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Keywords:

  • renal cell carcinoma;
  • targeted therapy;
  • rechallenge;
  • sequential therapy;
  • tyrosine kinase inhibitor;
  • sorafenib

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Study Type – Therapy (case series)

Level of Evidence 4

What's known on the subject? and What does the study add?

Targeted agents with a similar or different target molecule are often used sequentially in the treatment of metastatic RCC. Two tyrosine kinase inhibitors, sorafenib and sunitinib, have been reported to show little cross-resistance, when used sequentially. In addition, a recent report showed that sunitinib rechallenge could potentially benefit selected patients.

This case series shows that patients once refractory to sorafenib could regain disease control on rechallenge with sorafenib during sequential treatment. Outcomes of the sorafenib rechallenge were not significantly affected by the response to the initial sorafenib treatment or by the duration of intervening treatments between first sorafenib and rechallenge.

OBJECTIVE

  • • 
    To investigate clinical outcomes of sorafenib rechallenge during sequential therapy for patients with metastatic renal cell carcinoma (RCC).

PATIENTS AND METHODS

  • • 
    Patients with metastatic RCC who received sorafenib rechallenge after failed treatment first with sorafenib and subsequently with other agents, were retrospectively reviewed for patient characteristics, best response, progression-free survival (PFS), and adverse events (AEs).

RESULTS

  • • 
    Of the 14 patients who received sorafenib rechallenge, 12 were evaluable for response. Eleven patients had previously undergone nephrectomy, and 10 had previously received systemic therapy, mostly interferon-α (nine patients) and interleukin-2 (six patients), with a median duration of 9 months.
  • • 
    The best responses after the first sorafenib therapy were partial response (PR) in two patients, stable disease (SD) in seven, and progressive disease (PD) in two. The median PFS was 5.7 months. Initial sorafenib therapy was discontinued because of PD in eight patients and AEs in four patients.
  • • 
    Rechallenge with sorafenib was undertaken after a 7.6 month median interval from the initial sorafenib challenge. Eight patients achieved SD on sorafenib rechallenge and median PFS was 5.4 (95% confidence interval, 3.8–7.0) months.
  • • 
    The outcome of the sorafenib rechallenge was not significantly affected by the response to the initial sorafenib treatment or by the duration of treatments received between first sorafenib and rechallenge.
  • • 
    No severe AE was newly observed on the rechallenge.

CONCLUSION

  • • 
    In the systemic treatment of advanced RCC, it was suggested that patients once refractory to sorafenib could regain disease control on rechallenge with sorafenib during sequential treatment.

Abbreviations
PFS

progression-free survival

AE

adverse event

PR

partial response

SD

stable disease

PD

progressive disease

VEGF

vascular endothelial growth factor

TKI

tyrosine kinase inhibitor

mTOR

mammalian target of rapamycin

IFN

interferon

RECIST

Response Evaluation Criteria in Solid Tumour

IL

interleukin

MSKCC

Memorial Sloan-Kettering Cancer Center

RECORD

REnal Cell cancer treatment with Oral RAD001 given Daily

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Because cure of advanced RCC is still rare, even with newly developed molecular agents, the current goal for drug treatment for the disease is maximization of total disease control while maintaining the patients' quality of life, by using all available agents in a sequential manner [1–3].

Currently available molecular targeted agents for metastatic RCC are largely divided into two types. Vascular endothelial growth factor (VEGF) pathway inhibitors include anti-VEGF antibody bevacizumab in combination with interferon (IFN)-α, as well as tyrosine kinase inhibitors (TKIs) such as sunitinib [4], sorafenib [5], and pazopanib [6]. Another is mammalian target of rapamycin (mTOR) inhibitor, including temsirolimus [7] and everolimus [8]. Among them, several retrospective analyses consistently reported the limited cross-resistance between two TKIs sorafenib and sunitinib ([9–20], reviewed in [1–3]), broadening the options for the order of the drugs in sequential therapy. Furthermore, going a step further than sequential therapy with different agents of similar mechanisms, Zama et al. [21] recently reported sunitinib rechallenge for patients with metastatic RCC. The tolerability of targeted agents, however, can be affected in some patients who have comorbidities overlapping with characteristic toxicities of the drugs, such as sunitinib in patients with cardiac or renal disorders [22,23] and mTOR inhibitors in patients with diabetes or hyperlipidaemia [7,8,24].

Sorafenib, in general, is a well tolerated drug. In addition to its typical dermatological toxicities including hand-foot skin reactions, diarrhoea and hypertension are the most frequent and clinically important AEs [5,25]. Nonetheless, sorafenib has the advantage in long-term treatment because of its lower incidence of life-threatening toxicities that render patients intolerant to further treatment [26,27]. In an effort to control metastatic RCC with available agents, we observed successful rechallenge with sorafenib in a series of patients. The present study is a retrospective analysis of these patients.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Patients with metastatic RCC who received sorafenib rechallenge after failed treatment with sorafenib and subsequently other agent(s), were retrospectively reviewed for patient characteristics, maximum tumour shrinkage rate, best response according to the Response Evaluation Criteria in Solid Tumours (RECIST) v.1.1 [28], progression-free survival (PFS), and adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. The PFS for a single regimen was calculated from the onset of treatment to disease progression or death, with censoring of patients who discontinued treatment owing to AEs at the start of next treatment. Overall PFS of sorafenib rechallenge was calculated from the onset of initial sorafenib to the end of PFS in sorafenib rechallenge. We used Sigma Plot 11.0 (Systat Software, Inc.) for Kaplan–Meier analysis of PFS and Pearson correlation analysis of tumour size change between initial treatment and rechallenge,

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

PATIENT CHARACTERISTICS

The records of patients with metastatic RCC in our institution were retrospectively screened for the sorafenib rechallenge after discontinuation of previous sorafenib therapy. Of the 14 patients with metastatic RCC who were identified as having received sorafenib rechallenge after discontinuation of previous sorafenib therapy, two were excluded owing to lack of images. The characteristics of the evaluated patients at initial sorafenib treatment are shown in Table 1. Most patients were male, had previously undergone nephrectomy and had clear cell histology. The lungs and lymph nodes were the predominant metastatic sites, followed by liver, bone, brain, pancreas and kidney. At the time of initial sorafenib, 10 patients had previously received systemic therapy, including IFN-α, interleukin (IL)-2 and sunitinib, and two patients were treated with sorafenib as first-line therapy. The Memorial Sloan-Kettering Cancer Center (MSKCC) risk for first line patients [29] (n= 2) was intermediate for one patient and poor for the other, and for second line patients [30] (n= 10) it was favourable, intermediate, poor, and unknown for two, five, two and one patient(s), respectively. The median time from metastasis to the onset of the first sorafenib treatment was 9.1 months.

Table 1.  Characteristics of the 12 patients at initial sorafenib treatment
Characteristics 
  1. *Risk factors associated with shorter survival in first-line therapy were poor performance status, high lactate dehydrogenase, low serum haemoglobin, raised corrected serum calcium and time from initial RCC diagnosis to start of systemic therapy of <1 year. Intermediate, one or two risk factors; poor, three or more risk factors [29]. †Risk factors associated with shorter survival in second-line therapy were poor performance status, low serum haemoglobin and raised corrected serum calcium. Favourable, no risk factors; intermediate, one risk factor; poor, two or more risk factors [30].

Median age, years64
Range46–83
Sex, n 
 Male11
 Female1
ECOG performance status, n 
 06
 13
 22
 31
Previous nephrectomy, n 
 Yes11
 No1
RCC Subtype, n 
 Clear Cell10
 N/A2
Metastatic sites, n 
 Lung10
 Lymph node8
 Liver3
 Bone3
 Brain2
 Pancreas1
 Kidney1
Number of metastatic sites, n 
 13
 24
 ≥35
Previous systemic therapy, n 
 None2
 IFN-α9
 IL-26
 Sunitinib2
MSKCC risk for 1st-line therapy* (N= 2), n
 Intermediate1
 Poor1
MSKCC risk for 2nd-line therapy (N= 10), n
 Favourable2
 Intermediate5
 Poor2
 N/A1
Median time from diagnosis of mRCC
 to sorafenib, months9.1
 Range0.7–55.3

INITIAL SORAFENIB TREATMENT

A summary of sequential treatments from initial sorafenib treatment to sorafenib rechallenge is shown in Table 2. Initial treatment with sorafenib was started at the recommended dose (400 mg twice daily), and the dose was modified as recommended in the package insert. The best response to initial sorafenib was partial response (PR) in two patients, stable disease (SD) in seven patients, and progressive disease (PD) in two patients, using the RECIST. Best response data were not available for patient #9 because of early discontinuation owing to an AE. Therapy was discontinued because of disease progression in eight patients, including two patients with PR, while four patients discontinued treatment owing to AEs. Reasons for AE discontinuation included grade 3 hand-foot skin reactions (n= 3) and hypertension (n= 1). Two patients (#7 and #9 in Table 2) had received sunitinib therapy before initial sorafenib. Patient #7 (male, aged 60) had been treated for metastatic disease in the lung, bone and brain with first-line sunitinib. After 2.5 months of SD, the therapy was discontinued owing to grade 3 fatigue, and the patient was switched to sorafenib treatment. Patient #9 (male, aged 82) had been treated with first-line sunitinib for lung, lymph node and liver metastases. SD continued for 6 months, followed by discontinuation owing to grade 3 heart failure and he was also switched to sorafenib treatment. In both cases, subsequent initial sorafenib was discontinued relatively early (at 2.4 and 1.1 months) owing to AEs. The median PFS for initial sorafenib was 5.7 (95% CI, 5.2–6.3) months (Kaplan–Meier analysis, Fig. 1A). Five patients continued to receive sorafenib despite PD for more than 2 weeks (140, 24, 154, 32 and 21 days for patients #2, #5, #8, #10 and #11, respectively) until another therapy became available.

Table 2.  Outcomes of initial sorafenib treatment, intervening treatments and sorafenib rechallenge
Patient#Initial sorafenibInterval between1st sorafenib andintervening treatment, daysIntervening treatmentsInterval between the last intervening treatment and 2nd sorafenib (day)Sorafenib rechallengeOverallPFS, months
BestresponsePFS, monthsReason for discontinuationTreatmentTotalPFS, monthsReason for discontinuation of the last intervening treatmentBest responsePFS, monthsReason for discontinuation
  1. SD was defined as disease that remained unchanged for at least 56 days. HFSR, hand-foot skin reaction; N/A, not applicable; PS, performance status. *Censored patients. †Not PFS but interval between initial sorafenib and rechallenge for patient #12.

1SD5.4*AE (G3 HFSR)0Sunitinib6.9PDf0SD9.1Continued21.4
VEGFR1 vaccine
2SD15.6PD140Sunitinib7.2PD0PD3.9PD31.3
3PRg4.0PD5Sunitinib8.0PD10SD9.6PD22.1
4PR5.7PD14Sunitinib2.9PD2SD4.3Death13.4
5SD7.2PD26Sunitinib7.5PD1SD5.7Aspiration pneumonia21.3
6SD5.4*AE (G3 HFSR)0VEGFR1 vaccine12.8PD10PD0.9PD19.3
Sunitinib
IFN-α/IL-2
Everolimus
7SD2.4*AE (G3 HFSR)0Everolimus0.7*Consent withdrawal because of AE (G1 melena)0N/Ah1.1*AE (G3 HFSR)4.3+
8PD2.2PD154Everolimus6.1PD5SD5.4Death18.9
9N/A1.1*AE (G3 HT)0Everolimus4.2*AE (G3 pneumonitis)0SD4.0*Continued9.3+
10PD2.6PD32CA9 vaccine13.2PD0PD2.3PD19.2
VEGFR1 vaccine
11SD9.2PD38Thalidomide/IL-227.7PD0SD4.3Death42.5
VEGFR1 vaccine
12SD5.5PD0Alternative therapy32.7PD0SD6.0PS deterioration44.2
image

Figure 1. Kaplan–Meier plots for PFS of initial sorafenib and rechallenge. A, initial sorafenib treatment; B, sorafenib rechallenge; C, overall PFS (from the onset of initial sorafenib treatment to the end of PFS for rechallenge). Vertical marks indicate censored subjects, who were transferred to the next treatments or did not progress at the cut-off. Some marks are inverted downward to improve visibility.

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INTERVENING TREATMENTS

Table 3 shows the patient characteristics at the time of sorafenib rechallenge. Patients received a median (range) of 1 (1–4) regimen(s) between initial treatment and rechallenge with sorafenib. The median (range) interval between initial treatment and rechallenge was 7.6 (0.7–32.7) months. In this cohort, none of the intervening treatments resulted in PR (results not shown). SD was attained in four out of six patients treated with sunitinib, two out of four patients treated with everolimus, and in one patient treated with a thalidomide/IL-2 combination. Patient #12 received alternative therapy as intervening treatment at another medical facility. This did not result in tumour shrinkage during treatment. It was continued because of slow tumour growth, no salient subjective symptom, and the patient's own preference until he complained of severe dyspnoea resulting from progression of lung metastasis, and sorafenib rechallenge was adopted.

Table 3.  Characteristics of the 12 patients at sorafenib rechallenge
Characteristic 
Median (range) time between initial sorafenib and rechallenge, months7.6 (0.7–32.7)
Treatment between initial sorafenib and rechallenge, n 
 Sunitinib6
 Everolimus4
 VEGFR1 vaccine3
 IFN-α/IL-21
 Thalidomide/IL-21
 CA9 vaccine1
 Alternative therapy1
Number of treatment regimens between initial sorafenib and rechallenge, n 
 18
 23
 ≥31

SORAFENIB RECHALLENGE

Sorafenib rechallenge was started with the same dose as that used at the end of the initial treatment. Eight patients attained SD at rechallenge, although no PR was achieved using the RECIST (Table 2). Best response to sorafenib rechallenge was not applicable for patient #7 because of early discontinuation owing to an AE. The best response on rechallenge for three patients was PD, and for all three patients this was attributable to emergence of new metastatic diseases despite controlled targeted lesions (#2, #6 and #10; Table 2). Of the eight patients who discontinued the initial sorafenib treatment because of progression, six (not #2 and #10) achieved SD on rechallenge, indicating that sensitivity to sorafenib was restored for these patients. Two patients, whose best response to initial sorafenib was PD, received rechallenge. While for one patient (#10) the outcome was PD on rechallenge as in initial sorafenib, the other patient (#8) attained SD for 5.4 months. One patient (#7) discontinued rechallenge treatment owing to grade 3 hand-foot skin reactions, as in the initial treatment. No severe AE was newly observed in rechallenge. A summary of best response data with initial sorafenib treatment and rechallenge is shown in Table 4.

Table 4.  Best response with initial sorafenib and rechallenge
Best responseInitial sorafenibRechallenge
PR20
SD78
PD23
Not applicable11

The Kaplan–Meier curve for sorafenib rechallenge is shown in Fig. 1B. The median PFS on rechallenge was 5.4 (95% CI, 3.8–7.0) months, which was close to that of initial sorafenib in Fig. 1A (median, 5.7: 95% CI, 5.2–6.3). The Kaplan–Meier curve for overall PFS, defined as start of initial sorafenib treatment to death or progression at sorafenib rechallenge, is shown in Fig. 1C. The median overall PFS was 21.3 (95%CI, 18.1–24.5) months. PFS on sorafenib rechallenge did not correlate with that of the initial sorafenib treatment (Fig. 2A), nor did it correlate with the duration of the interval between initial treatment and rechallenge (Fig. 2B). A longer PFS with rechallenge compared with that observed with the initial sorafenib treatment was observed for five patients (Fig. 2A, plots above diagonal), three of whom had discontinued initial treatment because of disease progression.

image

Figure 2. Lack of correlation between PFS for sorafenib rechallenge and A, PFS for initial sorafenib, and B, duration of interval between initial sorafenib treatment and rechallenge.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Although the advent of molecular targeted agents has greatly increased treatment options for metastatic RCC, a cure for the disease is still rare; therefore, in many cases, multiple drugs are sequentially used to prolong survival before patients become refractory to all available drugs and eventually are moved to best supportive care [1–3]. By using three to four agents in an appropriate order, one can expect an increase in overall PFS of up to 27 months [2]. It is known that patients that failed one TKI can be successfully treated with another (e.g. sorafenib or sunitinib), although these TKIs largely have the same mechanisms. Zama et al. [21] recently reported on sunitinib rechallenge for patients with metastatic RCC and the phrase ‘resistance reset phenomenon’ was coined and detailed in a review by Hutson et al. [1].

The present report is, to our knowledge, the first study on sorafenib rechallenge, and indicates that suitability to rechallenge is not limited to sunitinib. In our experience of sorafenib rechallenge, eight out of 12 patients experienced SD, although PR was not achieved, and the median PFS was 5.4 months. A high ratio of disease control for a substantial period suggests that this regimen is a reasonable therapeutic option for metastatic RCC.

The present results are different from those for sunitinib [21], firstly, in that PFS with sorafenib rechallenge did not correlate with the duration of interval, while in sunitinib, rechallenge resulted in a longer PFS in patients with >6-months interval, and secondly, in that PFS with initial treatment and rechallenge was similar for sorafenib, while the latter was significantly shorter with sunitinib. It is unclear whether these differences originate from the intrinsic nature of each agent, or from other factors such as patient background or intervening treatments. In addition, tumour shrinkage was observed to some degree in eight patients with initial sorafenib treatment (diagonal bars in Fig. 3A) and the same number of patients showed some degree of tumour shrinkage on rechallenge (black bars in Fig. 3A). There was a trend for correlation of tumour shrinkage between initial sorafenib treatment and rechallenge (Fig. 3B, P= 0.06).

image

Figure 3. Tumour shrinkage with sorafenib on initial treatment and rechallenge. A, Waterfall plot. Maximum change in lesion diameter from start of the treatment with initial sorafenib (diagonal bars) and with rechallenge (black bars) of each patient are indicated. B, Tumour size change in sorafenib rechallenge (%) is plotted against that in initial sorafenib treatment.

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In the present series of patients, initial treatment with sorafenib was discontinued for two reasons. For the four patients who had discontinued initial sorafenib because of AEs, it is not surprising that a switch to the other agent with its different toxicity profile allowed recovery from the AE and enabled subsequent rechallenge. Nevertheless, rechallenge attained disease control even in six out of eight patients who discontinued treatment owing to PD, clearly showing acquired/restored sensitivity to one agent after treatment with other drugs. In addition, it is noteworthy that some patients received more benefit on rechallenge. A longer PFS was obtained on rechallenge in five out of 12 patients, and one of these attained SD on rechallenge despite the fact that the outcome of first sorafenib treatment was PD.

In addition to VEGF-pathway targeted agents, mTOR inhibitors comprise another group of agents for RCC. Everolimus has been shown to prolong PFS of patients treated with sunitinib and/or sorafenib in the REnal Cell cancer treatment with Oral RAD001 given Daily (RECORD)-1 study, and is regarded as one of the standard treatments after TKI failure [8]; however, everolimus may not always be the best option in this setting for safety reasons. Metabolic AEs may limit its use in patients with poorly controlled diabetes mellitus or hyperlipidaemia. In addition, interstitial lung disease, which often necessitates a substantial period of drug interruption, is reported in 14% of patients treated with everolimus [24], indicating the potential risk of treatment lag for the drug. Also from the efficacy point of view, the existing evidence has not proven the superiority of everolimus over TKIs in a TKI failure setting, because the RECORD-1 study only compared everolimus against placebo, and not against other TKIs. Indeed, 26% of patients in the RECORD-1 study had previously undergone treatment with both sunitinib and sorafenib. The hazard ratio for this subset (0.28) was similar for those treated with sunitinib (0.30) or sorafenib (0.29) only [8]. This indicates that efficacy of third line everolimus after treatment with both sunitinib and sorafenib could also be expected. Because a series of retrospective analyses suggest limited cross-resistance between consecutive TKIs [9–20], the use of sorafenib instead of everolimus as a second line treatment after the failure of first line sunitinib should not be excluded. Furthermore, because many of the above analyses have consistently shown a longer total PFS for a sorafenib–sunitinib sequence ([15–19], reviewed in [3]), first line sorafenib can be regarded as a suitable option from the viewpoint of maximizing total PFS in patients with metastatic RCC, although the final conclusion of an ongoing prospective trial comparing sunitinib-sorafenib vs. sorafenib-sunitinib (SWITCH study, NCT00732914 [31]) is still awaited. Sorafenib in first/second line from the above may provide benefit to some patients, and sorafenib rechallenge should therefore be considered, especially in patients with favourable/intermediate risk of MSKCC criteria, whose treatment course could be long.

The population of the current study differs from today's patients, in which most patients had previously received cytokine treatment (IFN in nine patients and IL-2 in six patients); however, because sorafenib resulted in a similar PFS in first line (median 5.7 months) [32] and cytokine-treated (5.5 months) [5] patients, pretreatment with cytokine may not affect the efficacy of sorafenib.

If sorafenib rechallenge is generally efficacious, it provides a further treatment option to the patients who have previously undergone multiple sequential therapies and then had disease progression or who have become intolerant to all available agents. It should be mentioned that, because our observations were retrospective and were based on a small number of patients, accumulation of cases from further reports or investigation by a prospective approach is needed before a final conclusion can be reached; however, sorafenib rechallenge can be considered, especially in a situation where treatment options are limited owing to a delay in regulatory approval or toxicity overlapping with comorbidity.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES