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Indication: For the treatment of pediatric patients aged 2 years and above, with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas
CADTH recommends that Koselugo be reimbursed by public drug plans for the treatment of pediatric patients aged 2 years and above, with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PNs), if certain conditions are met.
Koselugo should only be covered to treat patients who are aged between 2 and 18 years with a diagnosis of NF1 with PNs that are causing symptoms and cannot be completely removed by surgery.
Koselugo should only be reimbursed if prescribed by specialists with experience in managing NF1 and PNs, and the cost of Koselugo is reduced. To continue treatment with Koselugo longer than 18 months, the treating physician must provide proof that the patient is responding to treatment, including but not limited to reductions in symptoms of pain, improved motor function, and/or stabilization of disease, or proof of shrinking of tumours.
NF1 is a rare, progressive, genetic disease that affects multiple systems of the body, and results in noncancerous tumours that grow in and under the skin, as well as other complications. In up to 50% of patients with NF1, larger noncancerous tumours called PNs grow along the nerves anywhere in the body, causing pain, discomfort, and limiting mobility. NF1 affects 1 out of every 2,500 to 3,000 infants; however, the number of people with PNs due to NF1 that cannot be removed by surgery in Canada is unknown.
Prior to the approval of Koselugo, there were no drug treatments available for patients with PNs that cannot be removed by surgery. There is a need for new treatments options that reduce tumour sizes and improve quality of life (QoL).
Treatment with Koselugo is expected to cost approximately $268,678 per patient per year.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that selumetinib be reimbursed for the treatment of pediatric patients aged 2 years and above, with NF1 who have symptomatic, inoperable PNs only if the conditions listed in Table 1 are met.
Evidence from a phase II, single-arm study (SPRINT phase II) that included 50 pediatric patients with NF1 with inoperable PNs reported that after a median treatment duration of 4.3 years, 68.0% of patients (95% confidence interval [CI], ████ ██ ████) achieved an objective response rate (ORR) that was determined by a reduction from baseline in PN volumes of 20% or more. In addition, treatment with selumetinib resulted in an improvement in patient-reported pain (Numerical Rating Scale 11 [NRS-11] = █████ points [95% CI, █████ ██ █████]; Pain Interference Index [PII] = █████ points [95% CI, █████ ██ █████]), motor function (mobility = ████ points [95% CI, █████ ██ ████], upper extremity = ████ points [95% CI, █████ ██ ████]) as well as improvements in strength and range of motion (ROM). However, the magnitude of clinical benefit is uncertain due to the lack of minimal important difference (MID), or the change did not exceed the estimated clinically meaningful threshold of 2 points for the NRS-11 or 0.75 points or more for the patient-reported PII.
Patients identified a need for treatments that reduce pain and tumour size, improve physical function, and improve overall HRQoL. CDEC concluded that selumetinib addresses some of these important unmet needs as nearly all patients (95.8%) experienced a reduction in target PN volume during the SPRINT phase II trial, with 77.1% experiencing a maximum reduction of 20% or more. CDEC recognized that there is significant unmet need for patients with NF1-associated symptomatic, inoperable PNs for which no other effective treatments are currently available. CDEC concluded that selumetinib might address an unmet need for patients diagnosed with NF1-associated symptomatic, inoperable PNs.
The committee considered analyses conducted by CADTH that evaluated the cost-effectiveness of selumetinib with best supportive care (BSC) relative to BSC. CADTH could not address uncertainties associated with the lack of comparative treatment effects and limitations with the model’s structural assumptions that led to selumetinib substantially delaying disease progression compared to BSC. CDEC concluded that, based on the sponsor’s submitted price for selumetinib and publicly listed prices for all other drug costs, the most likely estimated incremental cost-effectiveness ratio (ICER) is $426,286 per quality-adjusted life-year based on the CADTH reanalysis that assumed a smaller residual benefit. In all reanalyses, a price reduction would be required for selumetinib to achieve an ICER of $50,000 per quality-adjusted life-year.
Reimbursement Conditions and Reasons.
NF1 is an autosomal dominant genetic disorder associated with progressive cutaneous, neurologic, skeletal, and neoplastic manifestations. Approximately half of all NF1 cases are familial, while half arise from spontaneous mutations in the NF1 gene. Currently, the incidence of NF1 in Canada is unknown, though it is estimated to occur in 1 in 2,500 to 3,000 births. The patient group input received by CADTH for this review highlighted that there are currently over 12,000 cases of NF1 in Canada. The most common manifestations of NF1 include abnormally coloured patches of skin (café-au-lait macules [CALMs]), freckling under the arms and in the inguinal region, and benign tumours predominantly in the skin and nerves, known as neurofibromas. Other manifestations may include bone dysplasia, scoliosis, ocular problems, and neurologic complications with impacts such as cognitive impairments and learning disabilities. Neurofibromas are histologically benign nerve sheath tumours, typically originating in the terminal nerve branches of the skin. PNs are the most common type of tumour in patients with NF1, occurring in up to 50% of patients. One or multiple PNs may grow along large nerves and plexuses anywhere in the body, with varying manifestations that continue to develop to early adulthood, and multiple PNs may be both symptomatic and asymptomatic in the same individual. Additionally, PNs have a complex shape and can reach large sizes, resulting in clinical symptoms such as disfigurement, motor dysfunction (weakness and restricted ROM), pain, and neurologic dysfunction. The severity of symptoms from PNs may range from mild to severe; however, the presence of symptoms may depend on their location and impact on surrounding structures. PNs grow most rapidly during the early childhood, though growth rate is highly variable between patients.
Treatment and clinical management options for NF1-associated PNs are extremely limited and are dependent on symptomatology. For symptomatic patients, treatments aim to relieve symptoms caused by the individual PNs. Currently, the only available options to treat and manage NF1-associated PNs include pain management and surgical excision to remove as much of the tumours as possible. However, for many patients, surgery is not a viable option as most PNs are not amenable to complete resection due to encasement of, or proximity to, vital structures.
Selumetinib has been approved by Health Canada for the treatment of pediatric patients aged 2 years and older with NF1 who have symptomatic, inoperable PNs. Selumetinib is a selective inhibitor of mitogen-activated protein kinase (MEK) 1 and 2. It is available as 10 mg or 25 mg oral capsules and the dosage recommended in the product monograph is 25 mg/m2 twice daily based on body surface area.
To make its recommendation, the committee considered the following information:
CADTH received input from 2 patient groups: the TFBC and CORD. The TFBC provides essential information and support services to patients with neurofibromatosis and their families. CORD works with governments, researchers, clinicians, and industry to promote research, diagnosis, treatment, and services for all rare disorders in Canada.
Both patient groups conducted online surveys in November 2022, recruiting patients with NF1 and their caregivers. Additionally, the TFBC conducted a Zoom focus group. The TFBC group recruited 25 patients and caregivers, and CORD recruited 8 caregivers. Key themes identified by patients and caregivers with NF1 included limitations on daily living, functional, and social activities; moderate to severe chronic pain; dependency on caregivers into adulthood; financial stress because of the diagnosis; and lack of treatment options, which negatively impacts the emotional well-being of patients and families.
Respondents from both patient and caregiver groups described difficulties in obtaining a diagnosis of NF1, as well as significant impacts on both affected children and their families in terms of managing the physical and mental aspects of the disease. Additionally, substantial negative mental health impacts were reported, with most patients living with anxiety and fear over their diagnosis, and some patients experiencing suicidal feelings or actions. Respondents to both surveys and interviews emphasized surprise and disappointment in the lack of treatment options or support available, with 46% of respondents not having been offered any kind of treatment, and only 17% of those who were offered treatment indicating that they experienced minimal improvement in symptoms.
No patients in the TFBC survey had experience with selumetinib. Half (n = 4) of the CORD respondents had experience with selumetinib through clinical trials and described it as “miracle drug” that was “life-changing” because of substantial improvements in pain levels; functional abilities, including speaking clearly and chewing food; and softening and shrinking tumours that were previously disabling and/or disfiguring.
Numerous outcomes were identified as important to patients, reflecting the heterogenous nature of the disease, but common themes included an overall improved QoL, a desire for reduction in pain and reduction or prevention in tumour size or growth, improved function and emotional well-being, greater independence from caregivers, and a reduced number of health care visits.
The information in this section is based on input received from a panel of 6 clinical specialists consulted by CADTH for the purpose of this review.
The clinical experts indicated that the main limitations and unmet needs of pediatric patients with NF1 with symptomatic PNs is the lack of access to disease-modifying medical interventions that can reduce the burden of disease or stabilize symptomatic PNs. The clinical experts noted that there are currently no established practice guidelines for this heterogenous disease. For patients with symptomatic PNs, surgery is the only available treatment option, which is either aimed at excising tumours, if possible, or debulking, if complete excision is not achievable. The experts noted that surgery is not curative for most large or extensive PNs and is associated with significant risks of secondary injuries based on the number, location, size, and vascularity of the tumours, particularly for PNs involving large arteries or nerves. Additionally, the experts cited that multiple invasive surgeries may be required, as tumours may regrow, or increase in size, thereby further increasing the risks to patients. Aside from surgery, current treatment strategies consist of “watch and wait” for patients with PNs that are not currently symptomatic. Otherwise, treatment for patients with symptomatic PNs focus on relieving pain, reducing functional impairment, and improving overall QoL. The panel highlighted the availability of MEK inhibitors through managed access programs, noting that selumetinib is the first, and only, Health Canada–authorized MEK inhibitor available outside of clinical trials for the treatment of PNs. The panel concluded that selumetinib is expected to cause a shift in the current treatment paradigm given the absence of other medications available for this population. The experts stated that should selumetinib be recommended for reimbursement, it would likely be the initial therapy of choice.
The clinical experts noted that only a minority of patients with NF1 have symptomatic PNs. Patients with NF1 are diagnosed based on standard, well-established, and recently updated clinical diagnostic criteria that include clinical characteristics such as CALMs and presence of neurofibromas. Although the recently updated diagnostic criteria include genetic testing, the experts noted that genetic testing is not required for diagnosis of NF1. The experts highlighted that results of genetic testing do not impact treatment decisions once a clinical diagnosis of NF1 has been established. The clinical diagnosis of NF1 is relatively straightforward in older children, adolescents, and adults, but can be challenging in younger children due to the absence of clinical characteristics such as CALMs or PNs. However, the updated diagnostic criteria, which includes genetic testing in patients without a family history, has improved confirmatory diagnosis in young children before they manifest other clinical features of NF1. The diagnosis of large, extensive, or rapidly growing PNs generally require more clinical expertise, and may require more complex tumour characterization, including MRI and sometimes biopsy if there is concern for malignant transformation.
The experts also highlighted that in terms of natural history, there is a trend for tumours to appear and grow rapidly in early childhood (before ages 6 to 8 years), and then slow down or remain static in adulthood. Rapid growth of a PN is a concern for transformation to a malignant peripheral nerve sheath tumour. The experts also discussed the uncertainty regarding treatment decisions for patients who are asymptomatic, which have not been established. In addition, there is no evidence available related to whether treatment with MEK inhibitors such as selumetinib prevent growth of new PNs.
The experts emphasized the heterogeneity of the disease in patients with NF1, with cutaneous neurofibromas and PNs often occurring throughout the body and ranging in severity from asymptomatic to severely debilitating due to pain, functional impairment, or disfigurement. One clinical expert highlighted that disfigurement due to large, visible PNs is a source of anxiety and concern due to public fear and social stigmatization. The panellist also highlighted the potential for ongoing problems into adulthood due to large PNs, which may result in severe disfigurement and displacement of joints and bones; however, it was also emphasized that there is no clear evidence that treating asymptomatic PNs with selumetinib in children will prevent the development of symptoms in adults. Other concerns raised by the experts for the NF1 population include deficient social skills, frequent learning disabilities, autism, and attention-deficit/hyperactivity disorder (ADHD), further highlighting the challenges these patients face.
Treatment with selumetinib offers the only available medical treatment for patients with NF1 whose extensive inoperable PNs are causing significant pain, functional impairment, and/or disfigurement. Although it is difficult to determine which patients are most likely to respond to treatment, 1 clinical expert currently treating pediatric patients via compassionate access to selumetinib stated that about 80% of patients will respond to treatment. The experts noted that most patients with NF1 with PNs are asymptomatic, and the benefit of treatment for these patients has not yet been established. Clinical trials are currently being conducted for selumetinib in the adult population, which will provide insight into similarities or differences in effectiveness by age. The experts agreed that there is a concern regarding the lack of knowledge about both the potential benefits and harms associated with long-term selumetinib treatment, given that NF1 is a lifelong disease. The experts also noted that the life expectancy of patients with NF1 has been reported to be reduced by 10 to 15 years, although estimates of life expectancy with currently available medical management are unknown.
The clinical experts noted that current clinical trials aim to address important outcomes; however, given the heterogeneity of the disease, standardizing subjective measures (such as pain perception) across this population is an issue, which means that interpreting the results relies heavily on clinical judgment. The clinical experts agreed that the most important outcomes in the management of pediatric patients with NF1 and symptomatic, inoperable PNs is the reduction or improvement in symptoms (i.e., reduced pain, improved function), as well as overall improvements in QoL and disease stabilization. The experts noted that volumetric MRI, though used in the clinical trial to define disease progression, is only used by the National Institute of Health (NIH) for research studies and is not available in Canadian clinical practice. The experts considered a change in planar tumour size of 20% to 25% to be indicative of response to treatment. One expert discussed the potential for symptomatic disease progression despite no evidence of progression on imaging studies and for improvement in symptoms without reduction of tumour size on imaging studies. In addition, the panellists emphasized that it is not always clear which tumours are the cause of symptoms when patients have large numbers of PNs, thereby making it difficult to know when the disease is progressing. The experts also highlighted that tumours are frequently irregular in shape, making measurements about changes in size difficult. As a result, the panel noted that response to treatment is multidimensional and must consider reductions in tumour sizes, changes in symptoms, and improvements in function and disfigurement.
The experts stated that young children with NF1 and symptomatic PNs may initially be followed with an MRI every 3 months, in addition to annual follow-ups with NF1 specialists to assess other features of the disease. Upon initiating treatment, the experts stated that patients would be seen weekly for a month, then monthly, and if treatment is well tolerated, or disease stabilizes, then follow-ups would be prolonged to every 6 months. The experts also noted that imaging in young children often requires a general anesthetic. The experts noted that no firm treatment duration for selumetinib has been determined but suggested that similar to the SPRINT phase II trial, in clinical practice patients would continue treatment until disease progression or toxicity. The experts considered that the initial treatment authorization for selumetinib should be 18 months. The clinical experts agreed that selumetinib would be discontinued in patients whose disease is not responding (i.e., tumour growth, lack of stabilization, or lack of improvement of symptoms), or in patients with severe adverse events (AEs) that are unable to be managed. The experts also noted that the need for surgery to further debulk tumours might be indicative that the treatment is not working and should therefore be discontinued. One clinical expert, however, highlighted that selumetinib may be used in conjunction with debulking surgery, though there is currently no evidence for this.
The experts indicated that expertise in using selumetinib is sparse and limited to pediatric oncologists and neurooncologists in tertiary care hospitals in Canada. Currently, only pediatric oncologists are prescribing treatment with selumetinib, as they have the experience and know-how to manage these patients. However, the experts highlighted that with further insight and growing experience, NF1 experts who are pediatricians could continue and manage this oral treatment. Given the heterogeneity in the disease and the individualized approach to treatment, decisions often involve a multidisciplinary team of pediatricians, NF1 experts, neurooncologists, and nurse practitioners. The experts also emphasized the importance of consulting with other specialists, including surgeons, cardiologists, ophthalmologists, dermatologists, and pharmacists, for the management of selumetinib, adverse effects, and drug interactions. The expert panel also highlighted that for patients in remote areas, access to specialty clinics may be a limiting factor, emphasizing that patients would be required to attend in-person appointments for treatment initiation and imaging follow-up as well as to assess safety.
Input for this review was received through shared clinical experiences from 1 clinician group: the CPBTC, which included 27 pediatric neurooncologists across Canada.
Overall, the clinician group input was aligned with that given by the clinical expert panel convened by CADTH, highlighting that no systemic therapies exist for treating NF1-associated PNs, which represents the major unmet need in this patient population, with surgical resection, if feasible, as the only option currently available for patients. The clinician group emphasized that selumetinib has clearly shifted the current treatment paradigm and emerged as the standard of care as first-line therapy for patients with inoperable, symptomatic PNs, with those most in need of intervention including those for whom PNs are invading critical structures, causing a deformity, or causing functional impairment in activities of daily living such as walking, swallowing, or eating. The clinician group also noted that in Canada, treatment initiation with selumetinib is currently limited to neurooncologists, pediatric oncologists, or pediatric neurologists with an expertise in neurooncology. The CPBTC suggested that treatment with selumetinib in Canada could be initiated by oncologists and followed remotely in conjunction with local clinicians.
Finally, the CPBTC noted that many parents of children with NF1 also have NF1 themselves and are likely to have lower socioeconomic standing, in part because of the disease. It was therefore the CPBTC’s opinion that many patients and parents of patients are more likely to lack private insurance to cover selumetinib, which could result in unequitable access in some parts of the country. The CPBTC emphasized that children without private insurance who are also not eligible for the provincial public drug plans will need special consideration and that the drug in question urgently requires reimbursement and equitable access as a standard of care treatment for patients with NF1 and symptomatic PNs.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for selumetinib:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
SPRINT phase II is a phase II, open-label, single-arm, multicenter study that aimed to evaluate the efficacy of 25 mg/m2 selumetinib twice daily in 50 pediatric patients with NF1 and inoperable PNs. The primary outcome of the SPRINT phase II study was ORR determined by change in PN volumes through volumetric MRI. Secondary outcomes included PROs and functional evaluations to determine the effect of selumetinib on pain, motor function, and HRQoL. Two DCOs were submitted for the SPRINT phase II trial. The primary DCO occurred on June 29, 2018, and an updated DCO on March 31, 2021, providing a maximum follow-up of 5.6 years.
At baseline, patients included in the SPRINT phase II trial were mostly white (42; 84.0%) males (30; 60.0%) with a mean age of 10.3 years (standard deviation [SD] = 3.92 years). The median number of target PNs causing morbidity was 3 (range = 1 to 4), and the mean target PN volume was 837.11 mL (SD = 925.011), ranging from 5.6 mL to 3,820.0 mL. Pain was present in the target PNs in 26 (52.0%) patients. The most common location of target PNs was the neck and trunk, and the trunk and extremity (12 each; 24.0%), and ██ ███████ patients had had at least 1 prior PN-related or NF1-related surgical procedure.
Evaluation of pain was a secondary end point of the SPRINT phase II trial. Pain intensity was measured by the NRS-11, a self-evaluation of pain in patients 8 years or older consisting of 4 questions scored on a scale 0 (no pain) to 10 (worst pain you can imagine). A threshold of 2 points was suggestive of clinically meaningful change, per the literature. The interference of pain on daily functioning was measured by the PII, a 6-item scale that assesses the extent to which pain has interfered with daily activities in the past 7 days (0, meaning not at all, to 6, meaning completely). Higher scores for both scales indicate greater impact of pain on patients.
At the June 29, 2018, DCO, the mean adjusted change from baseline score for target tumour pain intensity measured by the NRS-11 was reduced at precycle 13 by −2.07 points (95% CI, −2.84 to −1.31). At the March 31, 2021, DCO, representing a longer follow-up period, the NRS-11 target tumour pain was reduced at precycle 13 with an adjusted mean change from baseline of █████ points (95% CI, █████ ██ █████).
For the PII, the self-reported adjusted mean change from baseline score at precycle 13 was reduced by −0.65 points (95% CI, −0.89 to −0.42), and the adjusted mean change from baseline in parent-reported PII score at precycle 13 was reduced by −0.82 points (95% CI, −1.17 to −0.47) at the June 29, 2018, DCO. At the March 31, 2021, DCO, the results were consistent with the primary analysis, with a reduction in the adjusted mean change from baseline at precycle 13 of █████ (95% CI, █████ ██ █████) for the self-report total score, and █████ (95% CI, █████ ██ █████) for the parent-reported score.
Motor function was evaluated in patients with motor morbidity using the strength of muscle groups and ROM tests, as well as the Patient-Reported Outcomes Measurement Information System (PROMIS) mobility and upper extremity domains. The PROMIS was completed by both the patient and the parent. Higher scores indicate better physical functioning.
The baseline score for the self-reported and parent-report assessments in the mobility domains of PROMIS were 46.57 (SD = █████) and 37.43 (SD = █████), respectively, while the baseline scores for the self-reported and parent-report assessments in the upper extremity domain were 45.95 (SD = ██████) and 38.15 (SD = ██████), respectively, with higher scores indicating better physical functioning. At the March 31, 2021, DCO, self-reported mobility and self-reported upper extremity improved with an adjusted mean change from baseline at precycle 13 by ████ points (95% CI, █████ ██ ████) and ████ points (95% CI, █████ ██ ████), respectively. In the parent-reported assessments, the adjusted mean change from baseline at precycle 13 improved in the mobility and upper extremity domains by ████ points (95% CI, ████ ██ ████) and ████ points (95% CI, █████ ██ ████), respectively.
Strength using the manual muscle test (Medical Research Council 5-point Likert scale) was assessed in the 33 patients who had motor morbidity in any body quadrant at enrolment. At the March 31, 2021, DCO, ██ patients had evaluable strength assessments at baseline and precycle 13, with a mean strength score of ████ (SD = █████) at baseline, and an adjusted mean change from baseline increased by ████ points (95% CI, ████ ██ ████). For ROM, the mean ROM sum of all joints was ██████ degrees (SD = ███████), and the adjusted mean change from baseline at precycle 13 was an increase of █████ degrees (95% CI, █████ ██ ██████).
HRQoL was a secondary end point of the SPRINT phase II study and was measured using the Pediatric Quality of Life Inventory (PedsQL) tool, which assesses function in 4 domains: physical (8 items), emotional (5 items), social (5 items), and school (5 items) on a 5-point Likert scale (0 = never a problem; 4 = almost always a problem), with scores revere-transformed to a 0 to 100 scale, so that higher scores indicated better HRQoL. No MID threshold was identified in the literature. The observed mean score at baseline was 73.91 (SD = ██████) in the self-reported version and 60.79 (SD = ██████) in the parent-reported version. At the March 31, 2021, DCO, the adjusted mean change from baseline in the self-reported version of the PedsQL was ████ points (95% CI, ████ ██ █████) and █████ points (95% CI, ████ ██ █████) in the parent-reported version, suggesting improvements in HRQoL.
ORR was the primary end point of the SPRINT phase II study. At the June 29, 2018, DCO, 33 patients (66.0%; 95% CI, 51.2 to 78.8) achieved ORR per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. The ORR achieved in the sensitivity analysis based on independent central review (ICR) was █████. Differences in ORR between the primary central analysis and the ICR analysis were primarily due to differences in categorization of confirmed partial response (PR) versus stable disease (based on the chosen threshold of 20% shrinkage to determine response), where █ patients were considered to have confirmed PR despite reductions in tumour size being slightly below the threshold of 20%. At the later, March 31, 2021, DCO, the ORR was 68.0% (95% CI, ████ ██ ████). At both DCOs, ORR was based on confirmed PRs.
An exploratory ICR analysis using modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria that used a 30% volume reduction for PR as opposed to 20% with REiNS was also conducted at the June 29, 2018, DCO. Based on RECIST 1.1 assessment, the ORR was only ████, with █ ██████ patients having an unconfirmed PR, and ██ ███████ patients having stable disease.
Change in target PN volume was also assessed as part of the volumetric MRI and application of the REiNS criteria. At the March 31, 2021, DCO, the mean percent change from baseline in target PN volume at precycle 13 was ███████ (SD = ██████), corresponding to a mean absolute change of ███████ mL (███████). The proportion of patients with a maximum reduction from baseline of at least 20% was identical to the June 29, 2018, DCO, at 77.1%, and █ ███████ had a maximum reduction from baseline of 40% or more.
Nearly all patients in the SPRINT phase II trial experienced a treatment-emergent adverse event (TEAE) (49; 98.0%). The most frequent TEAEs reported at the March 31, 2021m, DCO were vomiting ███████████, increased blood creatine phosphokinase ███████████, diarrhea ██████████, nausea ██████████, and dry skin ██████████. Grade 3 or higher TEAEs were reported in ██ ███████ patients, with the most frequent consisting of ████████ ██ █████████ ███████ ██ ████████ ███ ███████ ██ ███████. Overall, ██ ███████ patients had at least 1 TEAE leading to dose interruption.
At the March 31, 2021, DCO, ██ ███████ patients experienced serious AEs, the most frequently occurring being ██████████ ███ ████████████ ██ █████████ ███ ████████████████ █████████ ██ ███████ █████████████ █████████ █████ ███ ██████████
A total of █ ███████ patients discontinued selumetinib due to AEs; █ of which were grade 3 ██████ ██████ ███████ █████████ ██████ ███████████ ███ ██████ ██████████ and █ were grade 4 ██████ ██████████ █████████ ███ ████ ███████ ████ ███ ███████ experiencing a grade 3 and grade 4 AE leading to withdrawal.
No AEs with a fatal outcome were reported in the SPRINT phase II study; however, after the March 31, 2021, DCO, █ patients died due to progressive neurofibrosarcoma after selumetinib treatment was terminated. These deaths were not attributed to treatment with selumetinib.
The most frequent notable harm associated with selumetinib was ██████████, occurring in ██ ███████ patients. The majority of cases were grade 1, █ were grade 2, and █ ███ grade 3. One patient had discontinued treatment due to grade 3 paronychia at the earlier (June 2018) DCO. Other notable harms included ███████ ██████ ███ ████████ ███ ██████████████ ██████ ███ ████████.
SPRINT phase II was a phase II, open-label, single-arm, multicenter study. The choice to conduct a single-arm study also has implications on the overall strength and interpretability of the results. In a single-arm study, there is an increased risk of bias in the estimation of treatment effects due to the potential for confounding related to natural history, and other unidentified prognostic factors that could affect all study outcomes. The noncomparative design of the SPRINT phase II trial precludes the ability to assess the therapeutic benefit or safety of selumetinib. Because all patients received the same treatment in this single-arm study, the treatment effect on time-to-event end points are uninterpretable and were only considered as exploratory and supportive. Awareness of treatment assignment by both patients and parents and/or caregivers increases the risk of detection bias and performance bias and may lead to systematic overestimation or underestimation of the overall treatment effect. As such, the open-label trial design limits interpretability of the clinical outcome assessments such as the PRO and functional end points, as well as AEs. The already small sample size (N = 50) was further restricted for secondary end points, including PROs and functional evaluations, as these were based on patients with target PNs in specific locations or limited to patients of a certain age. The outcome of the SPRINT phase II study was ORR, which was considered appropriate by the clinical experts consulted by CADTH and the CADTH review team as an objective measure to assess the activity of selumetinib. Secondary clinical outcome assessments (PROs and functional evaluations) were considered appropriate to evaluate the wide range of PN-related morbidities; however, based on the design of the SPRINT phase II study, and the lack of statistical tests or imputation of missing data, the results should only be viewed as supportive of the overall effect of selumetinib.
There is a lack of standardized end points for trials in NF1. As previously noted, multiple outcomes were included in the SPRINT phase II trial, including response and time-to-event outcomes based on volumetric MRI using the REiNS imaging criteria. The clinical experts consulted by CADTH highlighted that volumetric MRI is not used in routine clinical practice as it is not standard of care in Canada, and that evidence of disease progression is multifactorial, based on standard imaging techniques, though they emphasized the importance of clinical symptomatology and physical assessment in determining progression and response. As such, patients in Canadian clinical practice would be evaluated for progression slightly differently than in the SPRINT phase II trial, potentially impacting the generalizability of the results. PROs (i.e., NRS-11, PII, PROMIS, PedsQL) and functional outcomes (i.e., strength, ROM) were also evaluated in the SPRINT phase II trial. The clinical experts consulted by CADTH noted that the outcome scales reported in the trial were not used in routine clinical practice and may not be generalizable to the typical patient in Canada. They also noted that a gestalt-type approach is considered in clinical practice for overall improvement or deterioration in symptomatology overall, as opposed to specific changes in certain domains (e.g., grooved pegboard test, key pinch grip), though variation and heterogeneity by the patient and/or caregivers is significant in this population.
There are no appropriate comparators to conduct a standard ITC and a placebo-controlled trial design was considered unethical by National Cancer Institute (NCI) Pediatric Oncology Branch (POB) investigators due to significant PN-related morbidity and promising results shown in the phase I trial. Indirect comparisons were therefore necessary to estimate the relative benefit of selumetinib. The NCI POB has conducted 2 additional studies, a natural history (NH) study to develop a better understanding and quantification of NF1 manifestations, and to allow more sensitive end points to be developed for clinical studies, and Study 01-C-0222, which is a phase II, randomized, crossover, double-blinded, placebo-controlled study of tipifarnib in children and young adults with NF1 and progressive PN. Given the lack of direct comparative evidence for selumetinib, the sponsor conducted naive qualitative comparisons of the results from the SPRINT phase II study with the NH study and the placebo arm of Study 01-C-0222 to serve as external control arms. The sponsor also conducted a propensity score modelling analysis of PFS compared to the NH study.
The sponsor conducted a naive, side-by-side comparison of results from SPRINT phase II, stratum 1, versus patients with PNs from the NH study using the outcomes of tumour growth (absolute and annual rates) based on the full NH cohort as well as an age-matched NH cohort. The age-matched NH cohort included patients who were aged 3 to 18 years and had at least 1 volumetric MRI within this age and at least 1 subsequent volumetric MRI. A naive, side-by-side qualitative comparison was also conducted for the outcome of PFS between SPRINT phase II, stratum 1, and the placebo arm of Study 01-C-0222.
In the propensity scoring analysis, PFS from SPRINT phase II, stratum 1, was compared to the age-matched cohort of the NH study. Prognostic factors were identified based on data from the NH study. The univariate Cox model and multivariate Cox model (covariates: study, sex, race, target PN location, PN status, age, weight, height, and target PN volume) were fitted to estimate an unadjusted and adjusted hazard ratio, respectively. Age, weight, height, and target PN volume were kept as continuous variables in the model. Three different matching algorithms were explored (matching 1:1 without replacement, inverse probability of treatment weighting [IPTW], and matching 1:2 with replacement).
Data on the natural history of NF1-related PNs, based on the patients from the selected external controls, demonstrated that the majority of PNs grow continuously over time or, at best, remain stable in size (i.e., < 20% increase in volume from baseline). In contrast to the median annual volume change of ██████ or █████ seen in the SPRINT study (2018 and 2021 DCO, respectively), the median annual volume change in the NH study (age-matched cohort with maximum follow-up aligned to each DCO of the SPRINT study) was ██████ and ██████, respectively.
Over the full duration of the studies, the mean percentage change from baseline in the SPRINT trial was ██████ compared to ███████ in the NH study. The follow-up duration and included patients differ notably in these populations.
Patients who enrolled in the NH study and later went on to participate in SPRINT phase II, stratum 1 (n = █), experienced PN growth before selumetinib (median = ███ per year; maximum = ███ per year), and a median volume reduction of ██ per year after selumetinib treatment (median follow-up = ███ years; range, ███ ██ ███ years). Of these patients, █ had a reduction of at least 20% in their target PN and the response was sustained for █ patients at the latest DCO.
At the time of the March 31, 2021, DCO, disease progression was experienced by █████ of patients in the NH study compared to █████ of patients in SPRINT phase II, stratum 1, over a ███-year period. Median PFS in the NH age-matched cohort was ███ years (95% CI, 1.1 to 1.6) and was ███ ███████ in SPRINT phase II, stratum 1. The probability of remaining without progression in SPRINT phase II, stratum 1, and the NH study was █████ (95% CI, █████ ██ █████) and █████ (95% CI, █████ ██ █████), respectively.
Because Study 01-C-0222 required progressive disease for enrolment, a subgroup analysis was conducted for the earlier DCO (i.e., 2018) of SPRINT phase II, stratum 1, including only those with progressive PNs at enrolment. In this subgroup, the probability of remaining without progression at 2 years was 94.7% (95% CI, 80.6% to 98.7%), compared to 20.6% (95% CI, 7.7% to 37.8%) in the placebo arm of Study 01-C-0222. The sponsor did not update this comparison for the later DCO (i.e., 2021).
The univariate Cox analysis identified age, weight, height, and PN status at baseline (i.e., progressive, nonprogressive, or unknown) were associated with PFS; younger patients with progressive PNs at baseline had a higher risk of progression. The multivariate analysis identified only PN status as correlated with PFS.
After matching, the sample sizes were small, and some standardized differences remained unbalanced (> 0.1 to > 0.2) in the 1:1 and 1:2 matching analyses. In the IPTW analysis, no baseline characteristics differed by a standardized difference of more than 0.1. However, the effective sample size after IPTW was not reported. Across all 3 methods of propensity scoring analysis, the hazard ratios for PFS ranged from █████████ in favour of selumetinib with P values of less than 0.001.
Safety outcomes were not assessed in the ITCs.
Because it was deemed unethical to conduct placebo-controlled trials in this population by the NCI POB investigators, only unanchored ITCs were possible. There are substantial limitations inherent to unanchored naive comparisons as there is no method of control for inherent differences in the study design and patient populations, so differences seen in clinical outcomes may be confounded by underlying differences in the compared trials.
In the naive comparison, results were only reported for mean annual change in target PN volume, absolute and percent change in target PN volume from baseline, and PFS. In the propensity scoring analysis, only PFS was assessed. Patient and clinician input suggests that tumour volume or change in volume does not always directly correlate with symptomatology, in part because it is highly dependent on the location of the PNs with respect to important structures. Outcomes related to symptoms, morbidity, disability, HRQoL, and disfigurement were not assessed. No safety outcomes were evaluated.
There were notable differences between the patient populations of the 2 external controls in comparison to the SPRINT trial with regards to baseline age, race, target PN location, PN status (i.e., progressive, nonprogressive, or unknown), target PN volume, and treatment history. Additionally, the study designs differed with respect to follow-up and frequency of imaging. The risk of bias and imprecision is inherently high as a result of small study sizes, observed clinical heterogeneity, and the unanchored and naive approach to the comparison, but the direction of potential bias as a result of these differences is unknown. The sample size of the before-after analysis (████) of patients who participated in both the NH study and the SPRINT trial was especially small, limiting the interpretation of results.
Propensity scoring analysis was conducted using 3 standard methods. Although propensity scoring analysis is an appropriate approach to mitigate the impact of between-trial differences in baseline patient characteristics, it is unknown whether all key treatment effect modifiers and prognostic factors were accounted for. The methodology for selecting baseline characteristics was not explained or justified. Of the 3 methods of propensity score analysis, only IPTW demonstrated balance in every baseline characteristic examined, while in the 1:1 and 1:2 matching analyses, some standardized differences were still greater than 0.1 or greater than 0.2 in important characteristics. The sample size of all analyses were small as a result of the studies informing the comparisons, but the 1:1 and 1:2 matching analyses also resulted in further drops in sample size. The effective sample size of IPTW was not reported, limiting interpretation.
Overall, interpretation of the ITCs is substantially compromised by important limitations. From the naive comparisons and the propensity scoring analyses, the results suggest selumetinib confers a benefit in terms of reduction in the rate of tumour growth and improvement in PFS. However, the magnitude of benefit is uncertain, and there can be no conclusions from the ITCs regarding other clinically important outcomes or harms.
No long-term extension studies or other relevant studies were included in the sponsor’s submission to CADTH.
Patient group, clinician group, clinical expert, and drug program input gathered during this CADTH review, as well as relevant published literature, were reviewed to identify ethical considerations relevant to the use of selumetinib for the treatment of pediatric patients aged 2 and above with NF1 who have symptomatic, inoperable PNs.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis: uncertainties in the proportion of patients with NF1 who would have PNs; and the proportion of patients with symptomatic PNs would be expected to be smaller than estimated by the sponsor, according to clinical experts consulted by CADTH. CADTH performed reanalyses that aligned with clinical expert opinion by halving the prevalence of symptomatic PNs from the sponsor’s original estimate. In the CADTH reanalysis, the 3-year total budget impact from the introduction of selumetinib for the treatment of pediatric patients with NF1 and symptomatic, inoperative PNs was estimated to be $64,702,506 (year 1 = $15,723,217; year 2 = $22,868,414; year 3 = $26,110,875). Given that NF1 is considered a rare disease, there remains considerable uncertainty regarding the epidemiologic inputs needed to obtain a reliable estimate of the budget impact of selumetinib.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed
Meeting date: March 24, 2023
Regrets: Three expert committee members did not attend.
Conflicts of interest: None
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Indication: For the treatment of pediatric patients aged 2 years and above, with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas
Sponsor: Alexion Pharma GmbH
Final recommendation: Reimburse with conditions
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