Selpercatinib (Retevmo)

Input From Clinical Experts Consulted by CADTH

Two clinical experts provided expertise knowledge regarding treatment strategies in Canada. The clinical experts cited that there is currently no available therapy for RET fusion-positive NSCLC patients. Treatment goals identified by experts were similar to those highlighted by the clinician group input. The clinical experts indicated that the most important goals are to achieve OS, reduce symptom burden, delay disease progression, prolong life with improved quality of life, decrease or eliminate hospital admissions and hospital stays, and all of these were considered valuable in this patient population.

The experts noted that if selpercatinib is approved for funding, it will likely be used as first-line therapy for patients with metastatic RET fusion-positive NSCLC. The experts highlighted that platinum plus pemetrexed and pembrolizumab (triplet therapy) was the preferred treatment option in the first-line across jurisdictions (except the province of PEI where pembrolizumab is not funded) regardless of a patient’s PD-L1 TPS score. Beyond first-line, the experts noted that docetaxel is funded and can be administered depending on whether the patient received triplet therapy as first-line treatment. Patients may also receive single-drug immunotherapies (pembrolizumab, nivolumab or atezolizumab) in second-line if they had received platinum and pemetrexed in first- line; however, as highlighted in their input, patients with RET fusion are known to have shown low response rates to immunotherapy, therefore docetaxel may be administered in place of an immunotherapy in next-line settings. The clinical experts recommended that treatment be made available to all RET fusion-positive patients with advanced or metastatic NSCLC.

The clinician experts indicated that response to treatment in practice is usually assessed using the same methods implemented in the LIBRETTO-001 trial. However, the frequency of assessments differs from those of the trial setting. As described by the experts, the standard will be to perform radiographic assessments every 8 to 12 weeks or sooner if patient reports new symptoms or if their physical findings indicate disease progression. The experts also noted that symptom severity and adverse event occurrence are generally performed in practice every 3 to 4 weeks in patients receiving oral targeted therapies.

The experts highlight several molecular testing techniques are available to test RET fusion mutations across jurisdictions in Canada. The next-generation sequencing (NGS) technique was cited as the most commonly used technique while NGS with RNA sequence was considered the best test because of its sensitivity and specificity (e.g., 100% sensitivity and 99% specificity using the MSK IMPACT testing).

Clinician Group Input

This section was prepared by CADTH based on the input provided by clinician groups.

The clinician group input was submitted by 2 groups: The Lung Cancer Canada (LCC) and Ontario Health (Cancer Care Ontario) Lung and Thoracic Cancers Drug Advisory Committee (The OH-CCO). The OH-CCO’s Drug Advisory Committees provide timely evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. Twelve clinicians from LCC and 2 clinicians from Ontario Health (Cancer Care Ontario) Lung and Thoracic Cancers Drug Advisory Committee provided input for this review. Both groups highlighted similar treatment goals for patients with advanced or metastatic NSCLC disease. Key goals noted by both clinician group inputs included: improvement in median OS in patients, achieving quick and prolonged improvement in symptoms, achieving a median progression- free survival (mPFS), and reducing toxicity-related adverse events. Experts from LCC also added that treatment goals include: the prevention or treatment of brain metastases, the reduction of resource utilization, and the evaluation of the impact of COVID on the safety of systemic therapy. Input from LCC highlighted that current treatments for RET fusion-positive NSCLC patients have not improved OS in patients and are lacking in rapid and prolonged improvement in lung cancer symptoms measured by median time-to-response, ORR, or progressive disease rate and median PFS.

Both groups mention that adding selpercatinib to the Canadian treatment paradigm will allow the drug to be administered as first-line therapy in newly diagnosed patients with RET fusion-positive metastatic NSCLC. Clinicians in the LCC group mention that newly diagnosed patients with ECOG performance status of 0 to 3 could benefit from selpercatinib if approved for funding, although they expressed uncertainty related to the best therapy for second-line and suggested that subsequent therapy could include docetaxel and anti-PD-L1 therapy for those who have not received such drugs in prior lines of therapy.

Description of Studies

A single ongoing phase I/II multi-centre, multi-cohort, open-label study met the criteria for the CADTH systematic review. The LIBRETTO-001 trial evaluated the safety and efficacy of selpercatinib in patients with advanced solid tumours, including RET fusion-positive solid tumours (e.g., NSCLC, thyroid, pancreas, colorectal), RET-mutant medullary thyroid cancer, and other tumours with RET activation (e.g., mutations in other tumour types or other evidence of RET activation). Patients recruited were 12 years or older (depending on the site and country).

The study was initiated in May of 2017 and has over 84 participating centres, including in Canada. There were 3 interim analyses planned to support regulatory submissions in different jurisdictions. This review presents data obtained at the second (December 16, 2019) and third (March 30, 2020) interim data cut-offs. Data obtained at interim 1 were updated at interim 2 and formed the basis of the Health Canada submission.

The study consisted of a dose escalation (phase I) and a dose expansion (phase II) phase. The phase I portion was conducted initially as a 3 + 3 design (cohorts of 3 patients assigned to increasing dose levels until 1 or more dose-limiting toxicities is observed) but was later updated to a Fibonacci dose escalation design after the third escalation was implemented in patients in increments of approximately 67%, 50%, and 33%. The primary objective at phase I was to assess the maximum tolerable dose/ recommended dose at phase II (RP2D) and dose-limiting toxicities. The secondary objective at phase I is to evaluate the safety and tolerability of selpercatinib, to characterize the pharmacokinetic (PK) properties, and to assess the antitumour activity of selpercatinib.

The phase II portion, which is ongoing, has 5 cohorts which included patients with a confirmed RET gene alteration in their tumour. Cohort 1 included RET fusion-positive solid tumour patients who progressed on or were intolerant to 1 or more before standard first-line therapy. Cohort 2 was composed of patients with RET fusion-positive solid tumour without prior standard first-line therapy. The primary objective at phase II was to evaluate the antitumour activity of selpercatinib in patients recruited into the 5 cohorts. This was achieved by measuring the ORR using the Response Evaluation in Solid Tumors version 1.1 (RECIST 1.1) guidelines or Response Assessment in Neuro-Oncology, as per tumour type, performed by an independent radiographic committee (IRC) and the study investigator. Other outcomes were assessed as secondary objectives in phase II, which included best change in tumour size from baseline, duration of response (DOR), CNS ORR, CNS DOR, time to any and best response, clinical benefit rate, PFS, overall survival (OS), safety and tolerability of selpercatinib, and the characterization of the pharmacokinetic properties. HRQoL was assessed as an exploratory outcome.

This CADTH review focuses on outcomes observed in NSCLC patients with a confirmed RET fusion gene mutation enrolled into cohort 1 and 2 at phase II of the LIBRETTO-001 trial. These patients were further subgrouped into 3 datasets based on clinically meaningful distinctions observed during the trial. These subgroups include: the Primary Analysis Set ([PAS]: consisting of the first consecutively enrolled patients previously treated with platinum-based chemotherapy; n = 105), the Integrated Analysis Set ((IAS): consisting of patients treated with platinum-based chemotherapy) (n = 184 and n = 218 for December 16, 2019, and March 30, 2020, data cut-off):, and the supplementary analysis sets ((SAS): SAS1: consisting of previously untreated patients (n = 39 and n = 48 for December 16, 2019 and March 30, 2020, data cut-off); SAS 2: consisting of patients treated with other systemic therapies that are not platinum-based (n = 16 and n = 18 for December 16, 2019 and March 30, 2020, data cut-off); SAS3: consisting of patients without measurable disease according to RECIST v1.1 (n = 14 at the December 16, 2019 data cut-off, and n = 18 for at the March 30, 2020, data cut-off). These datasets supported the regulatory submission for marketing approval at Health Canada, the FDA, and the EMA.

Harms Results

At the December 16, 2019 data cut-off, the most common adverse events reported in the NSCLC patient population in LIBRETTO-001 trial were dry mouth, diarrhea, hypertension, aspartate aminotransferase (AST) increase, alanine aminotransferase (ALT) increase, fatigue, constipation, peripheral edema, headache, and nausea. Serious events in the NSCLC population were commonly associated with pneumonia, ALT increase, AST increase, abdominal pain, pleural effusion, drug hypersensitivity, diarrhea, and acute kidney injury.

At the December 16, 2019 data cut-off, AEs leading to dose withdrawal, interruption, and dose reductions in the RET fusion-positive NSCLC population were consistent with those in the overall population. Adverse events commonly associated with treatment discontinuations in the NSCLC population were alanine aminotransaminase (ALT) increase, sepsis, AST increase, drug hypersensitivity, fatigue and thrombocytopenia. ALT increase and AST increase were commonly associated with dose reductions and dose interruptions.

At the December 16, 2019 data cut-off, treatment was discontinued owing to death in 6 patients and 38 patients discontinued the study due to death. At the March 30, 2020 data cut-off, in the NSCLC population, treatment was discontinued owing to death in 6 (1.7%) patients and 55 (15.9%) patients discontinued the study due to death. In total, 36 (10.4%) patient deaths were attributed to disease progression, 13 (3.9%) deaths occurred due to adverse events, and 6 (1.7%) deaths were attributed to other reasons. One (0.3%) report of death was identified in the NSCLC population, which had occurred more than 28 days after the last selpercatinib dose. In the overall safety analysis set (OSAS) population, treatment was discontinued owing to death in 11 (1.5%) patients and 103 (13.8%) patients discontinued the study due to death.

Notable harms reported in the NSCLC set were consistent with the OSAS at the March 30, 2020, and December 16, 2019 data cut-offs. The most common adverse events were ALT increase (32.8%), AST increase (31%), hypertension (31.9%), drug hypersensitivity (2.4%) and electrocardiogram QT prolongation (16.7%). All notable harms identified in the LIBRETTO-001 trial have been properly labelled under the warnings and precaution section of the Canadian product monograph. These notable harms were considered manageable by the clinical experts.

Critical Appraisal

The open-label, non-comparative design of the LIBRETTO-001 trial, with no statistical testing, is the key limitation. The sponsor did not state in the statistical analysis plan, hypothesis statements for statistical significance for the primary outcome including secondary and subgroup analyses conducted. The design increases the risk of bias in estimating treatment effects because the potential for confounding related to variation in health status, and other unidentified prognostic factors that could affect subjectively assessed outcomes (i.e., response, HRQoL, AEs). The potential for bias was reduced by using IRC assessment for key study outcomes such as ORR and DOR.

Nonetheless, the lack of direct comparative data means there is uncertainty regarding the magnitude of effects obtained for the efficacy outcomes. Although the clinician experts consulted highlighted that the safety profile of selpercatinib was favourable compared to the other therapies available as standard of care in Canada, CADTH notes that in the absence of a comparative arm, the findings obtained from the safety analysis are uncertain as the single-arm design does not allow for the differentiation of the symptoms of underlying NSCLC disease from treatment-related adverse events. The sponsor agreed to provide results from the |||||||||||||||||||||||||||||||||||||||||||||||| to confirm the clinical benefit of selpercatinib in patients with previously treated RET fusion-positive NSCLC according to the NOC/c issued by Health Canada. The sponsor had noted in their response that |||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| || |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||| The sponsor submitted additional data with a new cut-off date of June 15, 2021 during the completion of this CADTH review (refer to appendix for new data). Despite the results obtained from the updated analyses performed on June 15, 2021, there remains uncertainty on whether the end points investigated are durable for long-term in this patient population.

The primary objective investigated at the phase II portion of the LIBRETTO-001 study was the ORR measured by the RECIST v1.1 criteria. The FDA considers ORR alone as a surrogate measurement when assessing treatment response in advanced or metastatic NSCLC patients that may not correlate well with survival, unless the effect size of the ORR is large and the responses are durable. The sponsor hypothesized a true ORR of at least 50% in the primary analysis of effectiveness, ruling out a lower limit of 30% for the ORR, which was considered clinically meaningful and consistent with the estimated response rates seen with approved targeted therapies in molecularly defined patient populations who have failed prior therapies (e.g., osimertinib, crizotinib, alectinib, and others). The ORR obtained by IRC in the PAS, IAS, and SAS1 sets were above the lower limit of 30% that the sponsor assumed in the sample size calculation for RET fusion-positive NSCLC patients who progressed on or after receipt of platinum-based chemotherapy. Although the FDA review team noted that the magnitude of the ORR and DOR obtained in RET fusion-positive NSCLC patients of the LIBRETTO-001 trial was large, and considered it sufficient to establish clinical benefit, the Health Canada reviewer’s input underlined |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||| Further, the Health Canada reviewers report highlighted that |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||　|　||||||||||| The sponsor agreed to provide results from the |||||||||||||||||||||||||||||||||||||||||||||||| to confirm the clinical benefit of selpercatinib in patients with previously treated RET fusion-positive NSCLC according to the NOC/ c issued by Health Canada. The sponsor also noted that |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||| In the LIBRETTO-001 trial radiographic scans were performed by an accredited laboratory and assessed by an independent radiology committee therefore, reducing bias. Results obtained from both IRC and investigator assessments did not differ greatly, which increases the validity of the ORR-related outcomes.

The time-to-events analyses, particularly the OS and PFS results, were considered exploratory by |||||||||||||||| the FDA, and CADTH due to lack of control arm. Health Canada highlighted in their report that, |||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Owing to immature data in the PAS, IAS, and SAS1 populations at the March 31, 2020 and December 16, 2019 cut-offs, the results were considered exploratory by CADTH. The sponsor submitted additional data to CADTH for a new cut-off date of June 15, 2021 later during the completion of the review. Although they report a median PFS of 24.94 months (95% CI, 9.3 to NE) in the IAS and a median PFS of 21.95 months (95% CI, 13.8 to NE) in the SAS1 population, the information was considered insufficient to form concrete conclusions on the PFS in this population because of the single-arm design of the LIBRETTO-001 trial and immature data. The median OS was non-estimable in the IAS and SAS1 datasets at the June 15, 2021 cut-off. Thus, there is uncertainty on whether the observed magnitude of benefit related to tumour response with selpercatinib would be translated as OS in patients in the 2 groups.

The analysis sets — PAS, IAS, and 3 SAS sets — were not predefined in the original statistical analysis plan. They were developed following consultation with the FDA and EMA. A key concern therefore is that these were post hoc analyses and may have been susceptible to bias. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||| CADTH reviewers agree with |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| these were unlikely to introduce bias because the investigators remained blinded to results until after the revisions were made.

The 3 planned interim analyses were prespecified. However, the analyses were performed on observed data only with no formal hypothesis testing and only descriptive statistics were provided, further complicating assessing the magnitude of effect observed in the different groups investigated.

HRQoL was evaluated as an exploratory outcome. There is uncertainty regarding these findings because the number of patients that completed questionnaires decreased from baseline through to cycles 13, thereby resulting in considerable missing data at later time points. In the absence of a comparator arm and open-label design which introduces reporting bias, the impact of selpercatinib on patient reported outcomes in relation to other therapies is unknown. Although CADTH recognizes that the rarity of RET fusion-positive mutations in NSCLC may have contributed to the small sample size in the datasets at baseline, and may have influenced the number of patients available to complete the questionnaires at later stages of the trial, no strong definitive conclusions can be made from the findings obtained for HRQoL attained in the different population sets of NSCLC patients.

The clinical experts consulted during this CADTH review thought that findings obtained for outcomes (ORR, DOR, CNS ORR, and HRQoL) investigated in the LIBRETTO-001 study are clinically meaningful for patients in practice. The LIBRETTO-001 trial recruited patients with ECOG PS of 0, 1 and 2. The clinician experts consulted considered these findings generalizable to patients with ECOG PS of 0 to 3 (except for patients with ECOG PS 4). The experts also considered the baseline findings obtained in the trial similar to those observed practice; thus, the findings are generalizable to patients in Canada. The RET fusion mutation in patients was identified in the LIBRETTO-001 trial using polymerase chain reaction. and NGS. The clinician experts highlighted that NGS is available across several jurisdictions in Canada for testing oncogenic driver mutations at initial diagnosis.

Description of Studies

Two sponsor-submitted ITCs were summarized and critically appraised. The sponsor-submitted ITCs aimed to evaluate the relative clinical efficacy of selpercatinib to other active treatments for RET fusion-positive NSCLC, in patients with or without prior systemic therapies. All included studies enrolled patients with unknown RET fusion status with the exception of LIBRETTO-001. Three outcomes that were analyzed were OS, PFS and ORR.

Efficacy Results

The sponsor-submitted ITCs conducted a systematic review to identify relevant individual studies and used Bayesian network meta-analysis to evaluate the relative clinical efficacy of selpercatinib to other treatments for NSCLC. In both ITCs, a pseudo-control arm was needed due to the lack of comparison arm in the study of selpercatinib. Adjustments on a number of prognostic factors for NSCLC, such as |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| were performed to match the comparator arm with selpercatinib arm.

In the ITC of patients who were previously untreated, results demonstrated that selpercatinib was favoured compared to other treatments for OS |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| PFS |||||||||||||||||||||||||||||||||||||||| and ORR |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Selpercatinib was compared to monotherapy or combination of platinum-based chemotherapy and immunotherapy drugs.

In the ITC of patients who had 1 or more prior therapies, results suggested that selpercatinib was favoured compared to other treatments for OS ||||||||||||||||||||||||||||||||||||||||||||, PFS |||||||||||||||||||||||||||||||||||||||| and ORR |||||||||||||||||||||||||||||||||||||| ||||||||||||||. Selpercatinib was compared to monotherapy or combination of chemotherapy drugs and immunotherapy drugs, such as docetaxel, cabozantinib, atezolizumab, or nivolumab.

Harms Results

Harms were not assessed in the sponsor-submitted ITCs.

Critical Appraisal

These ITCs have a number of limitations that impact their internal and external validity, such as not being able to comprehensively assess the clinical heterogeneities across the included individual studies and their influence on the study results due to the lack of reporting certain patient characteristics, uncertainty still exists on the treatment effect of selpercatinib despite of various adjustments, and generalizability of the study findings to patients with RET fusion-positive could be limited. In addition, other important outcomes such as DOR, HRQoL, and safety were not assessed.

Description of Studies

LIBRETTO-431: The CADTH review team identified an ongoing phase III, randomized, open-label study (LIBRETTO-431) comparing selpercatinib to platinum-based (carboplatin or cisplatin) and pemetrexed therapy with or without pembrolizumab in previously untreated patients with locally advanced or metastatic RET fusion-positive nonsquamous NSCLC. No results are currently available, as this trial is actively recruiting patients. The estimated primary completion date (the date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure) and study completion dates (the date on which the last participant in a clinical study was examined or received an intervention or treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events) are January 15, 2023 and August 18, 2025, respectively.

SIREN study: The CADTH review team identified another study analyzing the safety and efficacy of selpercatinib in a real-world setting (SIREN study), where the data were retrospectively collected and analyzed from RET fusion-positive NSCLC patients participating in a selpercatinib access program.

The ORR (defined as complete or partial response) was 68% (95% CI, 53 to 81), and the median PFS was 15.6 months (95% CI, 8.8 to 22.4) after a median follow-up of 9.4 months among all patients. In patients with untreated or previously progressed and measurable brain metastases (n = 8), the intracranial ORR reached 100%. In terms of adverse events, 43 (88%) of 50 patients experienced treatment emergent adverse events (TRAEs) of any grade, a large majority of them indicating grade 1 or 2. The most frequent TRAEs reported were fatigue or asthenia (40%), increased liver enzyme levels (34%), hypertension (26%), dry mouth (26%), and peripheral edema (20%). TRAEs of at least grade 3 were reported in 12 (24%) patients, with the most common TRAEs being increased liver enzyme levels (10%), abdominal pain (4%), prolonged QTc time (4%), hypertension (4%), and fatigue or asthenia (4%).

The following limitations were identified: The retrospective study design is prone to bias (e.g., reporting bias and non-differential biases), the patient population recruited may not be similar to the LIBRETTO-001 trial owing to differences in the eligibility and exclusion criteria applied in the study (potential selection bias). The ORR, although measured using the RECIST v1.1 criteria, was assessed by an unblinded review of practising physicians. There is also a potential measurement bias owing to differences in the frequency and conduct of disease assessments in clinical practice versus the trial setting, the follow-up time frame in the study, which differs from that of the trial and the therapies administered beyond disease progression. The small sample size of the study also limits the generalizability of the findings. Although the SIREN study provides additional data on the effectiveness and safety of selpercatinib in the real-world setting, the limitations identified introduces uncertainty.