combination therapy included pembrolizumab (200 or 400 mg/kg every 3 or 6 weeks) plus axitinib (10 mg twice daily), avelumab (10 mg/kg every 2 weeks) plus axitinib (10 mg twice daily), and nivolumab (240 or 480 mg/kg every 2 or 4 weeks) plus cabozantinib (40 mg once daily). Physicians selected the therapy based on the patients’ conditions. Patients who received IO+TKI combination therapy as first-line therapy were excluded. Experienced pathologists diagnosed RCC based on the results of histological examinations. Two cases involving unknown histological subtypes were diagnosed as RCC by an experienced radiologist and urologist who used computed tomography and magnetic resonance imaging to evaluate the patients. All patients were followed-up until death or loss of contact. Overall survival (OS) was analyzed as the period from the start of IO+TKI combination therapy until death or the last follow-up. The treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) [11]. We examined the adverse effects (AEs) induced by IO or TKI using blood sample tests and clinical assessments. The AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
2.2. Statistical Analysis
p < 0.05 was considered statistically significant. The Kaplan–Meier method and log-rank tests were performed to analyze the median OS and mPFS. Statistical analyses were performed using GraphPad Prism 9 software.
3. Results
3.1. Patient Characteristics
Patient characteristics before IO+TKI combination therapy are shown in Table 1. The characteristics of each patient before IO+TKI combination therapy are shown in Table 2. Seventeen patients with RCC were enrolled in this study. The median follow-up duration was 515 days (range, 75–1216 days). The median period from the diagnosis of RCC to the start of IO+TKI combination therapy was 1687 days (range, 127–5655 days). The median patient age was 73 years (range, 55–88 years). The proportions of men and women were 70.6% (n = 12) and 29.4% (n = 5), respectively. Comorbidities and disease histories before IO+TKI combination therapy were hypertension (29.4%; n = 5), diabetes mellitus (17.6%; n = 3), arrhythmia (11.8%; n = 2), dyslipidemia (11.8%; n = 2), angina (5.9%; n = 1), cataracts (5.9%; n = 1), chronic heart failure (5.9%; n = 1), gastric ulcer (5.9%; n = 1), glaucoma (5.9%; n = 1), Guillain-Barre syndrome (5.9%; n = 1), hemorrhoids (5.9%; n = 1), hyperuricemia (5.9%; n = 1), myocardial infarction (5.9%; n = 1), rheumatoid arthritis (5.9%; n = 1), and uterine fibroids (5.9%; n = 1). Additionally, 35.3% (n = 6) of patients did not have comorbidities or disease histories before IO+TKI combination therapy. All patients had stage IV disease. The patients were categorized as favorable risk (23.5%; n = 4), intermediate risk (58.8%; n = 10), and poor risk (11.8%; n = 2) according to the IMDC risk categories. Among the histological subtypes, the highest proportion of patients had the clear cell type (82.3%; n = 14), followed by the non-clear cell type (5.9%; n = 1). The histological subtype of 11.8% (n = 2) of patients was unknown. None of the patients exhibited sarcomatoid changes. The metastatic sites were the liver (23.5%; n = 4), lungs (76.5%; n = 13), and others such as the bones, brain, adrenal glands, pancreas, prostate, pleura, retroperitoneum, ileocecum, peritoneum, and parathyroid (70.6%; n = 12).
3.2. Therapeutic Features
The therapeutic features of the patients are summarized in Table 3. The administered treatments were pembrolizumab + axitinib (58.8%; n = 10), avelumab + axitinib (29.4%; n = 5), and nivolumab + cabozantinib (11.8%; n = 2). The median numbers of courses of these therapies were 15.5 (range, 3–51) for pembrolizumab + axitinib, 23 (range, 6–38) for avelumab + axitinib, and 5.5 (range, 2–9) for nivolumab + cabozantinib. The median daily dosages of TKI were 5.5 mg (range, 2.5–7.3 mg) for Axitinib and 35 mg (range, 30–40 mg) for Cabozantinib. Among those who received IO+TKI combination therapy, the highest proportion received it as second-line therapy (47.0%; n = 8), followed by third-line therapy (17.6%; n = 3), fourth-line therapy (5.9%; n = 1), fifth-line therapy (5.9%; n = 1), and sixth-line therapy and beyond (23.5%; n = 4). The therapies administered before IO+TKI combination therapy were nivolumab monotherapy (52.9%; n = 9 cases), sunitinib (52.9%; n = 9 cases), ipilimumab plus nivolumab (41.2%; n = 7 cases), axitinib (35.3%; n = 6 cases), everolimus (29.4%; n = 5 cases), Pazopanib (17.6%; n = 3 cases), sorafenib (17.6%; n = 3 cases), and temsirolimus (5.9%; n = 1 case). The subsequent therapies administered after IO+TKI combination therapy included axitinib (17.6%; n = 3), cabozantinib (5.9%; n = 1), and nivolumab monotherapy (5.9%; n = 1).
The therapeutic features of each patient are described in Table 4. Among eight patients who received IO+TKI combination therapy as second-line therapy, seven received ipilimumab plus nivolumab and one received pazopanib as first-line therapy before IO+TKI combination therapy (cases 1, 4, 12, 13, 14, 15, 16, and 17). The three patients who received IO+TKI combination therapy as third-line therapy received TKI monotherapy (sunitinib and pazopanib) and nivolumab monotherapy before IO+TKI combination therapy (cases 3, 7, and 8). One patient who received IO+TKI combination therapy as fourth-line therapy received TKI monotherapy (sunitinib and pazopanib) and nivolumab monotherapy before IO+TKI combination therapy (case 9). The five patients who received IO+TKI combination therapy as fifth-line therapy and beyond received two or more types of TKI monotherapy (sunitinib, axitinib, sorafenib, and/or pazopanib), nivolumab monotherapy, and mTOR inhibitors before IO+TKI combination therapy (cases 2, 5, 6, 10, and 11).
3.3. Efficacy and Safety of IO+TKI Combination Therapy
We analyzed the efficacy of IO+TKI combination therapy and found the following response rates: CR, 0.0% (n = 0); PR, 29.4% (n = 5); SD, 35.3% (n = 6); and PD, 35.3% (n = 6). The proportions of objective response rates and disease control rates were 29.4% (n = 5) and 64.7% (n = 11), respectively (Table 5). The Kaplan–Meier method showed that the median OS was not reached and that the mPFS was 552 days (Figure 1a,b).
Table 6 presents the details of the AEs. Of the patients included in this study, 94.1% (n = 16) experienced AEs. Among these AEs, 41.2% (n = 7) were grade ≥3. The incidences of AEs of any grade were as follows: diarrhea, 70.6% (n = 12); hypertension, 23.5% (n = 4); fever, 17.6% (n = 3); hoarseness, 17.6% (n = 3); decreased appetite, 11.8% (n = 2); rash, 11.8% (n = 2); fatigue, 11.8% (n = 2); pneumonitis, 11.8% (n = 2); and other disorders (nausea, alopecia areata, hand–foot skin reaction, diabetes mellitus, thyroid dysfunction, edema, serum creatine elevation, hyponatremia, myasthenia gravis, and proteinuria), 5.9% (n = 1). Grade ≥3 AEs were diarrhea, fatigue, pneumonitis, hand–foot skin reaction, diabetes mellitus, edema, hyponatremia, myasthenia gravis, and proteinuria (5.9%; n = 1).
The details of the AEs of each patient are shown in Table 7. Ten patients experienced three or more AEs (cases 1, 2, 4, 5, 7, 11, 12, 14, 15, and 16). Three patients experienced two AEs (cases 3, 13, and 17) and three patients experienced one AE (cases 8, 9, and 10). One patient did not experience any AEs (case 6). No patients experienced worsened comorbidities or had disease histories attributable to IO+TKI combination therapy.
The reasons for discontinuing treatment included disease progression (47.0%; n = 8) and AEs (17.6%; n = 3) (Table 8). Furthermore, 35.3% (n = 6) of patients enrolled in the current study experienced AEs attributable to IO therapy before IO+TKI combination therapy. Among these patients, 11.8% (n = 2) experienced further severe AEs after IO+TKI combination therapy and discontinued therapy.
3.4. Analysis of the Association between Efficacy and the IMDC Risk
Finally, we examined the association between the survival time and IMDC risk. The median OS and mPFS of patients with a poor IMDC risk were associated with poor clinical survival compared to those of patients with favorable and intermediate IMDC risks (OS: not reached vs. not reached vs. 407 days, p < 0.05; PFS: not reached vs. 802.5 days vs. 213 days, p = 0.08) (Figure 2a,b).
4. Discussion
We investigated the efficacy and safety of IO+TKI combination therapy as a late-line therapy. To date, IO+TKI combination therapy has been the first-line therapy [2,3,4,5]. A large-scale clinical trial reported mPFS from 13.8 to 23.9 months [2,3,4,5]. The current study demonstrated that the efficacy of IO+TKI combination therapy as a late-line therapy may be similar to its efficacy as a first-line therapy. Among TKI monotherapies, cabozantinib and axitinib are mainly selected as a late-line therapy for RCC. During a phase 3 trial, the mPFS of patients who received cabozantinib and axitinib were 7.4 months and 6.7 months, respectively [12,13]. However, these patients did not receive IO+TKI combination therapy or IO combination therapy as a previous systemic therapy, which may differ from the current treatment strategy. Several studies have reported real-world data regarding cabozantinib or axitinib as a late-line therapy [14,15,16,17,18,19]. Suzuki et al. reported that the mPFS of patients who received axitinib as a second-line therapy was 10.3 months [14]. Bodnar et al. and Stukalin et al. reported that the mPFS of patients who received cabozantinib as a second-line therapy were 12.5 months and 7.39 months, respectively [15,16]. Furthermore, Gan et al. and Domański et al. examined the efficacy of cabozantinib as a second-line therapy [17,18]. According to Gan et al., the mPFS associated with second-line therapy was 7.3 months, that associated with third-line therapy was 7.0 months, and that associated with fourth-line therapy was 8.0 months [17]. Domański et al. reported that the mPFS associated with second-line therapy and beyond was 11 months [18]. Procopio et al. evaluated the efficacy of cabozantinib for patients who received IO+TKI combination therapy or IO combination therapy as previous systemic therapy and reported an mPFS of 8.3 months [19]. The current study showed that the efficacy of IO+TKI combination therapy as late-line therapy may be comparable to or better than that of cabozantinib or axitinib therapy. Considering these results regarding the efficacy of first-line and second-line therapies and beyond, our study suggested that IO+TKI combination therapy may be suitable as a late-line therapy.
The safety of IO+TKI combination therapy as a first-line therapy has been reported in phase 3 trials [2,3,4,5]. The incidences of any grade and grade ≥3 AEs were 99.7% and 75.3% for nivolumab + cabozantinib, 99.7% and 82.4% for lenvatinib + pembrolizumab, 98.4% and 75.8% for pembrolizumab + axitinib, and 99.5% and 71.2% for avelumab + axitinib, respectively. Similar to these phase 3 trials, our study found that diarrhea had the highest incidence among AEs of any grade. Other AEs with high incidences were hypertension, decreased appetite, and fatigue. The current study showed that the incidences of any grade and grade ≥3 AEs were 94.1% and 41.2%, respectively. Additionally, diarrhea had the highest incidence in phase 3 trials. Phase 3 trials also reported the following incidences of treatment discontinuation attributable to AEs [2,3,4,5]: 19.7% for nivolumab + cabozantinib therapy; 37.2% for lenvatinib + pembrolizumab; 30.5% for pembrolizumab + axitinib; and 7.6% for avelumab + axitinib [2,3,4,5]. Furthermore, 17.6% of patients discontinued treatment because of AEs. In summary, the incidences of treatment discontinuation and AEs and the AE profiles observed during our study were similar to those observed during these clinical trials. Interestingly, 35.3% (n = 6) of patients who received IO therapy before IO+TKI combination therapy experienced immune-related AEs as a result of prior therapy. Nevertheless, it was difficult to continue treatment for 11.8% of patients because of further severe immune-related AEs attributable to IO+TKI combination therapy. Although decisions regarding the treatment of patients with comorbidities, disease histories, and prior therapy-related AEs require caution, the current study suggested that IO+TKI combination therapy as a late-line therapy is safe and tolerable.
Biomarkers that predict the efficacy of IO+TKI combination therapy have been reported [20,21,22,23,24,25]. For example, the expression levels of cyclin-dependent kinases 5 and 6, which play important roles in the cell cycle, are associated with efficacy and tumor-infiltrating immune cells [20,23]. Wang et al. showed that elevated RUNX3 expression levels in tumors are associated with poor efficacy [25]. However, those studies focused on the examination of tumors, and no reports have focused on blood parameters that can be easily investigated. Furthermore, no biomarkers are available for clinical use. Previously, we investigated biomarkers that could predict the effectiveness of IO therapy [26,27,28]. In the current study, the IMDC risk may have been associated with efficacy, as in our previous study [26]. These findings may predict efficacy and safety and should be considered when determining treatment strategies for patients with RCC.
There have been only two studies of the efficacy and safety of IO+TKI combination therapy as a late-line therapy [29,30]. However, those studies retrospectively examined a small number of patients. Dizman et al. examined the efficacy and safety of IO+TKI combination therapy for 38 patients who received pembrolizumab + aitinib treatment [29] and revealed that the mPFS was 9.7 months and that any grade, grade 3, and grade 4 AEs occurred in 86.8, 18.4%, and 6.4% patients, respectively. Yang et al. reported that the mPFS of second-line, third-line, and fourth-line therapies and beyond were 14.2 months, 10.1 months, and 6.8 months, respectively, and that the incidence of grade ≥3 AEs was 52.0% [30]. The efficacy and safety observed during the current study were comparable to those reported by previous studies. Therefore, the results of previous studies support our data that indicated that IO+TKI combination therapy may be suitable as a late-line therapy.
The present study had some limitations. First, it examined a small number of patients; therefore, a large-scale study is required to confirm the validity of our findings. Second, the retrospective design may have resulted in selection bias; therefore, prospective studies are warranted.
5. Conclusions
IO+TKI combination therapy may be used as a late-line therapy for patients with RCC who have received one or more other regimens, such as TKI monotherapy, nivolumab monotherapy, IO combination therapy, or mTOR inhibitors.
Author Contributions
S.H., Y.T. and T.Y. designed and conducted the study. S.H., Y.T. and Y.S. analyzed the majority of the data. S.H., Y.T. and Y.S. conducted statistical analyses. S.H., Y.T., T.M., T.N. (Taku Naiki), T.E., K.T., S.I., R.U., T.T., T.N. (Takashi Nagai), K.K., Y.M., Y.S., A.O., Y.F.-H. and T.Y. acquired data. S.H. and Y.T. wrote the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by the Nitto Foundation.
Institutional Review Board Statement
This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Nagoya City University Graduate School of Medical Sciences (protocol codes 60-19-0196 and 13 February 2020).
Informed Consent Statement
The protocol summary is described on the hospital website, and the subjects were provided with the opportunity to opt-out because this was a retrospective cohort study.
Data Availability Statement
We provided all data and methods in this manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- Siegel, R.L.; Giaquinto, A.N.; Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 2024, 74, 12–49. [Google Scholar] [CrossRef]
- Choueiri, T.K.; Powles, T.; Burotto, M.; Escudier, B.; Bourlon, M.T.; Zurawski, B.; Oyervides Juárez, V.M.; Hsieh, J.J.; Basso, U.; Shah, A.Y.; et al. Nivolumab plus cabozantinib versus sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2021, 384, 829–841. [Google Scholar] [CrossRef]
- Motzer, R.; Alekseev, B.; Rha, S.Y.; Porta, C.; Eto, M.; Powles, T.; Grünwald, V.; Hutson, T.E.; Kopyltsov, E.; Méndez-Vidal, M.J.; et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 2021, 384, 1289–1300. [Google Scholar] [CrossRef]
- Rini, B.I.; Plimack, E.R.; Stus, V.; Gafanov, R.; Hawkins, R.; Nosov, D.; Pouliot, F.; Alekseev, B.; Soulières, D.; Melichar, B.; et al. Pembrolizumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019, 380, 1116–1127. [Google Scholar] [CrossRef]
- Motzer, R.J.; Penkov, K.; Haanen, J.; Rini, B.; Albiges, L.; Campbell, M.T.; Venugopal, B.; Kollmannsberger, C.; Negrier, S.; Uemura, M.; et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019, 380, 1103–1115. [Google Scholar] [CrossRef] [PubMed]
- Motzer, R.J.; McDermott, D.F.; Escudier, B.; Burotto, M.; Choueiri, T.K.; Hammers, H.J.; Barthélémy, P.; Plimack, E.R.; Porta, C.; George, S.; et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer 2022, 128, 2085–2097. [Google Scholar] [CrossRef]
- Motzer, R.J.; Jonasch, E.; Agarwal, N.; Alva, A.; Baine, M.; Beckermann, K.; Carlo, M.I.; Choueiri, T.K.; Costello, B.A.; Derweesh, I.H.; et al. Kidney Cancer, version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2022, 20, 71–90. [Google Scholar] [CrossRef]
- Ljungberg, B.; Albiges, L.; Abu-Ghanem, Y.; Bedke, J.; Capitanio, U.; Dabestani, S.; Fernández-Pello, S.; Giles, R.H.; Hofmann, F.; Hora, M.; et al. European Association of Urology guidelines on renal cell carcinoma: The 2022 update. Eur. Urol. 2022, 82, 399–410. [Google Scholar] [CrossRef]
- Yi, C.; Chen, L.; Lin, Z.; Liu, L.; Shao, W.; Zhang, R.; Lin, J.; Zhang, J.; Zhu, W.; Jia, H.; et al. Lenvatinib targets FGF Receptor 4 to enhance antitumor immune response of anti-programmed cell Death-1 in HCC. Hepatology 2021, 74, 2544–2560. [Google Scholar] [CrossRef]
- Torrens, L.; Montironi, C.; Puigvehí, M.; Mesropian, A.; Leslie, J.; Haber, P.K.; Maeda, M.; Balaseviciute, U.; Willoughby, C.E.; Abril-Fornaguera, J.; et al. Immunomodulatory effects of lenvatinib plus anti-programmed cell death Protein 1 in mice and rationale for patient enrichment in hepatocellular carcinoma. Hepatology 2021, 74, 2652–2669. [Google Scholar] [CrossRef]
- Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. Cancer 2009, 45, 228–247. [Google Scholar] [CrossRef]
- Choueiri, T.K.; Escudier, B.; Powles, T.; Mainwaring, P.N.; Rini, B.I.; Donskov, F.; Hammers, H.; Hutson, T.E.; Lee, J.L.; Peltola, K.; et al. Cabozantinib versus everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2015, 373, 1814–1823. [Google Scholar] [CrossRef]
- Rini, B.I.; Escudier, B.; Tomczak, P.; Kaprin, A.; Szczylik, C.; Hutson, T.E.; Michaelson, M.D.; Gorbunova, V.A.; Gore, M.E.; Rusakov, I.G.; et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 2011, 378, 1931–1939. [Google Scholar] [CrossRef]
- Suzuki, K.; Terakawa, T.; Furukawa, J.; Harada, K.; Hinata, N.; Nakano, Y.; Fujisawa, M. Clinical outcomes of second-line treatment following prior targeted therapy in patients with metastatic renal cell carcinoma: A comparison of axitinib and nivolumab. Int. J. Clin. Oncol. 2020, 25, 1678–1686. [Google Scholar] [CrossRef]
- Bodnar, L.; Kopczyńska, A.; Żołnierek, J.; Wieczorek-Rutkowska, M.; Chrom, P.; Tomczak, P. Real-world experience of cabozantinib as second- or subsequent line treatment in patients with metastatic renal cell carcinoma: Data from the polish managed access program. Clin. Genitourin. Cancer 2019, 17, e556–e564. [Google Scholar] [CrossRef]
- Stukalin, I.; Wells, J.C.; Graham, J.; Yuasa, T.; Beuselinck, B.; Kollmansberger, C.; Ernst, D.S.; Agarwal, N.; Le, T.; Donskov, F.; et al. Real-world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Curr. Oncol. 2019, 26, e175–e179. [Google Scholar] [CrossRef] [PubMed]
- Gan, C.L.; Dudani, S.; Wells, J.C.; Donskov, F.; Pal, S.K.; Dizman, N.; Rathi, N.; Beuselinck, B.; Yan, F.; Lalani, A.A.; et al. Cabozantinib real-world effectiveness in the first-through fourth-line settings for the treatment of metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Cancer Med. 2021, 10, 1212–1221. [Google Scholar] [CrossRef]
- Domański, P.; Jarosińska, J.; Kruczyk, B.; Piętak, M.; Mydlak, A.; Demkow, T.; Kuncman, Ł.; Darewicz, M.; Sikora-Kupis, B.; Dumnicka, P.; et al. Activity of cabozantinib in further line treatment of metastatic clear cell renal cell carcinoma. Real-world experience in a single-center retrospective study. Contemp. Oncol. 2023, 27, 190–197. [Google Scholar] [CrossRef] [PubMed]
- Procopio, G.; Claps, M.; Pircher, C.; Porcu, L.; Sepe, P.; Guadalupi, V.; De Giorgi, U.; Bimbatti, D.; Nolè, F.; Carrozza, F.; et al. A multicenter phase 2 single arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pre-treated with one immune-checkpoint inhibitor: The BREAKPOINT trial (Meet-Uro trial 03). Tumori 2023, 109, 129–137. [Google Scholar] [CrossRef]
- Xu, X.; Wang, Y.; Chen, Z.; Zhu, Y.; Wang, J.; Guo, J. Favorable immunotherapy plus tyrosine kinase inhibition outcome of renal cell carcinoma patients with low CDK5 expression. Cancer Res. Treat. 2023, 55, 1321–1336. [Google Scholar] [CrossRef] [PubMed]
- Xu, X.; Wang, Y.; Chen, Z.; Zhu, Y.; Wang, J.; Guo, J. Unfavorable immunotherapy plus tyrosine kinase inhibition outcome of metastatic renal cell carcinoma after radical nephrectomy with increased ADAM9 expression. Immunogenetics 2023, 75, 133–143. [Google Scholar] [CrossRef]
- Wang, J.; Zhang, S.; Wang, Y.; Zhu, Y.; Xu, X.; Guo, J. Alternative complement pathway signature determines immunosuppression and resistance to immunotherapy plus tyrosine kinase inhibitor combinations in renal cell carcinoma. Urol. Oncol. 2023, 41, 51.e13–51.e23. [Google Scholar] [CrossRef]
- Wang, J.; Zhang, S.; Wang, Y.; Zhu, Y.; Xu, X.; Guo, J. The prognostic significance of CDK6 expression in renal cell carcinoma treated by immune checkpoint plus tyrosine kinase inhibition. Scand. J. Immunol. 2023, 98, e13304. [Google Scholar] [CrossRef]
- Xu, X.; Wang, Y.; Hu, X.; Zhu, Y.; Wang, J.; Guo, J. Effects of PYCR1 on prognosis and immunotherapy plus tyrosine kinase inhibition responsiveness in metastatic renal cell carcinoma patients. Neoplasia 2023, 43, 100919. [Google Scholar] [CrossRef]
- Wang, J.; Zhang, S.; Wang, Y.; Zhu, Y.; Xu, X.; Guo, J. RUNX3 pathway signature predicts clinical benefits of immune checkpoint inhibition plus tyrosine kinase inhibition in advanced renal cell carcinoma. BMC Urol. 2024, 24, 8. [Google Scholar] [CrossRef] [PubMed]
- Tomiyama, N.; Tasaki, Y.; Hamamoto, S.; Sugiyama, Y.; Naiki, T.; Etani, T.; Taguchi, K.; Matsuyama, N.; Sue, Y.; Mimura, Y.; et al. Hemoglobin and neutrophil levels stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk predict the effectiveness of ipilimumab plus nivolumab in patients with advanced metastatic renal cell carcinoma. Int. J. Urol. 2023, 30, 754–761. [Google Scholar] [CrossRef] [PubMed]
- Tasaki, Y.; Hamamoto, S.; Sugiyama, Y.; Tomiyama, N.; Naiki, T.; Etani, T.; Taguchi, K.; Matsuyama, N.; Sue, Y.; Mimura, Y.; et al. Elevated eosinophils proportion as predictor of immune-related adverse events after ipilimumab and nivolumab treatment of advanced and metastatic renal cell carcinoma. Int. J. Urol. 2023, 30, 866–874. [Google Scholar] [CrossRef]
- Tasaki, Y.; Sugiyama, Y.; Hamamoto, S.; Naiki, T.; Uemura, T.; Yokota, K.; Kawakita, D.; Nakamura, M.; Ogawa, R.; Shimura, T.; et al. Eosinophil may be a predictor of immune-related adverse events induced by different immune checkpoint inhibitor types: A retrospective multidisciplinary study. Cancer Med. 2023, 12, 21666–21679. [Google Scholar] [CrossRef]
- Dizman, N.; Austin, M.; Considine, B.; Jessel, S.; Schoenfeld, D.; Merl, M.Y.; Hurwitz, M.; Sznol, M.; Kluger, H. Outcomes with combination pembrolizumab and axitinib in second and further line treatment of metastatic renal cell carcinoma. Clin. Genitourin. Cancer 2023, 21, 221–229. [Google Scholar] [CrossRef]
- Yang, Y.; Psutka, S.P.; Parikh, A.B.; Li, M.; Collier, K.; Miah, A.; Mori, S.V.; Hinkley, M.; Tykodi, S.S.; Hall, E.; et al. Combining immune checkpoint inhibition plus tyrosine kinase inhibition as first and subsequent treatments for metastatic renal cell carcinoma. Cancer Med. 2022, 11, 3106–3114. [Google Scholar] [CrossRef] [PubMed]
Figure 1.
Kaplan–Meier survival curves for (a) overall survival (n = 17) and (b) progression-free survival (n = 17). (a,b) Log-rank test. mOS, median overall survival; mPFS, median progression-free survival.
Figure 1.
Kaplan–Meier survival curves for (a) overall survival (n = 17) and (b) progression-free survival (n = 17). (a,b) Log-rank test. mOS, median overall survival; mPFS, median progression-free survival.
Figure 2.
Kaplan–Meier survival curves for (a) overall survival (favorable IMDC risk group: n = 4; intermediate IMDC risk group: n = 10; poor IMDC risk group: n = 2) and (b) progression-free survival (favorable IMDC risk group: n = 4; intermediate IMDC risk group: n = 10; poor IMDC risk group: n = 2) of patients with renal cell carcinoma. (a,b) Log-rank test. IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; mOS: median overall survival; mPFS: median progression-free survival.
Figure 2.
Kaplan–Meier survival curves for (a) overall survival (favorable IMDC risk group: n = 4; intermediate IMDC risk group: n = 10; poor IMDC risk group: n = 2) and (b) progression-free survival (favorable IMDC risk group: n = 4; intermediate IMDC risk group: n = 10; poor IMDC risk group: n = 2) of patients with renal cell carcinoma. (a,b) Log-rank test. IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; mOS: median overall survival; mPFS: median progression-free survival.
Table 1.
Patient characteristics.
| Characteristics | |
|---|---|
| Total, n (%) | 17 (100) |
| Age, median (range) | 73 (55–88) |
| Sex, n (%) | |
| Male | 12 (70.6) |
| Female | 5 (29.4) |
| Comorbidities and disease histories | |
| Hypertension | 5 (29.4) |
| Diabetes mellitus | 2 (11.8) |
| Arrhythmia | 2 (11.8) |
| Dyslipidemia | 2 (11.8) |
| Angina | 1 (5.9) |
| Cataracts | 1 (5.9) |
| Chronic heart failure | 1 (5.9) |
| Gastric ulcer | 1 (5.9) |
| Glaucoma | 1 (5.9) |
| Guillain–Barre syndrome | 1 (5.9) |
| Hemorrhoids | 1 (5.9) |
| Hyperuricemia | 1 (5.9) |
| Myocardial infarction | 1 (5.9) |
| Rheumatoid arthritis | 1 (5.9) |
| Uterine fibroids | 1 (5.9) |
| None | 7 (41.2) |
| Stage | |
| I | 0 (0.0) |
| II | 0 (0.0) |
| III | 0 (0.0) |
| IV | 17 (100) |
| IMDC risk group, n (%) | |
| Favorable | 4 (23.5) |
| Intermediate | 10 (58.8) |
| Poor | 2 (11.8) |
| Not evaluable | 1 (5.9) |
| Histological subtype, n (%) | |
| Clear cell | 14 (82.3) |
| Non-clear cell (Bellini duct carcinoma) | 1 (5.9) |
| Unknown | 2 (11.8) |
| Sarcomatoid change | |
| No | 17 (100) |
| Yes | 0 (0.0) |
| Metastasis site, liver, n (%) | |
| No | 13 (76.5) |
| Yes | 4 (23.5) |
| Metastasis site, lung, n (%) | |
| No | 4 (23.5) |
| Yes | 13 (76.5) |
| Metastasis site, others, n (%) | |
| No | 5 (29.4) |
| Yes | 12 (70.6) |
IMDC: International Metastatic Renal Cell Carcinoma Database Consortium.
Table 2.
Characteristics of each patient before IO+TKI combination therapy.
| Case Number | Age | Sex | Comorbidities and Disease Histories | Period from the RCC Diagnosis to the Start of IO+TKI Combination Therapy (Days) | Stage | IMDC Risk Group | Histological Subtype | Metastasis Site |
|---|---|---|---|---|---|---|---|---|
| 1 | 74 | Female | Diabetes | 177 | IV | Favorable | Clear cell | Lung |
| Dyslipidemia | ||||||||
| Hypertension | ||||||||
| 2 | 85 | Male | Chronic heart failure | 2401 | IV | Favorable | Clear cell | Lung |
| Hypertension | ||||||||
| 3 | 88 | Male | None | 5193 | IV | Intermediate | Clear cell | Lung |
| Peritoneum | ||||||||
| 4 | 85 | Female | None | 258 | IV | Intermediate | Unknown | Lung |
| 5 | 67 | Male | None | 5655 | IV | Intermediate | Clear cell | Liver |
| Pancreas | ||||||||
| Ileocecum | ||||||||
| Retroperitoneum | ||||||||
| 6 | 76 | Female | Hypertension | 3712 | IV | Intermediate | Clear cell | Lung |
| Uterine fibroids | Bone | |||||||
| 7 | 80 | Male | Cataract | 3986 | IV | Favorable | Clear cell | Lung |
| Gastric ulcer | Bone | |||||||
| Glaucoma | Pancreas | |||||||
| Hemorrhoids | Adrenal glands | |||||||
| 8 | 61 | Male | Diabetes | 2647 | IV | Favorable | Clear cell | Lung |
| Dyslipidemia | Pleura | |||||||
| Parathyroid | ||||||||
| Hyperuricemia | Prostate | |||||||
| 9 | 73 | Male | Hypertension | 2043 | IV | Intermediate | Clear cell | Lung |
| Bone | ||||||||
| Rheumatoid arthritis | Adrenal glands | |||||||
| 10 | 67 | Female | Hypertension | 3328 | IV | Not evaluable | Unknown | Lung |
| Liver | ||||||||
| Bone | ||||||||
| 11 | 65 | Female | None | 1687 | IV | Intermediate | Clear cell | Bone |
| 12 | 68 | Male | Arrhythmia | 920 | IV | Intermediate | Clear cell | Adrenal glands |
| Guillain-Barre syndrome | Bone | |||||||
| 13 | 81 | Male | Angina | 1246 | IV | Intermediate | Bellini duct carcinoma | Lung |
| Liver | ||||||||
| 14 | 59 | Male | None | 385 | IV | Intermediate | Clear cell | Bone |
| 15 | 55 | Male | None | 168 | IV | Intermediate | Clear cell | Lung |
| Bone | ||||||||
| 16 | 79 | Male | Arrhythmia | 127 | IV | Poor | Clear cell | Lung |
| Myocardial infarction | Liver | |||||||
| 17 | 58 | Male | None | 412 | IV | Poor | Clear cell | Lung |
| Bone | ||||||||
| Brain | ||||||||
| Adrenal glands |
IMDC: International Metastatic Renal Cell Carcinoma Database Consortium.
Table 3.
Therapeutic features of the included patients.
| Characteristics | |
|---|---|
| Total, n (%) | 17 (100) |
| IO+TKI combination therapy, n (%) | 17 (100) |
| Pembrolizumab + axitinib | 10 (58.8) |
| Avelumab + axitinib | 5 (29.4) |
| Nivolumab + cabozantinib | 2 (11.8) |
| Median of number of courses, (range) | |
| Pembrolizumab + axitinib | 15.5 (3–51) |
| Avelumab + axitinib | 23 (6–38) |
| Nivolumab + cabozantinib | 5.5 (2–9) |
| Median daily dosage of TKI, mg (range) | |
| Axitinib | 5.5 (2.2–7.3) |
| Cabozantinib | 35 (30–40) |
| Line of IO+TKI combination therapy | 17 (100) |
| Second line | 8 (47.0) |
| Third line | 3 (17.6) |
| Fourth line | 1 (5.9) |
| Fifth line | 1 (5.9) |
| Sixth line and beyond | 4 (23.5) |
| Therapy before IO+TKI combination therapy | |
| Specifications, n (%) | |
| Nivolumab monotherapy | 9 (52.9) |
| Sunitinib | 9 (52.9) |
| Ipilimumab plus nivolumab | 7 (41.2) |
| Axitinib | 6 (35.3) |
| Everolimus | 5 (29.4) |
| Pazopanib | 3 (17.6) |
| Sorafenib | 3 (17.6) |
| Temsirolimus | 1 (5.9) |
| Subsequent therapy after IO+TKI combination therapy | |
| Specifications, n (%) | |
| Axitinib | 3 (17.6) |
| Cabozantinib | 1 (5.9) |
| Nivolumab monotherapy | 1 (5.9) |
IO+TKI: immuno-oncology plus tyrosine kinase inhibitor.
Table 4.
Therapeutic features of each patient.
| Case Number | First Line | Second Line | Third Line | Fourth Line | Fifth Line | Sixth Line | Seventh Line | Eighth Line |
|---|---|---|---|---|---|---|---|---|
| 1 | Ipilimumab + nivolumab | Pembrolizumab + axitinib | Cabozantinib | - | - | - | - | - |
| 2 | Sunitinib | Axitinib | Everolimus | Nivolumab monotherapy | Pembrolizumab + axitinib | Nivolumab monotherapy | - | - |
| 3 | Pazopanib | Nivolumab monotherapy | Avelumab + axitinib | Axitinib | - | - | - | - |
| 4 | Ipilimumab + nivolumab | Avelumab + axitinib | - | - | - | - | - | - |
| 5 | Sorafenib | Sunitinib | Everolimus | Axitinib | Nivolumab monotherapy | Pazopanib | Temsirolimus | Pembrolizumab + axitinib |
| 6 | Sunitinib | Everolimus | Sorafenib | Sunitinib | Nivolumab monotherapy | Pembrolizumab + axitinib | - | - |
| 7 | Sunitinib | Nivolumab monotherapy | Avelumab + axitinib | - | - | - | - | - |
| 8 | Sunitinib | Nivolumab monotherapy | Pembrolizumab + axitinib | - | - | - | - | - |
| 9 | Sunitinib | Axitinib | Nivolumab monotherapy | Pembrolizumab + axitinib | - | - | - | - |
| 10 | Sorafenib | Sunitinib | Everolimus | Axitinib | Nivolumab monotherapy | Pembrolizumab + axitinib | - | - |
| 11 | Nivolumab monotherapy | Sunitinib | Everolimus | Nivolumab monotherapy | Axitinib | Nivolumab + cabozantinib | - | - |
| 12 | Pazopanib | Pembrolizumab + axitinib | - | - | - | - | - | - |
| 13 | Ipilimumab + nivolumab | Nivolumab + cabozantinib | - | - | - | - | - | - |
| 14 | Ipilimumab + nivolumab | Avelumab + axitinib | Axitinib | - | - | - | - | - |
| 15 | Ipilimumab + nivolumab | Pembrolizumab + axitinib | - | - | - | - | - | - |
| 16 | Ipilimumab + nivolumab | Avelumab + axitinib | - | - | - | - | - | - |
| 17 | Ipilimumab + nivolumab | Pembrolizumab + axitinib | - | - | - | - | - | - |
Table 5.
Efficacy profile.
| Characteristics | |
|---|---|
| Total, n (%) | 17 (100) |
| Best response to IO+TKI combination therapy, n (%) | 17 (100) |
| Complete response | 0 (0.0) |
| Partial response | 5 (29.4) |
| Stable disease | 6 (35.3) |
| Progressive disease | 6 (35.3) |
| Overall response rate, n (%) | |
| Yes | 5 (29.4) |
| No | 12 (70.6) |
| Disease control rate, n (%) | |
| Yes | 11 (64.7) |
| No | 6 (35.3) |
IO+TKI: immuno-oncology plus tyrosine kinase inhibitor.
Table 6.
AE profiles.
| Patients | ||
|---|---|---|
| AE Profiles | Any Grade, n (%) | Grade ≥ 3, n (%) |
| Any event | 16 (94.1) | 7 (41.2) |
| Diarrhea | 12 (70.6) | 1 (5.9) |
| Hypertension | 4 (23.5) | 0 |
| Fever | 3 (17.6) | 0 |
| Hoarseness | 3 (17.6) | 0 |
| Decreased appetite | 2 (11.8) | 0 |
| Rash | 2 (11.8) | 0 |
| Fatigue | 2 (11.8) | 1 (5.9) |
| Pneumonitis | 2 (11.8) | 1 (5.9) |
| Nausea | 1 (5.9) | 0 |
| Alopecia areata | 1 (5.9) | 0 |
| Hand–foot skin reaction | 1 (5.9) | 1 (5.9) |
| Diabetes mellitus | 1 (5.9) | 1 (5.9) |
| Thyroid dysfunction | 1 (5.9) | 0 |
| Edema | 1 (5.9) | 1 (5.9) |
| Elevated serum creatine | 1 (5.9) | 0 |
| Hyponatremia | 1 (5.9) | 1 (5.9) |
| Myasthenia gravis | 1 (5.9) | 1 (5.9) |
| Proteinuria | 1 (5.9) | 1 (5.9) |
AE: adverse event.
Table 7.
AEs of each patient.
| Case Number | AEs | Grade | AEs | Grade | AEs | Grade | AEs | Grade |
|---|---|---|---|---|---|---|---|---|
| 1 | Diarrhea | 1 | Hand–foot skin reaction | 3 | Pneumonitis | 3 | - | - |
| 2 | Decreased appetite | 1 | Diarrhea | 3 | Hoarseness | 1 | - | - |
| 3 | Edema | 3 | Hypertension | 1 | - | - | - | - |
| 4 | Diabetes mellitus | 4 | Fever | 1 | Hyponatremia | 3 | - | - |
| 5 | Diarrhea | 2 | Fever | 2 | Hypertension | 2 | - | - |
| 6 | - | - | - | - | - | - | - | - |
| 7 | Fatigue | 1 | Hypertension | 2 | Nausea | 2 | - | - |
| 8 | Diarrhea | 1 | - | - | - | - | - | - |
| 9 | Diarrhea | 1 | - | - | - | - | - | - |
| 10 | Diarrhea | 1 | - | - | - | - | - | - |
| 11 | Diarrhea | 1 | Serum creatine elevation | 2 | Proteinuria | 3 | - | - |
| 12 | Diarrhea | 1 | Fever | 1 | Pneumonitis | 1 | Rash | 2 |
| 13 | Diarrhea | 1 | Fatigue | 3 | - | - | - | - |
| 14 | Diarrhea | 1 | Myasthenia gravis | 3 | Thyroid dysfunction | 2 | - | - |
| 15 | Alopecia areata | 2 | Hoarseness | 1 | Rash | 2 | - | - |
| 16 | Decreased appetite | 2 | Diarrhea | 1 | Hoarseness | 1 | - | - |
| 17 | Diarrhea | 1 | Hypertension | 1 | - | - | - | - |
AE: adverse event.
Table 8.
Reasons for discontinuing treatment.
| Characteristics | |
|---|---|
| Total, n (%) | 17 (100) |
| Patients who discontinued because of disease progression | 8 (47.0) |
| Patients who discontinued because of AEs | 3 (17.6) |
| Patients who experienced AEs attributable to IO therapy before IO+TKI combination therapy | 6 (35.3) |
| Patients who discontinued because of AEs attributable to IO+TKI combination therapy among patients who experienced AEs attributable to pretreatment | 2 (11.8) |
IO+TKI: immuno-oncology plus tyrosine kinase inhibitor; AE: adverse event.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Hamamoto, S.; Tasaki, Y.; Morikawa, T.; Naiki, T.; Etani, T.; Taguchi, K.; Iwatsuki, S.; Unno, R.; Takeda, T.; Nagai, T.; et al. Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma. J. Clin. Med. 2024, 13, 3365. https://doi.org/10.3390/jcm13123365
AMA Style
Hamamoto S, Tasaki Y, Morikawa T, Naiki T, Etani T, Taguchi K, Iwatsuki S, Unno R, Takeda T, Nagai T, et al. Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma. Journal of Clinical Medicine. 2024; 13(12):3365. https://doi.org/10.3390/jcm13123365
Chicago/Turabian StyleHamamoto, Shuzo, Yoshihiko Tasaki, Toshiharu Morikawa, Taku Naiki, Toshiki Etani, Kazumi Taguchi, Shoichiro Iwatsuki, Rei Unno, Tomoki Takeda, Takashi Nagai, and et al. 2024. "Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma" Journal of Clinical Medicine 13, no. 12: 3365. https://doi.org/10.3390/jcm13123365
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
