Abstract
Context:
Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem.
Objective:
The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure.
Design:
This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013.
Patients:
The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). Patients who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS).
Outcome Measures:
Progression-free survival, best response, and median OS were measured.
Results:
Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3).
Conclusions:
Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.
Differentiated thyroid cancer (DTC) is the most common endocrine cancer. Most patients with DTC are cured with standard primary treatments, including surgery, radioactive iodine (RAI), and thyroid-stimulating hormone suppression. However, once DTC metastasizes to distant sites and is no longer responsive to RAI therapy or surgery, expected survival declines rapidly (1–3). Despite effective standard treatments, 1850 patients are expected to die of thyroid cancer in 2013 (4); therefore, patients who develop RAI-refractory, rapidly progressive, and/or symptomatic disease require an effective treatment approach. Until November 2013, the only treatment approved by the US Food and Drug Administration for these patients was doxorubicin, but owing to low and short-lived response rates, this treatment is now considered a poor option. Sorafenib in now the first efficacious therapy approved for advanced DTC.
The availability of tyrosine kinase inhibitors (TKIs) represents the first significant progress in treating patients with advanced DTC. A number of biological agents are being tested and have shown positive initial results (5). Sorafenib is an oral multikinase inhibitor whose targets includes vascular endothelial growth factor receptor, RET, BRAF, and c-KIT, and it is frequently the first-line treatment of choice for DTC. Several phase II studies (6–10) of sorafenib in DTC have shown promising results, which led to the development of a phase III placebo-controlled study (11). In this study, the investigators found a progression-free survival (PFS) advantage in the sorafenib group (11.8 months, compared with 5.8 months in the placebo group). This represents the first major breakthrough in treating metastatic DTC since the development of RAI.
However, most patients eventually stop responding to sorafenib, and many patients must discontinue use of the drug because of its toxicity. Other systemic therapies are also used in clinical practice to treat DTC, either off label or as part of a clinical trial, and many have similar targets to sorafenib. It is unclear whether the similarities of drug targets in DTC would lead to complete cross-resistance or whether sequential application would be efficacious. In renal cell carcinoma, the sequential administration of sunitinib after first-line sorafenib failure has shown efficacy (12–16). In DTC, according to a few cases, clinical cross-resistance of TKIs may not be complete, and objective responses were observed when sunitinib or cabozantinib was used as second agent after sorafenib failure (17–19). Although similar, systemic therapies have additional unique targets such as c-KIT, c-MET, or BRAF or different potencies, which may overcome the resistance to sorafenib. In the present study, we sought to determine the efficacy of salvage therapy in patients with advanced DTC for whom first-line treatment with sorafenib failed.
Patients and Methods
Study population
After receiving institutional review board approval, we retrospectively collected data on adult patients with metastatic DTC who received first-line treatment with sorafenib between January 2005 and May 2013 at The University of Texas M. D. Anderson Cancer Center. Patient data collected included age, sex, histological findings, disease stage at diagnosis, cumulative I-131 activity, site of distant metastases, information about treatment with sorafenib (time from diagnosis to start of treatment, duration of treatment, dosage, reason for discontinuation, or changes to dosage), information about any salvage treatments received, tumor response, and follow-up time or date of death.
For overall survival (OS) analysis, patients were assigned to one of two groups: patients in group 1 received first-line treatment with sorafenib only, and patients in group 2 received salvage treatment with another kinase inhibitor after initial treatment with sorafenib. Group 1 was included for OS analysis only. All patients were included for OS analysis of the entire cohort. For comparison between the two groups, we excluded from this analysis patients who died within 3 months of starting treatment with sorafenib because these patients were unable to receive salvage therapy (possibly skewing toward worse outcomes in group 1). We also excluded patients who developed a pathologically confirmed, unrelated malignancy during treatment with sorafenib, but we did not exclude patients with malignancies that occurred as an adverse event related to their treatment (such as squamous cell skin carcinomas).
For PFS and best response analysis, we focused on the subset of patients who received salvage therapy after their initial treatment with sorafenib and who had a baseline and at least one follow-up imaging study during treatment with sorafenib and during salvage therapy. This group included patients treated with sorafenib outside a clinical trial. The drugs used as salvage therapy were administered either outside a clinical trial (sunitinib, pazopanib, and vemurafenib) or as part of a clinical trial (cabozantinib and lenvatinib). Patients receiving cabozantinib and lenvatinib were participating in phase I (NCT01100619) and phase II (NCT 00784303) clinical trials, respectively. We obtained approval from the sponsors of the studies to use these data.
Study objectives
The primary end points in our analysis were PFS duration and best response with first-line sorafenib and salvage therapy. The secondary end point was OS duration in patients who received subsequent salvage therapy after sorafenib failure and in patients who received first-line treatment with sorafenib only.
Assessments and definitions
Radiographic assessments were performed by a single radiologist (C.D.) using computed tomography or magnetic resonance imaging. Tumor response was categorized using Response Evaluation Criteria in Solid Tumors version 1.1 (20, 21), and responses were defined as follows: progressive disease (PD): 20% or greater increase in total target lesions size or new metastatic lesion; stable disease (SD): any change in lesions size between a 19% increase and a 29% decrease; partial response (PR): 30% or greater decrease in target lesions size. Sorafenib failure was defined as disease progression or unacceptable toxicity leading to drug discontinuation. PFS was defined as the time from sorafenib or salvage therapy start until Response Evaluation Criteria in Solid Tumors progression determined from objective tumor measurements, clinical progression as determined by the treating physician, or death, whichever occurred first. Duration of treatment was defined as the time from the start of treatment until disease progression or unacceptable toxicity leading to drug discontinuation. OS was calculated from the date on which the treatment with sorafenib was started to the date of death. Patients who had not died at the time of analysis were censored at the time they were last known to be alive.
Statistical analysis
Descriptive statistics were used to summarize patient characteristics by group. Comparisons were made between groups to identify any significant imbalances in patient characteristics. An independent-samples t test was used to compare continuous variables and a χ2 test was used to compare categorical variables. OS and PFS were illustrated using Kaplan-Meier plots. A log-rank test was used to compare survival distributions between groups. The best responses for individual patients, calculated using the percentage change in target lesion size compared with baseline (see above), were plotted graphically using a waterfall plot. Values were considered statistically significant at P < .05. Statistical analyses were performed using Stata version 12 software (StataCorp)and R version 3.0.2.
Results
Study population
Figure 1 depicts a flow chart of the patients who were included in our study. We identified 64 patients with metastatic DTC who received first-line treatment with sorafenib between January 2005 and May 2013. All patients were included for OS analysis of the entire cohort.
Figure 1.
Patient population flow chart.
Group 1 included 35 patients who received sorafenib only (no treatment followed after sorafenib failure or are still receiving sorafenib), and group 2 included 25 patients who received salvage therapy after sorafenib failure. Four patients (all in group 1) were excluded, one owing to early death within 3 months after starting treatment with sorafenib and three owing to other unrelated malignancies. One patient was diagnosed with diffuse large B cell lymphoma with leptomeningeal disease while on sorafenib for 77 weeks; the drug was discontinued for this reason and the patient died 27 weeks later. One patient had an intraductal papillary mucinous neoplasm (based on radiographic characteristics) prior to the sorafenib start, which was later diagnosed as pancreatic adenocarcinoma. This patient was on treatment with sorafenib for 71 weeks. Malignant transformation was noted on positron emission tomography/computed tomography 1 year after sorafenib discontinuation. One patient had history of metastatic colon cancer and non-small cell lung carcinoma prior to sorafenib initiation.
For best response and PFS analyses, eight patients in group 2 were excluded owing to missing radiographic assessments, leaving 17 evaluable patients for these analyses. Two patients experienced toxicity with sorafenib that led to drug discontinuation before restaging; therefore, the response rate and PFS with sorafenib was reported for 15 patients.
Overall survival analysis
Patient characteristics
The clinical characteristics of all 64 patients who received first-line treatment with sorafenib are summarized in Table 1 along with a comparison between groups. For all patients, the mean age at diagnosis was 54 years and 53% were male. Histological findings showed that 37 patients (58%) had papillary, 13 (20%) had follicular, and 14 (23%) had poorly differentiated carcinoma (papillary-poorly differentiated, follicular-insular, or poorly differentiated-not otherwise specified), and most patients had stage III or IV disease at diagnosis. All patients had RAI-refractory disease. At the time that treatment with sorafenib was started, 62 patients (97%) had distant metastases in the lung and 22 patients (34%) had distant metastases in the bone. Data regarding sorafenib discontinuation were available in 44 patients: 37 (85%) discontinued sorafenib owing to progression and seven (16%) owing to toxicity. Information concerning sorafenib dose reduction and drug interruption was available in 57 patients: drug interruption was needed in 35 patients (61%) and dose reduction was needed in 30 patients (53%).
Table 1.
Patient Characteristics for the Whole Group (n = 64) and Comparison Between Group 1 (n = 35) and Group 2 (n = 25).
| Characteristic | n, % |
|||
|---|---|---|---|---|
| All Patients (n = 64) | Group 1 (n = 35) | Group 2 (n = 25) | P Value | |
| Age at diagnosis, mean ± SD | 53.9 ± 9.2 | 54.9 ± 10.0 | 53.3 ± 8.6 | .519a |
| Sex | ||||
| Female | 30 (47) | 17 (49) | 12 (48) | .965b |
| Male | 34 (53) | 18 (51) | 13 (52) | |
| Histology | ||||
| Papillary-conventional | 25 (39) | 15 (43) | 7 (28) | .07c |
| Papillary-follicular | 11 (17) | 7 (20) | 4 (16) | |
| Papillary-tall | 1 (2) | 1 (3) | 0 (0) | |
| Papillary-poorly differentiated | 4 (6) | 4 (11) | 0 (0) | |
| Follicular | 5 (8) | 2 (6) | 3 (12) | |
| Follicular-Hurthle | 8 (13) | 1 (3) | 6 (24) | |
| Follicular-insular | 6 (9) | 2 (6) | 4 (16) | |
| Poorly differentiated-NOS | 4 (6) | 3 (9) | 1 (4) | |
| Stage at diagnosis | ||||
| I | 7 (11) | 6 (17) | 1 (4) | .646c |
| II | 4 (6) | 2 (6) | 2 (8) | |
| III | 18 (28) | 8 (23) | 9 (36) | |
| IVA | 13 (20) | 7 (20) | 4 (16) | |
| IVC | 19 (30) | 11 (31) | 8 (32) | |
| Unknown | 3 (5) | 1 (3) | 1 (4) | |
| Cumulative I131 activity, mean ± SD | 362 ± 230 | 333 ± 223 | 397 ± 239 | .337a |
| Site of distant metastases at start of treatment with sorafenib | ||||
| Lung | 62 (97) | 33 (94) | 25 (100) | .506c |
| Bone | 22 (34) | 11 (31) | 10 (40) | .420b |
| Time from diagnosis to start of treatment with sorafenib, y, mean ± SD | 5.1 ± 4.4 | 6.0 ± 4.4 | 4.6 ± 3.3 | .192a |
| Starting daily dose of sorafenib | ||||
| 200 mg | 1 (2) | 1 (3) | 0 (0) | .817c |
| 400 mg | 17 (27) | 8 (23) | 7 (28) | |
| 800 mg | 43 (67) | 24 (69) | 17 (68) | |
| Unknown | 3 (5) | 2 (6) | 1 (4) | |
| Reason for sorafenib discontinuationd | ||||
| Progression | 37/44 (84) | 12/17 (71) | 23/24 (96) | .066c |
| Toxicity | 7/44 (16) | 5/17 (29) | 1/24 (4) | |
| Sorafenib interruptione | 35/57 (61) | 18/31 (58) | 15/22 (68) | .454b |
| Sorafenib dose reductione | 30/57 (53) | 17/31 (55) | 12/22 (55) | .984b |
| Time to sorafenib failure, mo, median (95% CI) | 11 (5.4–16.5) | 10 (5.3–14.6) | 14 (5.8–22.1) | .372f |
Abbreviation: NOS, not otherwise specified. Percentages may not equal to 100% due to rounding error.
P value based on an independent-samples t test.
P value based on a χ2 test.
P value based on a Fisher's exact test.
Evaluable in 44 patients.
Evaluable in 57 patients.
P value based on a log-rank test.
No statistical differences were observed between the two groups, but group 1 (sorafenib only) contained more patients with papillary thyroid cancer (64%) and group 2 (salvage therapy) contained more patients with follicular thyroid cancer (52%). In group 1, 11 patients were still receiving sorafenib at the time of this analysis. In group 2, nine patients were still receiving second-line treatment and six patients had received more than two lines of treatment. Salvage treatments included sunitinib (n = 10), pazopanib (n = 4), cabozantinib (n = 4), lenvatinib (n = 4), and vemurafenib (n = 3). Patients receiving cabozantinib and lenvatinib were part of a clinical trial.
Overall survival
The median OS of all 64 patients treated with first-line sorafenib was 36.6 months [95% confidence interval (CI) 30.4-NA] (Figure 2A). The median OS in group 2 (the salvage therapy group) was 58.4 months (95% CI 33.4–NA [not reached]), which was significantly longer than the median OS in group 1 (the sorafenib-only group) (28.8; 95% CI 16.1–NA); P = .013; Figure 2B). Median OS did not differ on the basis of sex, histological findings, stage at diagnosis, discontinuation owing to toxicity or progression, dose reduction, or drug interruptions. Nineteen patients in group 1 (54%) and 15 patients in group 2 (60%) were still alive at the time of this analysis. The median follow-up time was 36.6 months (95% CI 30.4–NA) in all patients, 26.2 months (95% CI 22.7–42.4) in group 1, and 46.6 months (95% CI 35.7–66.4) in group 2.
Figure 2.
A, Median OS from the start of treatment with sorafenib for all 64 patients was 36.6 months. B, Median OS from start of sorafenib in group 1 (sorafenib alone) compared with group 2 (sorafenib followed by salvage therapy) was 58.4 vs 28.8 months (P = .013).
When all patients were included in group 1 (n = 39), the median OS was 24.2 months (95% CI 17.8–NA). The OS in this group remains significantly shorter when compared with group 2 [58.4 months (95% CI 34.0-NA); P = .007].
To evaluate the effect of salvage therapy on survival, a second OS analysis was performed using sorafenib end as the start date for OS analysis. To date, 42 patients failed first-line sorafenib, of which 17 were in group 1 and 25 in group 2. Using this definition, the median OS was still significantly longer with salvage treatment compared with sorafenib alone (4.25 vs 42 months, P < .001).
Efficacy analysis of salvage therapy
Patient characteristics
The baseline characteristics of the subgroup of patients included in this analysis are shown in Table 2. The mean age at diagnosis was 52 years, and 53% of patients were male. Histological findings showed that nine patients had papillary (six conventional and three follicular) and seven patients had follicular thyroid cancer (four Hurthle cell carcinoma, two insular type, and one poorly differentiated cancer). T3 and T4 tumors were present in 16 patients (94%), and seven (41%) had metastatic disease at the time of diagnosis. Seven of 17 evaluable patients receiving salvage therapy were still on treatment with a second agent at the time of this analysis. Ten patients discontinued the drug due to progression. To date, there were no discontinuations due to toxicity during treatment with salvage therapy, although most patients needed dose adjustment to manage side effects.
Table 2.
Baseline Characteristics of the Subgroup of Patients Included in the Best Response and PFS Analysis (n = 17)
| Characteristic | n, % |
|---|---|
| Age at diagnosis, y, mean ± SD | 52.5 ± 8.8 |
| Sex | |
| Female | 8 (47) |
| Male | 9 (53) |
| Histology | |
| Papillary, all variants | 9 (53) |
| Follicular, all variants | 7 (41) |
| Poorly differentiated | 1 (6) |
| TNM stage at diagnosis | |
| T3, T4 | 16 (94) |
| M1 | 7 (41) |
| Site of distant metastases | |
| Lung | 17 (100) |
| Bone | 6 (35) |
| Reason for sorafenib discontinuation | |
| Progressive disease | 15 (88) |
| Toxicity | 2 (12) |
| Salvage therapy | |
| Sunitinib | 4 |
| Cabozantinib | 4 |
| Pazopanib | 3 |
| Lenvatinib | 3 |
| Vemurafenib | 3 |
Abbreviation: TNM, tumor node metastasis. Percentages may not equal to 100% due to rounding error.
Best response and PFS
Two patients experienced toxicity with sorafenib that led to drug discontinuation before restaging (mucositis and hand foot syndrome). In the remaining 15 patients, best responses with first-line sorafenib were PR in two (13%), SD in 10 (67%), and PD in three (20%) patients (Figure 3A). In all 17 patients, best responses with salvage therapy were PR in seven (41%) and SD in 10 (59%) patients (Figure 3B). No PD was observed with salvage therapy as the best response. All three patients who had PD during treatment with sorafenib achieved PR with the second drug (>55% tumor size reduction). Two patients discontinued sorafenib owing to toxicity in less than 1 month but tolerated and responded to second-line treatment with sunitinib. One of these patients achieved SD with tumor regression (15% reduction) for 16 months. The second patient achieved PR (61% reduction) and is still receiving sunitinib after 30 months. Tumor responses in individual patients are shown in Figure 4.
Figure 3.
Best response with sorafenib (A) and with salvage therapy (B) in 17 patients whose first-line treatment with sorafenib failed. In panel A, two patients were excluded owing to sorafenib toxicity. Note that patients are not shown in the same order in panels A and B.
Figure 4.
Best responses in individual patients whose first-line treatment with sorafenib failed (n = 17).
The median PFS was 7.4 months (95% CI 3.1–11.3) with first-line sorafenib and 11.3 months (95% CI 5.3–24.4) with salvage therapy.
Discussion
Our results suggest that other molecular targeted agents can be effective as salvage therapies after sorafenib failure in patients with metastatic DTC.
Salvage therapy after sorafenib failure is used in clinical practice because responses are not durable and nearly 20% of patients do not tolerate sorafenib (11). Several trials of TKIs for the treatment of DTC have included patients who received prior treatment with other TKIs, but information regarding the efficacy of such an approach is limited. The results of a small phase I study of cabozantinib showed that patients with thyroid cancer in whom treatment with first-line TKIs failed, continued to respond to cabozantinib. Of 14 evaluable patients, eight received sorafenib prior to cabozantinib, and five of these patients achieved PR with cabozantinib (17). In the phase II sunitinib trial, two patients were treated with sorafenib and had the drug discontinued due to toxicity. After starting sunitinib, one patient had 29% reduction of tumor and was on therapy for 12 months (18).
Our study is the first to examine the efficacy of salvage therapy in patients with metastatic, RAI-refractory DTC whose first-line treatment with sorafenib failed. Inevitably, all patients treated with sorafenib develop disease progression or toxicity leading to discontinuation, and it is not clear whether salvage therapy is advantageous. The results of our study suggest that salvage treatment with drugs that have similar mechanisms of action to those of sorafenib can be beneficial. We have shown that patients continued to respond to second-line treatment after first-line sorafenib failure. PR occurred in 41% and SD in 59% of the patients receiving salvage therapy. PFS with a second-line TKI therapy was 11.4 months. This is similar to the PFS durations and response rates reported in phase II trials with various TKIs, such as sunitinib, pazopanib, vandetanib, cabozantinib, and lenvatinib (17, 18, 22–24). Three patients in our study who had PD as the best response to sorafenib achieved impressive responses (more than 55% tumor reduction) with a second-line TKI (two cabozantinib and one lenvatinib). The rest of the patients continued to have prolonged SD or PR with the second-line treatment despite PD with sorafenib. Furthermore, two patients developed severe toxicity with sorafenib, leading to drug discontinuation early in the treatment but responded to and tolerated another TKI (sunitinib) with a similar toxicity profile.
Because patients responded to the salvage therapy, disease progression or toxicity with sorafenib should not exclude use of another TKI. To address this issue in a prospective fashion, a phase II trial of cabozantinib in patients with DTC that progressed during treatment with first-line treatment with antiangiogenic TKIs is currently underway (clinicaltrials.gov, NCT identifier 1811212). Whether the differences in response between first-line and salvage therapy are caused by inhibition of different vascular endothelial growth factor receptors, inhibition of other targets such as RET, c-KIT, c-MET, or BRAF, or different potencies of each compound (IC50 concentrations) (Supplemental Table 1) needs to be determined.
In our study, the efficacy and tolerability with sorafenib are similar to those reported in the phase III trial (11). The best response to first-line treatment with sorafenib was 13% PR and 67% SD, PFS was 7.4 months, and discontinuation rate owing to toxicity was 15%. PFS presented in our study is slightly shorter than previously reported, possibly due to inclusion of more aggressive histologies, namely poorly differentiated thyroid cancer and more patients with metastasis to bone. Results of the phase III placebo-controlled trial with TKI-naive patients with DTC demonstrated a statistically significant PFS advantage in the sorafenib arm (10.8 months compared with 5.8 months in the placebo arm). The PR rate was 12.2% with sorafenib compared with 0.5% with placebo, and no complete responses were observed. SD of 6 or more months was present in 42% of patients receiving sorafenib. The discontinuation rate owing to toxicity was 19%.
To date, data reporting median OS duration in treatment-naive patients with DTC receiving first-line treatment with sorafenib are limited. Our study, which included a relatively large number of patients, is the first to report a median OS of 37 months in patients with TKI naive DTC treated with first-line sorafenib. In the phase III clinical trial, the median OS has not been reached in either arm (11). Two phase II studies that included a smaller number of patients and a different patient population reached a median OS. Schneider et al (9) reported an estimated median OS of 34.5 months in 31 patients with DTC receiving sorafenib, but these patients were not all TKI-naive. For a subgroup of 33 patients with papillary thyroid cancer treated with first-line sorafenib, Kloos et al (6) reported a median OS of 23 months.
Another important finding of our study is the longer survival we observed in patients who were able to receive salvage therapy. Our study is the first to show that patients who are able to receive salvage therapy may survive longer than those treated with sorafenib followed by no salvage treatment. The median OS was 58 months for those who received salvage therapy compared with 28 months in those treated with sorafenib alone. The two groups were similar in terms of baseline characteristics, including age, sex, stage at diagnosis, site of distant metastases, time from diagnosis to the start of treatment with sorafenib, and duration of treatment with sorafenib. More patients had papillary thyroid cancer in the group receiving sorafenib alone and more patients had follicular thyroid cancer in the group receiving salvage therapy, although these differences were not statistically significant. Because of this, the two groups are not directly comparable on the basis of histological findings, although one would expect a worse outcome in the group with more follicular thyroid cancer. The difference in OS between the two groups may also be explained by differences in performance status; the group of patients who did not receive salvage therapy after sorafenib may have been much sicker. Because of the retrospective nature of the study, we were unable to assess the performance status of our patients. To the best of our knowledge, patients did not receive second-line therapy for several reasons: 1) limited knowledge regarding the efficacy of salvage therapy during the first years in which targeted therapies were in use, therefore preventing the treating physician from offering this as an option; 2) unavailability of other therapies; 3) patient refusal; and 4) palliative treatment offered instead owing to poor performance status. Furthermore, several patients were still receiving sorafenib at the time of this analysis and likely will be offered salvage therapy in the event of disease progression.
This study contains several limitations resulting from its retrospective design, including missing information regarding patient performance status, lack of a clear reason for not receiving salvage therapy, and lack of conclusive evidence that all patients had progressive disease before the start of treatment with sorafenib. Because advanced thyroid cancer is rare and TKIs are a fairly new treatment approach, the subgroup of patients in our study population who received salvage therapy was small, and they received a variety of different drugs. Therefore, a comparison between different drugs used as salvage therapy was not feasible.
In summary, sorafenib failure did not predict response to salvage treatment with other drugs despite similar mechanisms of action. Although the groups in our study are not directly comparable, our findings indicate that patients who are able to receive salvage therapy after sorafenib failure benefit from this approach, and the current standard should be to offer targeted therapy as a salvage treatment to these patients. Future directions of study include elucidating the mechanism of resistance with targeted therapies, determining the best order of targeted therapy use, and analysis of combination and additive therapies.
Acknowledgments
This work was supported by the National Institutes of Health/National Cancer Institute under Award P30CA016672.
Disclosure Summary: R.D., C.D., M.H., S.G.W., M.I.H., C.J., M.A.H., R.V.S., A.K.Y., and G.J.C. have nothing to disclose. N.L.B. has received research funding from Bayer/Onyx. S.I.S. is a consultant to Bayer, Eisai, and Exelixis. M.E.C. has received research funding from Roche, Eisai, and Exelixis and has served on the advisory boards for Eisai and Exelixis.
For editorial see page 1995
- CI
- confidence interval
- DTC
- differentiated thyroid cancer
- OS
- overall survival
- PD
- progressive disease
- PFS
- progression-free survival
- PR
- partial response
- RAI
- radioactive iodine
- SD
- stable disease
- TKI
- tyrosine kinase inhibitor.
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