Summary Basis of Decision for Augtyro

Clinical Pharmacology

Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1), the enzyme encoded by ROS proto-oncogene 1 (ROS1). It is also an inhibitor of anaplastic lymphoma kinase (ALK), tropomyosin receptor tyrosine kinase (TRK)A, TRKB, and TRKC. Fusion proteins that include ROS1 kinase domains can drive tumourigenic potential through hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation. Repotrectinib has demonstrated anti-tumour activity in cell lines expressing the targeted fusion oncogenes ROS1 and corresponding solvent front mutations ROS1^G2032R and ROS1^D2033N and gatekeeper mutation ROS1^L2026M. Repotrectinib binds inside the boundary of the adenosine triphosphate (ATP)-binding pocket and avoids steric interference from both solvent front and gatekeeper mutations.

The recommended dosage of Augtyro is 160 mg orally once daily for 14 days, then increase to 160 mg twice daily until disease progression or unacceptable toxicity.

Following the administration of repotrectinib 160 mg twice daily, the steady state geometric mean (coefficient of variation %) of the maximum serum concentration (C_max) and area under the concentration-time curve from 0 to 24 hours (AUC_0-24) were 713 ng/mL (32.5%) and 7,210 ng•h/mL (40.1%), respectively.

Clinical drug interaction studies showed that repotrectinib interacts with midazolam, (a sensitive cytochrome P450 [CYP] 3A4 substrate), and that itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein [P-gp] inhibitor) and rifampin (a strong CYP3A4 inducer) significantly increased and decreased repotrectinib exposure, respectively. It is recommended to avoid co-administration of repotrectinib with CYP3A inducers, CYP3A/P-gp inhibitors, and CYP3A substrates.

The updated population-based pharmacokinetic model did not identify clinically significant differences in the pharmacokinetics of repotrectinib based on race, age (12 years to 93 years of age), gender, genetic alteration, prior tyrosine kinase inhibitor status, body weight, or hepatic/renal impairment.

For further details, please refer to the Product Monograph for Augtyro, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Augtyro was evaluated in TRIDENT-1, a Phase I/II, multicentre, single-arm, open-label, multi-cohort study. Eligible patients were required to have ROS1-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1), and 14 or more months of follow-up from the first dose. All patients were assessed for central nervous system lesions at baseline and patients with symptomatic brain metastases were excluded from the study. Patients from Phase I received Augtyro at various doses (range 40 mg orally once daily to 200 mg twice daily), while patients from Phase II received Augtyro 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity.

The efficacy evaluation was based primarily on a prespecified pooled analysis set of 71 ROS1-positive tyrosine kinase inhibitor (TKI)-naïve patients (8 from Phase I and 63 from Phase II) who received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy and 56 patients (3 from Phase I and 53 from Phase II) who received 1 prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy, who were followed for at least 14 months from the first dose.

Demographics and baseline disease were representative of the disease. In the TKI-naïve group, the mean age was 55.5 years, 60.6% were female, 67.6% were Asian, 1.4% were Black or African American, 1.4% were Native Hawaiian or Other Pacific Islander, 25.4% were White, 4.2% were not reported, 4.2% were Hispanic or Latino, 66.2% had an ECOG performance status of 1, and 33.8% had an ECOG performance status of 0. In the TKI-pretreated group, the mean age was 55.9 years, 67.9% were female, 48.2% were Asian, 1.8% were Black or African American, 1.8% were Native Hawaiian or Other Pacific Islander, 44.6% were White, 1.8% were not reported, 1.8% were unknown, 1.8% were Hispanic or Latino, 67.9% had an ECOG performance status of 1, and 32.1% had an ECOG performance status of 0.

The primary efficacy endpoint was the overall response rate (ORR), according to RECIST v1.1 and assessed by blinded independent central review (BICR). The key secondary endpoints were duration of response (DOR) and intracranial response, according to RECIST v1.1 and assessed by BICR.

Treatment with Augtyro resulted in a clinically meaningful ORR in both TKI-naïve and TKI-pretreated locally advanced or metastatic ROS1-positive NSCLC. The ORR was 78.9% (56 out of 71 patients; 95% Confidence Interval [CI]: 67.6, 87.7) in TKI-naïve patients, including 7 complete responses and 49 partial responses. The efficacy benefit was consistent between patients with or without prior chemotherapy. The ORR was 37.5% (21 out of 56 patients; 95% CI: 24.9, 51.5) in TKI-pretreated patients, including 3 complete responses and 18 partial responses.

Durable responses were observed with an estimated median DOR of 34.1 months (95% CI: 25.6, not estimable) in TKI-naïve patients and 14.8 months (95% CI: 7.6, not estimable) in TKI-pretreated patients.

The benefit of Augtyro treatment was also generally consistent across the prespecified subgroups, including prior TKI treatments and patients with resistance mutations.

Consistent efficacy results were observed in patients pretreated with crizotinib (ORR of 36.5 %; 85 patients) and entrectinib (ORR of 37.5 %; 16 patients), suggesting an Augtyro benefit regardless of the type of prior TKI therapy.

The central nervous system is a common site of metastases in patients with advanced ROS1-positive NSCLC, and is one of the first and most frequent sites of disease progression in patients treated with TKI. If untreated, it’s associated with poor prognosis. Therefore, demonstrating the intracranial activity of Augtyro is important to establish the clinical benefit of the drug. Despite the limited number of patients in TRIDENT-1, Augtyro showed intracranial activity in patients with measurable brain metastases at baseline by BICR, with an intracranial ORR of 88.9% (8 out of 9 patients) in TKI-naïve patients and an intracranial ORR of 38.5% (5 out of 13 patients) in TKI-pretreated patients, consistent with the overall ORR in both TKI-naïve and TKI-pretreated patients.

Several potential fusion gene partners for ROS1 have been observed in the clinic setting. Fusion proteins that include ROS1 kinase domains can drive tumourigenic potential through the hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation. Responses to treatment with Augtyro were observed regardless of ROS1 fusion partner.

Overall, the results from the TRIDENT-1 study demonstrated a clinical meaningful efficacy benefit with durable responses for Augtyro in adult patients with locally advanced or metastatic ROS1-positive NSCLC in the ROS1 TKI-naïve and ROS1 TKI-pretreated populations. The efficacy data remains favourable in the context of historic benchmark data for existing approved therapies in the naïve setting (i.e., crizotinib and entrectinib) and in the TKI-pretreated setting where there is currently no approved targeted therapies. The magnitude of the clinical benefit was generally consistently observed in all prespecified subgroups, although, there are still uncertainties that remain regarding the intracranial efficacy of Augtyro and its ability to overcome resistance mutations.

Indication

The New Drug Submission for Augtyro was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Augtyro (repotrectinib capsules) is indicated for:

• Treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

For more information, refer to the Product Monograph for Augtyro, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Augtyro was evaluated in TRIDENT-1, a Phase I/II, multicentre, single-arm, open-label, multi-cohort study described in the Clinical Efficacy section. The clinical safety package included an additional 6 months of follow-up since the original clinical study report (median follow-up of 15.6 months; 75 additional patients). The full safety population from TRIDENT-1 included 426 patients (416 patients in Phase II and 10 patients in Phase I) who received at least one dose Augtyro at the recommended clinical dose of 160 mg twice daily, regardless of tumour type or genetic rearrangement. Within this population, 320 patients had ROS1-positive NSCLC and 106 patients had other solid tumours harbouring a ROS1, ALK, or neurotrophic tyrosine receptor kinase (NTRK) gene alteration.

Patient demographics and disease characteristics for ROS1-positive NSCLC patients were representative of this population. The median age of patients was 55 years, the majority of patients were between 18 to 64 years of age and female, over 40% of patients were white or Asian, and 3% were Black. Most patients were able to escalate from 160 mg once a day to the recommended clinical regimen of 160 mg twice a day. Additionally, 48% of patients were exposed for at least 6 months and 28% were exposed for greater than 1 year.

There were no clinically relevant differences in the safety profile of Augtyro between ROS1-positive NSCLC patients and patients with other solid tumours harbouring a ROS1, ALK or NTRK gene alteration. Overall, serious adverse events (SAEs) were reported in 35% of patients in the full safety population, with the most common (occurring in 2% or more of patients) characterized as pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%), and hypoxia (2.6%). Fatal adverse events were observed in 3.5% of patients. There were no overt safety signals for SAEs or Augtyro-related fatal events; these events were confounded by prior medical history, concomitant medication, existent risk factors and/or overall expected in patients with advanced cancer.

The clinically significant TEAEs that were identified in the full safety population included central nervous system effects (77%; dizziness [65%], ataxia [28%], cognitive impairment [25%], mood disorders [6%], and sleep disorders [18%]), peripheral neuropathy (49%), hepatotoxicity (increased aspartate aminotransferase [41%] and alanine transaminase [38%]), myalgia (13%), vision disorders (12%), hyperuricemia (5%), interstitial lung disease/pneumonitis (3.1%), and skeletal fractures (2.3%). The most common (occurring in 10% or more of patients) TEAEs reported in ROS1-positive NSCLC patients were dizziness (64%), dysgeusia (52%), peripheral neuropathy (50%), constipation (37%), dyspnea (30%), ataxia (28%), fatigue (26%), cognitive disorder (24%), muscular weakness (22%), headache (19%), nausea (18%), cough (17%), increased weight (16%), edema (15%), diarrhea (13%), myalgia (12%), vision disorders (11%), and pneumonia (10%).

Overall, there was a low incidence of Grade 3 to 4 events. Treatment-emergent adverse events were mainly managed with Augtyro dose interruption and/or standard medical practice, specifically, 50% of patients required a dose interruption, 38% required a dose reduction, and 7% required permanent drug discontinuation

The cardiac safety report concluded that Augtyro does not cause a mean increase in the QTc interval greater than 20 milliseconds at the recommended clinical dose of 160 mg twice daily.

Appropriate warnings and precautions are in place in the approved Product Monograph for Augtyro to address the identified safety concerns.

For more information, refer to the Product Monograph for Augtyro, approved by Health Canada and available through the Drug Product Database.

In vitro enzymatic assays demonstrated that repotrectinib inhibits autophosphorylation and the catalytic kinase activities of human proto-oncogene tyrosine-protein kinase ROS1 (ROS1) fusion protein and corresponding solvent front mutations ROS1^G2032R and ROS1^D2033N and gatekeeper mutation ROS1^L2026M. The kinase half-maximal inhibitory concentration (IC₅₀) values for ROS1 and ROS1^G203R when exposed to 10 µM adenosine triphosphate (ATP) were 0.0706 nM and 0.456 nM, respectively. Repotrectinib also inhibited the autophosphorylation and catalytic kinase activities of human anaplastic lymphoma kinase (ALK) and receptor tyrosine kinase (TRK)A, TRKB, and TRKC wild type and their mutant fusion proteins.

Repotrectinib demonstrated in vitro anti-proliferation activity in murine NIH3T3 and Ba/F3 cells expressing human syndecan 4 (SDC4)-ROS1 or cluster of differentiation 74 (CD74)-ROS1 and corresponding ROS1^G2032R, ROS1^D2033N, and ROS1^L2026M mutations. Repotrectinib also demonstrated significant in vivo anti-tumour activity in mouse subcutaneous xenograft tumour models with murine NIH3T3 and Ba/F3 cells expressing human SDC4-ROS1 or CD74-ROS1 and corresponding ROS1^G2032R, ROS1^D2033N, and ROS1^L2026M mutations at clinically relevant concentrations (twice daily an oral dose of 15 to 75 mg/kg/day for up to 28 days). Repotrectinib showed anti-proliferation activity and anti-tumour activity against other primary targets, including ALK, TRKA, TRKB, and TRKC, and their corresponding mutant fusion proteins.

Overall, the non-clinical pharmacodynamic data support the potential clinical efficacy benefit of repotrectinib in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) in first-line treatment and in patients developing resistance to crizotinib and entrectinib due to solvent front mutations.

Dedicated in vivo safety pharmacology studies were not conducted, which is consistent with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S9 Guideline. However, in vitro, repotrectinib had no significant inhibitory effect on the human ether-a-go-go-related gene (hERG), voltage-gated sodium (hNav1.5), or voltage-gated calcium (hCav1.2) channels.

In single oral dose pharmacokinetic studies, repotrectinib exhibited rapid absorption and low to moderate bioavailability in the preclinical species; the bioavailability of repotrectinib ranged from 32% to 38% in mice and 44.7% to 61.4% in rats, and was 25.3% in beagle dogs and 13.5% in cynomolgus monkeys.

Repotrectinib binding to human plasma protein was 95.4% in vitro. The blood-to-plasma ratio was 0.56 in vitro, indicating that the distribution into humans blood cells was low.

A quantitative whole-body autoradiography study in the Long-Evans rat demonstrated rapid and widespread distribution of radiolabeled repotrectinib ([¹⁴C]repotrectinib) with low penetration into the brain. Pigmented skin, uveal tract, liver, renal cortex, and kidneys were the tissues with the highest radioactivity exposure in male and female rats. All radioactivity was cleared by 168 hours post dose, suggesting that there was no accumulation of repotrectinib or long-lived metabolites.

The major route of excretion for repotrectinib and its metabolites was via the feces in monkeys and rats. Urinary elimination was a minor pathway. Unchanged repotrectinib was the major drug-related substance in plasma.

Repotrectinib is primarily metabolized by cytochrome P450 (CYP) 3A4 to form oxidative metabolites, followed by secondary glucuronidation. All metabolites formed in humans were also formed in rats and monkeys. No individual metabolite represented greater than 10% exposure to the parent compound in rats and monkeys or in humans. Based on in vitro studies, repotrectinib potentially inhibits CYP2C8, CYP2C9, and CYP3A4/5 (at the gut level) at clinically relevant concentrations but has minimal potential to inhibit other CYP enzymes. Repotrectinib also induces CYP2B6, CYP3A4, CYP2C8, CYP2C9, and CYP2C19 enzymes at clinically relevant concentrations. Repotrectinib also has the potential to induce uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1.

In vitro data indicate that repotrectinib may have the potential to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and multidrug and toxin extrusion protein (MATE)2-K at clinically relevant concentrations. Repotrectinib is also a substrate for P-gp and a potential substrate for MATE2-K and BCRP.

The reproductive and developmental toxicity studies for repotrectinib were conducted in accordance with ICH S5(R3) and ICH S9 guidelines, and are considered appropriate given the indication in patients with advanced lung cancer. Given the findings of fetal external malformations (hindlimbs) in an initial exploratory dose-finding study in rats, there were no dedicated embryofetal toxicity studies conducted. Other findings from this exploratory study included skin scabbing/abrasions in pregnant females, consistent with the skin effects observed in the three-month general toxicology study in rats, and decreased mean fetal body weight. There were no effects on uterine implantation parameters, uterine weight, or fetal sex ratio. Additionally, a dedicated, Good Laboratory Practices (GLP)-compliant juvenile toxicity study showed decreased birth weight gain and femur lengths in pups. Finally, another GLP-compliant study in rats showed no evidence of cutaneous or ocular phototoxicity with repotrectinib.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Augtyro. In view of the intended use of Augtyro, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Augtyro, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Augtyro has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

One excipient in the capsule shell, gelatin, is of animal origin. The sponsor provided a Certificate of Suitability from the European Directorate for the Quality of Medicines.