Additional File 3: MCDA Evidence Matrix for lenvatinib in the Italian context
1.1Scoring the performance of Lenvatinib – quantitative MCDA core model
PRODUCT DESCRIPTION / Drug class / intervention category: Protein kinase inhibitors (ATC code: L01XE29) – Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor receptors, in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors 1, 2, 3, and 4, the platelet derived growth factor receptors PDGFRα, KIT, and RET.Indication (EMA, anticipated):For the treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.
Dosage/Administration:Provided as 4-mg and 10-mg hard capsules for oral administration. The recommended daily dose of lenvatinib is 24 mg taken once daily. The daily dose is to be modified as needed according to the dose/toxicity management plan.
Intervention duration:Treatment should continue as long as there is clinical benefit
Comparators: Sorafenib and best supportive care
ECONOMIC BURDEN OF DISEASE* / Economic burden of illness: Total thyroid cancer-related annual healthcare cost per patient with advanced or metastatic differentiated thyroid carcinoma (DTC) in the US: €8,081 (US$10,953, 2014 values).[1] Outpatient costs represented 45%, inpatient costs 39%, and pharmacy costs 12% of this total cost. Of these patients, only 2.3% received targeted thyroid cancer therapy and 6.8% chemotherapy. Among US patients with radioiodine refractory DTC who had received a RTK inhibitor, the total thyroid-cancer-related annual healthcare cost per patient was €71,817 (US$97,344, 2014 values)[2]
*Not considered a criterion that contributes to the value of an intervention but provides useful background information. The overall economic burden of the disease is a composite measure of disease severity, size of affected population and cost of current treatment which are all captured in 3 distinct criteria of the quantitative MCDA core model.
INSTRUCTIONS:- For each criterion, assign a score (or a range of scores to reflect your uncertainty) based on the evidence available. Comments may be provided.
- In case of no data, assign a score or a range of scores reflecting how you usually deal with such situations.
Criteria / Synthesis of available data for product / Score and comments
Domain: DISEASE IMPACT
Disease severity
How severe is the disease targeted by the intervention? /
- Differentiated thyroid cancer (DTC), comprises papillary, follicular and Hürthle cell carcinomas.[3,4]Radioiodine-refractory DTC(RRDTC) is generally defined as disease in which at least one lesion is unable to take up radioiodine (131I) or progresses despite radioiodinetherapy.[5,6]
- Thyroid cancer can occur at any age; peak incidence is 65–69 years.[7] Main risk factors are exposure to ionising radiation, family history and female gender. No specific risk factors for RRDTC have been identified.[8,9]
- Data from placebo arms of two Phase III RCTs of patients with progressive, predominantly metastatic RRDTC indicate 63% overall survival at 18 months from randomisation;[10] median overall survival was 19.1 months from randomisation.[11,12]
- In a retrospective study of patients with papillary or follicular thyroid carcinoma, survival 10 years after detection of metastasis was 10% among patients with lesion(s) unable to take up 131I, and 29% among patients who showed no remission following therapy with 131I.[13]
- Initial symptoms of RRDTCinclude a lump or swelling in the neck, dyspnoea, dysphagia, and hoarseness.[14] Increasing tumour burden with progressive RRDTC can cause severe symptoms due to airway obstruction, including pain, dysphagia, haemoptysis, hoarseness, and dyspnoea leading to asphyxia.[14,15]
- Metastasis most commonly occurs in the lungs; other sites frequently affected are the lymph nodes, bone, head and neck, pleura, and liver.[11] Pain and organ dysfunction can occur with metastasis to distant sites.[15]
- In a retrospective chart review of RRDTC patients receiving systemic treatments, bone pain was the most common symptom (reported by 30.7%).[16] Patients were hospitalised an average of 0.25 times for disease-related reasons in the last 12 months for an average of 7.5 days.[16]
- Time-trade-off mean health utility (range 0=death, to 1=perfect health): stable disease, 0.80; progressive disease, 0.50
- Visual Analog Scale mean score (range 0=death, to 100=perfect health): stable disease, 57; progressive disease, 31
4
3
2
1
0 Not severe
Comments:
Size of affected population
What is the size of the population targeted by the intervention? / DTC account for approximately 95% of all cancers of the thyroid.[4] The proportion of diagnosed DTC cases that become RRDTC is estimated at 2.5% based on data from the Marne-Ardennes Thyroid Registry, France, from 1983 to 2005.[18] Only a proportion of RRTDC patients are candidates for systematic therapy.
- Estimated prevalence of metastatic RRDTC in Italy: 3.8/100,000, based on 5-year prevalence of thyroid cancer (GLOBOCAN[19]) and 6% estimated proportion of metastatic RRDTC (market research data)
- Overall (Italy): 10.8/100,000 (2012)[20]
- Females (Italy): 24/100,000; males (Italy): 8.1/100,000 (2005–2009)[21]
Incidence of thyroid cancer × proportion of thyroid cancers that are DTC × proportion of DTC that become RRDTC
10.8 × 0.95 × 0.0245 = 0.3/100,000 population
See additional data in : Additional data – EPIDEMIOLOGY / X=Prevalence or incidence
5: X > 500/10,000
4: X < 500/10,000
3: X < 100/10,000
2: X <10/10,000
1: X <5/10,000 (rare)
0: X < 2 in 100,000 (ultra rare)
Based on EMA definition
Comments:
Domain: CONTEXT OF INTERVENTION
Expert consensus/clinical practice guidelines
Is the product (or product of the same class) recommended in well-established guidelines? What type of recommendation (first line?, Level 1?) / Excerpt from clinical practice guidelines specific for RRDTC
National Comprehensive Cancer Network (NCCN) 2.2014:[14,22] (all recommendations evidence level 2A):
- No specific recommendations for lenvatinib (not FDA-approved at the time of publication)
- For progressive and/or symptomatic disease, consider sorafenib. Other small molecular kinase inhibitors (not FDA approved) can be considered if clinical trials or other systemic therapies are not available or appropriate.
- Consider resection of distant metastases and/or external beam radiotherapy (EBRT) to metastatic lesions if progressive and/or symptomatic. EBRT may also be considered for asymptomatic bone metastases at weight-bearing sites.
- Watchful waiting may be appropriate in asymptomatic patients with indolent disease. Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease.
- Sorafenib and lenvatinib are the targeted agents demonstrating the most clinical activity for RRDTC (no evidence level; these agents were not approved at the time of publication)
- The principal indication for targeted treatments is radiologically progressive, symptomatic disease, refractory to conventional treatments (evidence level 4, grade D)
- Use targeted therapies outside clinical trials after careful consideration of the balance between potential benefits and harm (evidence level 4, grade D).Targeted therapies should only be administered in cancer units that have experience in monitoring and managing adverse effects (evidence level 4, grade D).
Spanish Society of Medical Oncology (SEOM), 2014: [25]
- Patients with locoregional disease who do not have 131I uptake: external beam radiotherapy (EBRT) (category 2B)
- Patients with locoregional or metastatic thyroid cancer refractory to 131I, who exhibit disease progression by “Response Evaluation Criteria In Solid Tumours” or who become symptomatic: sorafenib (category 1) or lenvatinib (category 1) or clinical trial or best supportive care
French ENT & Head Neck Surgery Society (SociétéFrançaised’Oto-Rhino-Laryngologie et de Chirurgie de la Face et du Cou (SFORL)), 2012: [27] No recommendations regarding lenvatinib or other MKIs.
French National Authority for Health (Haute Autorité de santé), 2010: [28] Chemotherapy can be discussed for the treatment of progressive disease refractory to conventional treatment, optionally in combination with targeted therapies (MKIs or HSP-90 inhibitors; in Phase II trials at the time of publication). / 5 Strong first-line recommendation for drug above all other alternatives
4
3
2
1
0 No recommendation or not recommended
Comments:
Unmet needs
Are there many unmet needs to manage this disease with regard to the outcomes of comparative alternative interventions? / Cytotoxic systematic chemotherapy, such as doxorubicin, has minimal efficacy in patients with metastatic disease.[14] Palliation of isolated skeletal metastases can be achieved with external beam radiation or surgical excision.[14] Bisphosphonates may help prevent skeletal adverse events. Brain metastases may respond to neurosurgical resection or stereotactic radiosurgery.[14]
------
Oral sorafenib is currently the only alternative treatment indicated for patients with progressive RRDTC. Its limitations include:
- Efficacy: In a phase III RCT, 12.2% of patients showed a response to sorafenib therapy and the median duration of response was 10.2 months.[11] PFS was prolonged by a median of 5.0 months compared to placebo (10.8 vs 5.8 months, P<.0001).[11] Effect on overall survival is uncertain: while ITT analyses show no statically significant differences in survival,[11,29] analyses that correct for placebo patients’ cross-over to sorafenib after disease progression (71% of placebo patients) indicate that sorafenib may provide a survival benefit.[30]
- Safety / tolerability: The most important serious adverse reactions of sorafenib therapy are myocardial infarction (≥1%)/ischaemia, gastrointestinal perforation (≥0.1%), drug induced hepatitis (≥0.01%), haemorrhage (≥10%), and hypertension (≥10%)/hypertensive crisis (≥0.1%).[29] The most common (≥10% each) adverse reactions are diarrhoea, fatigue, alopecia, infection hand foot skin reaction and rash.[29]
- Health-related quality of life (HRQL): Sorafenib therapy showed a small but statistically significant negative impact on both generic (EQ-5D) and specific (FACT-G) measures of HRQoL.[30]
- Other: While TSH levels should be suppressed to <0.1 U/mL in patients with metastatic disease,[26]sorafenib therapy may increase TSH to >0.5 U/mL necessitating frequent TSH monitoring and adjustment in levothyroxine dose.[11,29]
5 Many & serious
4
3
2
1
0 No limitations
Scenario 2:Sorafenib available
5 Many & serious
4
3
2
1
0 No limitations
Comments:
Domain: COMPARATIVE OUTCOMES OF INTERVENTION (EXTENT OF BENEFIT)
– see detailed Evidence Table in: Evidence tables
Comparative effectiveness
How does this intervention compare to alternatives with respect to efficacy / effectiveness outcomes? / Efficacy data: one pivotal phase 3 trial: SELECT: Randomized, double-blind, placebo-controlled, multicentre; progressive, locally advanced or metastatic (lung 89%; bone 39%) RRDTC; 96% ECOG 0-1; 61-64 yrs (median); only one previous tyrosine kinase inhibitor allowed.
Additional information: a global study (not started) will be conducted to evaluate the efficacy and safety of a lower (< 24 mg once daily) lenvatinib starting dosage.
Comparators included in evaluation:
- Best supportive care: placebo arm of SELECT trial (thyroid hormone suppression therapy received).
- Sorafenib: no head-to-head trials available; one pivotal phase 3 trialDECISION double-blind placebo controlled; progressive locally advanced or metastatic (lung 86%; bone 27%) RRDTC; 97% ECOG 0-1; 63 yrs (median); no prior targeted therapy allowed; Indirect treatment comparison of lenvatinib versus sorafenib (EISAI, manuscript in preparation)
Lenvatinib
24 mg/day / Placebo / Sorafenib
400 mg bid / Placebo / Lenvatinib/
sorafenib
N / 261 / 131 / 207 / 210 / Risk Ratio (95% CI)
Treatment duration, median / 13.8 mo / 3.9 mo / 10.6 mo / 6.5 mo
Follow-up duration, median / 17.1 mo
(1st dataset) / 17.4 mo / 16.2 mo
Primary (ITT): Progression-free survival
median (range) mo / 18.3*mo
(15.1–NE) / 3.6 mo
(2.2–3.7) / 10.8* / 5.8 / 0.38
(0.24–0.58)
HR (95% CI); P value / 0.21 (0.14–0.31); P.001* / 0.59 (0.45–0.76); P.0001*
Overall survival (ITT), median (95% CI)†
24 mo (lenvatinib 1stdataset) / Non estimable (22.0–NE) / Non estimable
(14.3–NE) / Non estimable / Non estimable / Not available
HR (95% CI); P value / 0.62 (0.40–1.00); P=.05
34 mo (lenvatinib 2nd dataset) / Non estimable*
(30.9–NE) / 19.1
(14.3–NE) / 0.80 (0.54–1.19); P=.14** / 0.66
(0.36–1.19)
HR (95% CI); P value / 0.53 (0.34–0.82); P.0051*
Disease Control Rate
(complete + partial response + stable disease) / 87.7%* / 55.7% / 54.1%* / 33.8% / 0.98
(0.74–1.31)
Odds ratio (95% CI) / 5.05 (2.98–8.54); P.001* / P.0001*
Clinical Benefit Rate (complete + partial response + stable disease ≥23 weeks) / 80.1%* / 31.3% / --
Odds ratio (95% CI) / 7.63 (4.55–12.79); P.001* / Not reported
Objective Response Rate (ORR, complete + partial response) / 64.8%* / 1.5% / 12.2%* / 0.5% / 1.72
(0.15–19.40)
Complete response
Partial response
Stable disease
Progressive disease
ORR duration, median (95%CI) mo
Time to response, median (95% CI) mo / 1.5%
63.2%
23.0%
6.9%
NR (16.8–NR)
2.0 (1.9–3.5) / 0%
1.5%
54.2%
39.7%
--
5.6 (1.8–9.4) / 0
12.2%*
--
--
10.2
-- / 0
0.5%
--
--
--
-- / --
CI: confidence interval; HR: hazard ratio; ITT: intent-to-treat; mo: month; NE: non estimable; NR: not reached; * Statistical significance versus placebo; †adjusted for cross-over, using rank-preserving structural failure time (RPSFT).**Source pour les valeurs des essais cliniques: Sorafenib DECISION trial, Brose et al., Lancet 2014; 384 (9940): 319-328.
Effictiveness data: Not available / Scenario 1:Sorafenib NOT available
5 Much better than placebo
4
3
2
1
0 No difference
-1
-2
-3
-4
-5 Much worse than placebo
Scenario 2:Sorafenib available
5 Much better than sorafenib
4
3
2
1
0 No difference
-1
-2
-3
-4
-5 Much worse than sorafenib
Comments
Comparative safety / tolerability
How does this intervention compare to alternatives with respect to safety outcomes? / safety data – Data from pivotal trials of lenvatinib (SELECT) and sorafenib (DECISION), indirect treatment comparison
SELECT trial[10] (follow-up: 17 months) / DECISION trial[11] (follow-up: 11.6 months)
Lenvatinib
N=261 / Placebo
N=131 / Sorafenib
N=207 / Placebo
N=209
Grade / Any / 3 / Any / 3 / Any / 3 / Any / 3
AEs, % / 97.3 / 75.9 / 59.5 / 9.9 / 98.6 / -- / 87.6 / --
Most common treatment-emergent AEs (occurring in 30% patients), %
Hypertension / 67.8 / 41.8 / 9.2 / 2.3 / 40.6 / 9.7 / 12.4 / 2.4
Diarrhea / 59.4 / 8.0 / 8.4 / 0 / 68.6 / 5.3 / 15.3 / 1.0
Fatigue or asthenia / 59.0 / 9.2 / 27.5 / 2.3 / 49.8 / 5.3 / 25.4 / 1.4
Decreased appetite / 50.2 / 5.4 / 11.5 / 0 / -- / -- / -- / --
Decreased weight / 46.4 / 9.6 / 9.2 / 0 / 46.9 / 5.8 / 13.9 / 1.0
Nausea / 41.0 / 2.3 / 13.7 / 0.8 / 20.8 / 0 / 11.5 / 0
Stomatitis / 35.6 / 4.2 / 3.8 / 0 / -- / -- / -- / --
Palmar–plantar erythrodysesthesia syndrome / 31.8 / 3.4 / 0.8 / 0 / 76.3 / 20.3 / 9.6 / 0
Proteinuria / 31.0 / 10.0 / 1.5 / 0 / -- / -- / -- / --
Alopecia / 11.1 / 0 / 3.8 / 0 / 67.1 / -- / 7.7 / --
Rash/desquamation / 16.1 / 0.4 / 1.5 / 0 / 50.2 / 4.8 / 11.5 / 0
Anorexia / -- / -- / -- / -- / 31.9 / 2.4 / 4.8 / 0
Discontinuation due to AEs, % / 14.2 / 2.3 / 18.8 / 3.8
Any serious AEs, % / 49.8 / 22.9 / 37.2 / 26.3
Treatment-related serious AEs, % / 30.3 / 6.0 / -- / --
Most common serious AEs (occurring in 2% patients), %
Hypertension / 3.4† / 0† / -- / --
Pneumonia / 2.3† / 0† / -- / --
Secondary malignancy / -- / -- / 4.3 / 1.9
Dyspnea / -- / -- / 3.4 / 2.9
Pleural effusion / -- / -- / 2.9 / 1.9
Fatal treatment-related AEs, % / 2.3* / 0 / 0.4 / 0.4
AE: adverse event; CI: confidence interval; *1 case each of pulmonary embolism, haemorrhagic stroke, and general deterioration of physical health; †treatment-related serious AEs
Indirect treatment comparison: risk ratio of lenvatinib/sorafenib for serious AEs 1.52 (95% CI: 0.98–2.36); RR for discontinuation due to AEs: 0.73 (95% CI: 0.24–2.21) (EISAI, manuscript in preparation)
WARNINGS
Lenvatinib: hypertension; proteinurea; renal failure and impairment; cardiac failure; hepatotoxicity; haemorrhage; GI perforation; impairment of TSH suppression.[32]
Sorafenib: hypersensitivity; haemorrhage; hypocalcemia; TSH levels changes; dermatological toxicity; hypertension; cardiac ischemia/infarction; GI perforation; hepatic impairment.[33]
MONITORING
Lenvatinib: regularly monitor blood pressure, urine protein, clinical symptoms or signs of cardiac decompensation, liver function, electrolyte abnormalities, and TSH levels.[32]
Sorafenib: regularly monitor blood pressure, electrocardiograms and electrolytes, liver function, and TSH levels.[33] / Scenario 1:Sorafenib NOT available
5 Much better than placebo
4
3
2
1
0 No difference
-1
-2
-3
-4
-5 Much worse than placebo
Scenario 2:Sorafenib available
5 Much better than sorafenib
4
3
2
1
0 No difference
-1
-2
-3
-4
-5 Much worse than sorafenib
Comments
Comparative patient-perceived health/ patient-reported outcomes
How does this intervention compare to alternatives with respect to patient-perceived health / patient-reported outcomes? / PATIENT-REPORTED OUTCOMES (PRO)/QUALITY OF LIFE (QOL) DATA
Lenvatinib– SELECT trial: PRO/QoL data not collected.
Sorafenib – DECISION trial: small but statistically significant deterioration of health-related quality of life versus placebo[30]
- EQ-5D index and VAS scores: 0.69 vs 0.76 placebo and 67.62 vs 73.71 placebo, respectively; P.0001 mixed linear model analysis
- FACT-G scores functional well-being and total scores: treatment effect for FACT-G total score is -3.45 (95% CI: -5.41,-1.49), P.0006 (mixed linear model analysis).
- Deterioration (decrease) due to AEs and disease progression
- Modest improvement (increase) upon response to treatment
Base state – Stable/no response / 0.87 / 0.84 / 0.91
Response to therapy / +0.04 / 0.01 / 0.07
Progressive disease / -0.35 / -0.41 / -0.29
Diarrhoea / -0.47 / -0.523 / -0.41
Fatigue / -0.08 / -0.12 / 0.04
Hand and foot syndrome / -0.34 / -0.40 / 0.28
Alopecia / -0.05 / -0.08 / 0.01
CONVENIENCE
Lenvatinib (and its comparator sorafenib) is administered orally once daily. / Scenario 1:Sorafenib NOT available
5 Much better than placebo
4
3
2
1
0 No difference
-1
-2
-3
-4
-5 Much worse than placebo
Scenario 2:Sorafenib available
5 Much better than sorafenib
4
3
2
1
0 No difference
-1
-2
-3
-4
-5 Much worse than sorafenib
Comments
Domain: TYPE OF HEALTH BENEFIT OF INTERVENTION
Type of preventive benefit
What type of preventative health gain or reduction of risk of disease is provided by the intervention? / Lenvatinib does not prevent or modify the risk of developing RRDTC. / 5 Eradication / major risk reduction
4
3
2
1
0 No reduction in risk of disease
Comments
Type of therapeutic benefit
What type of health gain is provided by the intervention? / Lenvatinib does not cure RRDTC. It delays disease progression and there is data to support a prolongation of survival. / 5 Cure / life saving
4
3
2
1
0 No impact on existing condition
Comments
Domain: ECONOMIC CONSEQUENCES OF INTERVENTION
Comparative cost consequences – cost of intervention
What is the direct cost impact of the intervention (including acquisition and administration costs? /
- Intervention price, frequency and/or duration of administration and cost of administration (based on manufacturer’s budget impact model) — Note: The lenvatinib prices shown represent a potential estimated price range.
Price per available dosing form / 4-mg or 10-mg capsule: €53.99–67.49 / 200-mg capsule: €31.86 / NA
Recommended daily dose (SmPC) / 24 mg/day / 800 mg/day / NA
Actual daily dose † / 16.6 mg/day / 689 mg/day / NA
Average daily drug cost per patient (based on actual dose) / €113 – €141 / €110 / €3
Average monthly drug cost per patient / €3,428 – €4,285 / €3,341 / €96
Administration cost per month‡ / €387 / €387 / €860
Average total monthly cost per patient / €3,815 – €4,672 / €3,728 / €956
Average duration of treatment § / 18.3 months / 10.8 months / 12 months
Average total cost per treatment course / €69,815 – €85,498 / €40,262 / €11,472
NA: not applicable
Assumptions and sources:
* All patients assumed to be treated with doxorubicin.
†Lenvatinib: Patients assumed to receive recommended dose (24 mg/d) for 2.76 months and then reduce dose to mean last dose in phase III (SELECT) trial (15.3 mg/d); sorafenib: Patients assumed to receive recommended dose (800 mg/d) for 2.76 months and then reduce dose to mean dose in phase III (DECISION trial) (651 mg/d)[11]
‡Lenvatinib and sorafenib: includes required monthly laboratory tests;[34]chemotherapy: includes IV administration costs[34]
§Lenvatinib and sorafenib: based on progression-free survival (PFS) duration in phase III studies (SELECT and DECISION);[10,11]chemotherapy: assumption
- Annual projected impact of reimbursing lenvatinibon Italian drug spending for RRDTC (includes drug and administration costs, based onmanufacturer’s epidemiological budget impact model)
Number of patients treated with lenvatinib / Average annual total* cost per patient treated with lenvatinib† / Total* annual cost of lenvatinib / Incremental (net) impact of lenvatinib on total* RRDTC drug spending