FDA Approval Summary: Repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer

Abstract

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro^®, Bristol Myers Squibb Corporation), for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter “ROS1-positive”) NSCLC, (NCT03093116), who were either treatment naïve or had received prior ROS1 TKI and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors (RECIST) version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI 68, 88); median duration of response was 34.1 months (95% CI 26, NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI 25, 52). The median duration of response was 14.8 months (95% CI 7.6, NE) BICR-assessed responses were observed in CNS metastases in patients in both cohorts, and in patients who developed resistance mutations following prior TKI therapy. The most common (> 20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

Introduction

There are more than 238,000 new cases of lung cancer annually in the United States, and lung cancer is the leading cause of cancer-related death accounting for approximately 127,000 deaths per year¹. Over 85% of lung cancer cases are non-small cell lung cancer (NSCLC), and ROS1 rearrangement is an actionable target alteration that occurs in 1 to 2% of patients with NSCLC.² The clinicopathologic characteristics of patients with ROS1-positive NSCLC include median age at diagnosis of 50 years, higher incidence in patients of Asian race, and greater incidence in never-smokers compared to patients with NSCLC without ROS1 fusions.³

Overall survival (OS) for patients with NSCLC at 5-years has been reported as 22% and between 5.5% to 8% in the metastatic setting,^4,5 and patients with ROS1-positive NSCLC likely have similar outcomes to the overall population of patients with NSCLC⁶ In addition to poor survival, many patients experience sequelae of their disease and treatment that include central nervous system (CNS) effects, liver toxicity, pulmonary toxicity, and skeletal fractures. ROS1 TKI therapy is the current standard of care for the treatment of patients with advanced or metastatic ROS1-positive NSCLC⁷ Crizotinib and entrectinib were approved for adult patients with metastatic ROS1-positive NSCLC in 2016 and 2019, respectively, but the data supporting these approvals did not include patients previously treated with a ROS1-targeted therapy. Further, mechanisms for resistance have been identified in patients with ROS1-positive NSCLC who have progressed on ROS1 TKIs⁸.

Repotrectinib is an oral inhibitor of ROS1, and it represents the first approved targeted therapy that specifically includes patients previously treated with a ROS1 TKI in FDA labeling. In this summary, FDA’s review of the marketing application that led to the approval of repotrectinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC will be discussed.

Regulatory History

On September 26, 2016, the original protocol, TPX-0005-01 (TRIDENT-1), was submitted to the FDA and on June 22, 2017, repotrectinib was granted orphan drug status for NSCLC with adenocarcinoma histology.⁹ On December 07, 2020 and May 09, 2022, FDA granted Breakthrough Therapy Designation for the treatment of the TKI-naïve ROS1-positive NSCLC and ROS1-positive NSCLC with previously treated with one ROS1 TKI and no prior chemotherapy populations, respectively. The new drug application (NDA) for new molecular entity (NME), repotrectinib, was submitted on March 27, 2023. The NDA included use of the Assessment Aid to facilitate FDA review, received Priority Review designation, and was conducted in conjunction with international regulatory agencies as part of Project Orbis.^{10, 11, 12, 13, 14}

Mechanism of Action

Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited antitumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1^G2032R, CD74-ROS1, CD74-ROS1^G2032R, CD74-ROS1^D2033N, and CD74-ROS1^L2026M.¹⁵

Clinical Pharmacology

The approved recommended dosage of repotrectinib for adult patients is 160 mg QD for 14 days followed by an increase to 160 mg BID without regard to food; this dosing regimen compensates for time-dependent auto-induction and early timing of CNS-related adverse reactions. No clinically significant differences in the pharmacokinetics of repotrectinib were observed based on age (18 to 84 years), sex, race/ethnicity (White 54%, Asian 38%, Black 7%), mild to moderate renal impairment (eGFR 30 to < 90 mL/min), or mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment, kidney failure (eGFR < 30 mL/min), or dialysis on repotrectinib pharmacokinetics is unknown or not fully characterized. No clinically significant differences in repotrectinib pharmacokinetics were observed in patients with cancer following administration of a high-fat meal (approximately 800-1000 calories, 50% fat).

Concomitant use with itraconazole (strong CYP3A and P-gp inhibitor) increased repotrectinib AUC_inf by 5.9-fold and C_max by 1.7-fold; concomitant use with rifampin (strong CYP3A and P-gp inducer) decreased repotrectinib AUC_inf by 92% and C_max by 79%. Concomitant use of repotrectinib at the recommended dosage decreased midazolam (CYP3A substrate) AUC_inf by 69% and C_max by 48%. Recommendations for use with concomitant medications are included in product labeling.¹⁵

The recommended dosage was supported by a positive trend for ORR with repotrectinib exposures in patients who were both TKI naïve and TKI pretreated. The proposed recommended dosage was also supported by statistically significant relationships that were identified for steady state repotrectinib exposures, i.e., Cmax,ss and/or Cavg,ss, and multiple safety endpoints including dizziness (Grade 2 and above).

Clinical Trials

The approval of repotrectinib was based on pooled data from two cohorts of patients who either received a prior ROS1 TKI and no prior chemotherapy, or were ROS1 TKI-naïve with or without prior platinum-based chemotherapy. Patients were enrolled in the Phase 1 and Phase 2 portions of TRIDENT-1, an international, single-arm, first-in-human, dose escalation and expansion study of repotrectinib in patients with advanced solid tumors with ALK, ROS1, or NTRK1-3 rearrangements. Patients were treated with repotrectinib administered daily at the recommended phase 2 dose (RP2D) or for some patients, the dose administered in Phase 1. The primary objective was confirmed ORR as assessed by blinded independent central review (BICR) using RECIST version 1.1. Additional efficacy outcome measures included DOR and intracranial objective response rate (IC-ORR) per modified RECIST v1.1. The investigators’ analysis of the TRIDENT-1 study has been publicly presented and published.^{16, 17} FDA’s independent analyses of data submitted by the Applicant in the applications are presented below.

Demographics, Disease Characteristics and Prior Treatment

The primary efficacy analysis population included 71 ROS1 TKI-naïve patients and 56 patients who had received 1 prior ROS1 TKI and no prior chemotherapy; population characteristics are described in Table 1. The pooled efficacy population included patients with confirmed diagnosis of locally advanced or metastatic ROS1-positive NSCLC, with ROS1 fusion detected by a Clinical Laboratory Improvement Amendments (CLIA) lab or equivalent. Adenocarcinoma was the predominant histology (Table 2). Most patients had metastatic disease (94% of ROS1 TKI naïve patients and 98% of patients with prior ROS1 TKI). At study entry, 25% and 43% of ROS1 TKI-naïve patients and TKI-pretreated patients, respectively, had brain metastases. Approximately one fourth of patients received prior platinum-based chemotherapy (26% of patients who were ROS1 TKI-naïve and 28% of patients with prior ROS1 TKI, respectively). In patients with a prior ROS1 TKI, most patients had pretreatment with crizotinib and solvent front mutations were the most frequently identified resistance mutations at baseline (Table 2). The trial was conducted at 152 sites in the US, UK, Canada, the European Union, and Asia (China, Japan, South Korea, Singapore, Hong Kong, and Taiwan), and 35% of patients were treated in the United States (U.S.). Although there is limited knowledge regarding the specific incidence ROS1 rearrangement by race and ethnicity, there appears to be a slight Asian predominance in patients with ROS1-positive NSCLC; the demographic and baseline disease characteristics of the primary efficacy population are generally representative of US patients.

Table 1:

Demographics and Baseline Characteristics

	ROS1-positive NSCLC with no prior ROS1 inhibitor	ROS1-positive NSCLC with a prior ROS1 inhibitor
	Total (N = 71)	Total (N = 56)
Age (years)
Median	57.0	57.0
Min, Max	28, 80	33, 78
Sex, n (%)
Female	43 (60.6)	38 (67.9)
Male	28 (39.4)	18 (32.1)
Race, n (%)
Asian	48 (67.6)	27 (48.2)
White	18 (25.4)	25 (44.6)
Black or African American	1 (1.4)	1 (1.8)
Native Hawaiian or Other Pacific Islander	1 (1.4)	1 (1.8)
Not Reported/Unknown	3 (4.2)	2 (3.6)
Ethnicity, n (%)
Hispanic or Latino	3 (4.2)	1 (1.8)
Not Hispanic or Latino	68 (95.8)	53 (94.6)

Source: U.S. Food and Drug Administration. NDA Multi-disciplinary Review and Evaluation and Approval packages, repotrectinib.²¹

Table 2:

Pathology and Disease Characteristics

	TKI-Naïve ROS1-positive NSCLC (Pooled EXP-1)	TKI-Pretreated ROS1-positive NSCLC (Pooled EXP-4)
	Total (N = 71)	Total (N = 56)
Histology, n (%)
Adenocarcinoma	69 (97.2)	53 (94.6)
Adenosquamous carcinoma	1 (1.4)	1 (1.8)
Squamous	1 (1.4)	1 (1.8)
Mucoepidermal carcinoma	0	1 (1.8)
Disease at Study Entry
Metastatic	67 (94.4)	55 (98.2)
Locally Advanced	4 (5.6)	1 (1.8)
Brain Metastasis by BICR, n (%)
Yes	18 (25.4)	24 (42.9)
No	53 (74.6)	32 (57.1)
Prior Therapy, n (%)
Prior TKI Therapy	0	56 (100.0)
Platinum-based Chemotherapy	20 (28.2)	0
Immunotherapy Alone	2 (2.8)	0
Other Targeted Therapy	1 (1.4)	0
Prior TKI Therapy, n (%)
Crizotinib	NA	46 (82.1)
Entrectinib	NA	9 (16.1)
Ceritinib	NA	1 (1.8)
Resistance Mutations, n (%)
Solvent Front (G2032R)	NA	6 (10.7)
Gatekeeper (L2026M)	NA	1 (1.8)
Other (S1986F/Y)	NA	1 (1.8)
Not Detected/QC Failure	NA	5 (8.9)
Not tested	NA	43 (76.8)

Source: U.S. Food and Drug Administration. NDA Multi-disciplinary Review and Evaluation and Approval packages, repotrectinib.²¹

Abbreviations: BICR: Blinded Independent Central Review, EXP: expansion cohort, max: maximum, min: minimum, NA: Not Applicable, NSCLC: non-small cell lung cancer, ROS1: receptor tyrosine kinase encoded by the ROS1 gene, TKI: tyrosine kinase inhibitor.

Notes: Data cutoff date of June 20, 2022.

Efficacy results

Among the 71 ROS1 TKI-naïve patients, the ORR was 79% (95% CI 68, 88). The median duration of response was 34.1 months (95% CI 26, NE); 70% of responders had a DOR ≥ 12 months (Table 3). Eight of the 71 patients had measurable CNS metastases at baseline as assessed by BICR. Responses in measurable intracranial lesions were observed in 7 of 8 patients. Interpretation of data for intracranial response is limited by small sample size, and the administration of brain irradiation in three responding patients, including 2 patients who received brain irradiation within 60 days of initiating repotrectinib.

Table 3:

Efficacy Results Based on Independent Review in the TRIDENT-1 Study

Efficacy Parameters	ROS1 Inhibitor Naïve Patients (N=71)	ROS1 Inhibitor Pretreated Patients (N=56)
Confirmed Overall Response Rate, % (95% CI)	79% (68, 88)	38% (25, 52)
Complete Response	6%	5%
Partial Response	73%	32%
Duration of Response (DOR)a
Median in Months (95% CI)b	34.1 (25.6, NE)	14.8 (7.6, NE)
Range (months)	1.4+, 42.4+	3.6, 22.9+
% DOR ≥12 monthsc	70	48

Abbreviations: CI: confidence interval, NE: not evaluable, and “+” indicates ongoing response

^aDOR results are based on the updated data as of December 19, 2022.

^bMedian DOR (95% CI) are based on Kaplan-Meier estimates.

^cDOR analysis is based on the observed DOR.

Source: U.S. Food and Drug Administration Repotrectinib Label (USPI).¹⁵

Among the 56 patients previously treated with a ROS1 TKI, the ORR was 38% (95% CI 25, 52), with a median duration of response of 14.8 months (95% CI 7.6, NE); 48% of responders had a DOR ≥ 12 months (Table 3). Twelve had measurable CNS metastases at baseline as assessed by BICR, with 5 responses in measurable intracranial lesions were observed. Two patients who demonstrated an intracranial response had received prior brain irradiation, both within 60 days of initiating repotrectinib. Eight patients who had received 1 prior ROS1 TKI had ROS1 resistance mutations following TKI therapy. Responses were observed in 6 of these 8 patients; responders included patients with solvent front (G2032R), gatekeeper (L2026M), and other mutations (S1986F/Y). The interpretation of data for intracranial responses and responses in patients with ROS1 resistance mutations is limited by small sample size.

The efficacy results demonstrate clinically meaningful durable antitumor activity of repotrectinib in both ROS1 TKI-naïve and ROS1 TKI-pretreated (1 prior ROS1 TKI with no chemotherapy or immunotherapy) patients with ROS1-positive NSCLC. The efficacy of repotrectinib was consistent across prespecified subgroups (in patients with CNS metastasis and resistance mutations) and supported by sustained durability of responses given an additional 6 months of follow-up, providing substantial evidence of antitumor activity over time. Efficacy was generally consistent across subgroups by age, sex, and race without meaningful differences in durable responses.

Safety Results

The safety review evaluated primary safety data from a pooled safety population consisting of 351 patients with ROS1-positive NSCLC and other solid tumors who received repotrectinib as a single agent dosed at the RP2D, 160 mg orally once daily for 14 days, then increased to 160 mg twice daily, until disease progression or unacceptable toxicity in the TRIDENT-1 trial.

A focused safety evaluation was performed in 264 patients with ROS1-positive NSCLC, including patients in the primary efficacy population and those who had received alternative prior therapy (e.g., ROS1 TKI pretreatment with platinum-based chemotherapy or two prior ROS1 TKIs). There were similar characteristics and rates of common and serious adverse events (AEs) between the total and disease-specific safety populations. In the total population who received the RP2D, Grades 3-4 treatment emergent adverse events (TEAEs) were observed in 44% of patients. Grade 5 (fatal) TEAEs occurred in 4.8% of patients receiving the RP2D. Twenty-four (5%) patients in the total RP2D population were reported to have a TEAE with fatal outcome; these TEAEs included cardiac arrest, death, hypoxia, pneumonia, pneumonia aspiration, cardiac failure, disseminated intravascular coagulation, dyspnea, respiratory failure, sudden cardiac death, sudden death, and tremor.

Among the ROS1-positive NSCLC safety population of 264 patients, 52% were exposed to repotrectinib for at least 6 months, and 27% were exposed for greater than 1 year. Serious adverse reactions occurred in 33% of patients who received repotrectinib, with fatal adverse reactions occurring in 4.2%. Permanent discontinuation of repotrectinib was required due to dyspnea, pneumonitis, and muscular weakness. Dosage interruptions of repotrectinib were due to CNS toxicity, dyspnea, and muscular weakness. Dose reductions of repotrectinib occurred due to dizziness. The most common adverse reactions (≥10%) are included in Table 4, which summarizes adverse reactions observed in the TRIDENT-1 trial.

Table 4:

Adverse Reactions (≥10%) in Patients with ROS1-positive NSCLC Who Received Repotrectinib in TRIDENT-1

Adverse Reaction1	Repotrectinib N=264
	All Grades (%)	Grade 3 or 4 (%)
Nervous System Disorders
Dizzinessa	63	1.9
Dysgeusiab	48	0
Peripheral neuropathyc	47	1.9
Ataxiad	28	0.4
Cognitive disorderse	23	0.8
Headachef	19	0
Gastrointestinal Disorders
Constipation	36	0
Nausea	19	0.4
Diarrhea	13	0.4
Vomiting	10	0.8
Respiratory, Thoracic, and Mediastinal Disorders
Dyspneag	30	7
Coughh	14	0
General Disorders
Fatiguei	24	1.1
Edemaj	12	0.8
Musculoskeletal and Connective Tissue Disorders
Muscular weakness	21	1.5
Myalgiak	12	0.4
Metabolism and Nutritional
Increased weight	14	1.9
Eye Disorders
Vision disordersl	11	0

¹Based on NCI CTCAE v4.03

Source: U.S. Food and Drug Administration Repotrectinib Label (USPI).¹⁵

^aIncludes terms dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional

^bIncludes terms dysgeusia, ageusia, anosmia, hypogeusia

^cIncludes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia

^dIncludes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia

^eIncludes terms memory impairment, disturbance in attention, cognitive disorder, confusional state, amnesia, attention deficit hyperactivity disorder, delirium, altered state of consciousness, aphasia, delusion, depressed level of consciousness, hallucination, mental status changes, neurological decompensation

^fIncludes terms headache, migraine, tension headache

^gIncludes terms dyspnea and dyspnea exertional

^hIncludes terms productive cough, cough, and upper-airway cough syndrome

ⁱIncludes terms fatigue and asthenia

^jIncludes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema

^kIncludes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain

^lIncludes terms vision blurred, dry eye, visual impairment, visual field defect, cataract, conjunctivitis, eye pain, photophobia, photosensitivity reaction, visual acuity reduced, vitreous floaters, blepharospasm, color blindness, diplopia, eye hematoma, eye swelling, eyelid disorder, eyelid injury, eyelids pruritus, glaucoma, night blindness, ophthalmic herpes zoster

There were no significant safety concerns identified during application review requiring risk management beyond labeling or warranting consideration for a Risk Evaluation and Mitigation Strategy (REMS). Warnings and Precautions include: CNS adverse reactions; interstitial lung disease (ILD) and pneumonitis; hepatotoxicity; myalgia with Creatine Phosphokinase (CPK) elevation; hyperuricemia; skeletal fractures; and fetal harm when administered to a pregnant woman.

Ocular toxicity is a known effect of drugs in this class, and there was a signal of visual adverse events in the clinical trial. Among the 351 patients treated with repotrectinib at the RP2D, vision disorders occurred in 12%, including Grade 3 to 4 in 0.3%. Most visual disorder AEs were reported as low grade. Eye and vision exams were not included in the TRIDENT-1 protocol and vision disorders were thus not adequately characterized in the safety dataset. A post-marketing requirement (PMR) was issued to conduct a prospective study to evaluate risk factors, manifestations, and outcomes associated with the potential safety signal of serious ocular toxicity with repotrectinib in patients with ROS1-positive NSCLC or other solid tumors on study.¹⁸

Regulatory Insights

FDA’s approval of repotrectinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC represents the first approval of a ROS1 TKI where evidence of efficacy for both ROS1 TKI-naïve and -pretreated populations is included in the U.S. prescribing information. The presentation of data describing efficacy outcomes in patients who received prior crizotinib or entrectinib reflects the changing landscape of available therapies for patients with ROS1-positive NSCLC since the approvals of other ROS1 TKIs and provides valuable information for clinicians with patients with progression on prior ROS1-directed therapy.

The high response rate with durable responses in adult patients with ROS1-positive NSCLC treated with repotrectinib represents evidence of clinical benefit of repotrectinib in this population. A clinically meaningful and durable ORR was observed among adult patients with locally advanced or metastatic ROS1-positive NSCLC who were ROS1 TKI-naïve and ROS1 TKI-pretreated. Key considerations in the review of the application included assessment of the benefit of repotrectinib in patients with prior ROS1 TKI therapy, CNS metastases, and ROS1 resistance mutations. Subgroup analyses, while based on limited numbers of patients, indicated clinically meaningful activity in patients with CNS metastases and in patients with ROS1 resistance mutations following prior ROS1 TKI therapy. The efficacy population results are considered to be sufficient to establish clinical benefit in this genetically defined, rare subgroup of patients with ROS1-positive metastatic NSCLC. FDA also considered that the body of nonclinical evidence and data supporting approvals of in-class ROS1 TKIs support the mechanistic use of repotrectinib as a single agent in the ROS1-positive NSCLC population.

Randomized controlled designs are the gold standard to demonstrate evidence of safety and efficacy, allowing for assessment of comparative safety and time to event endpoints. However, compelling results from single-arm trials evaluating ORR and DOR have led to both accelerated and traditional FDA approvals depending on the magnitude of effect and clinical context. Traditional approvals based on single arm data are generally only considered for high and durable response rates in rare, molecularly defined populations with limited treatment options.^19,20 Objective response rate and DOR data from single arm trials have been used to support accelerated approvals when there is a need for additional evidence of an effect on long-term outcome, or further evidence of durability of responses to support a traditional approval. For this application, similar to applications for other ROS1 TKIs, FDA considered that given the rarity of ROS1-positive NSCLC, the conduct of a randomized trial to adequately evaluate an effect on a time-to event endpoint in such a disease setting may be challenging, requiring a large number of patients, prolonged trial length, or both. Further, the high response rate and in particular, the durability of response, observed in TRIDENT-1 was considered evidence of a meaningful benefit to patients, and sufficient to support a traditional approval.

Based on the described efficacy and safety results, the potential for clinical benefit outweighs the risks of repotrectinib identified during review (Table 5).²¹ The clinical study is ongoing as of the time of this approval summary, and a post-marketing commitment (PMC) was issued to provide final results from TRIDENT-1 to further characterize the clinical benefit of repotrectinib for the treatment of adult patients with ROS1-positive metastatic NSCLC by providing a more precise estimation of the BICR-assessed ORR and DOR.

Table 5:

FDA Benefit-Risk Analysis

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	• ROS1 rearrangement occurs in 1 to 2% of NSCLC.2 • Overall survival (OS) for patients with NSCLC at 5-years has been reported as 22% and between 5.5% to 8% in the metastatic setting.4,5 Patients with or without ROS1-positive NSCLC have similar outcomes.4	Locally advanced or metastatic ROS1-positive NSCLC is a life-threatening condition with poor survival.
Current Treatment Options	• ROS1 TKI therapy is the current standard of care for the treatment of advanced or metastatic ROS1-positive NSCLC.7 • Two products are approved for patients with advanced or metastatic ROS1-positive NSCLC; the response rate included in the product label is 66% (95% CI 51, 79) for crizotinib and is 74% (95 CI 64, 83) for entrectinib. • There are resistance mechanisms to TKIs for ROS1-positive NSCLC; common ROS1-resistance mutations include G2032R, D2033N, and S1986F.8 • Currently, there are no approved targeted therapies in patients previously treated with ROS1 TKI.	Although there are approved therapies for advanced or metastatic ROS1-positive NSCLC, patients may experience drug-related toxicity or their disease may develop resistance mechanisms. Therefore, there is an unmet medical need for adult patients with ROS1-positive NSCLC.
Benefit	• The primary efficacy data supporting this NDA is derived from the TRIDENT-1 Study, an open-label, multi-center, first-in-human study of repotrectinib conducted in adult patients with ROS1-positive NSCLC who were either ROS1 TKI naïve or who had received prior ROS1 therapy. • Among the ROS1 TKI-naïve patients, the ORR was 79% (95% CI 68, 88). The median duration of response was 34.1 months (95% CI 26, NE). In addition, seven out of 8 patients with measurable CNS metastases at baseline had responses in intracranial lesions. • Among the patients who had received 1 prior ROS1 TKI (crizotinib 82%, entrectinib 16%, and other 2%) with no prior platinum-based chemotherapy or immunotherapy, the ORR was 38% (95% CI 25, 52). The median duration of response was 14.8 months (95% CI 7.6, NE). Five of twelve patients with measurable CNS metastases at baseline had responses in intracranial lesions. • Eight of fifty-six patients who had received 1 prior ROS1 TKI had resistance mutations following TKI therapy. Responses were observed in 6 of these 8 patients.	Based on the observed durable ORR, nonclinical, and supportive mechanistic data, the submitted evidence meets the statutory evidentiary standard for traditional approval. A PMR has been issued to obtain the final ORR and DOR in the ROS1 TKI-naive and ROS1 TKI-pretreated patients with ROS1-positive NSCLC enrolled on TRIDENT-1.
Risk and Risk Management	• The pooled safety population for this NDA includes 351 adult patients advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements who received at least one dose of repotrectinib at the RP2D. • The most common (> 20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%), decreased sodium (3.5%), increased AST (2.9%), increased magnesium (2.9%), increased alkaline phosphatase (2.6%), and increased glucose (2%).	The observed safety profile is acceptable in the context of the treatment of patients with ROS1-positive NSCLC and is overall consistent with the known adverse effects of in-class drug products. There were no significant safety concerns identified during NDA review requiring risk management beyond labeling or warranting consideration for a Risk Evaluation and Mitigation Strategy (REMS). PMRs to address issues related to treatment toxicity with repotrectinib include studies to assess the risk of ocular toxicity, to address the impact of moderate or severe hepatic impairment, and to assess the risk of drug-drug interactions.

Source: Adapted from U.S. Food and Drug Administration, NDA Multi-disciplinary Review and Evaluation and Approval Package: repotrectinib (Augtyro^®).²¹

At the time of approval, a companion diagnostic for repotrectinib was under development but not yet available. Local tests to identify ROS1 fusions may be utilized pending availability of a formal companion diagnostic, and there is strong evidence supporting clinically meaningful and durable responses; therefore, FDA considers that repotrectinib should be approved with the approved post-marketing commitments. The product labeling reflects the lack of an approved companion diagnostic for the selection of patients for treatment with repotrectinib. A PMC was issued for the development of an in vitro diagnostic device in support of the safe and effective use of repotrectinib for the treatment of adult patients with ROS1-positive NSCLC.

Based on the amendment to the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c)²², the FDA Reauthorization Act of 2017 (FDARA) (Amendments to Sec. 505B of the FD&C Act)²³ an investigation of repotrectinib, which is a targeted therapy with a molecular target relevant to pediatric cancers, is required in the pediatric cancer population. Thus, FDA issued a PMR with this approval to conduct an assessment of the safety, PK and efficacy of repotrectinib in pediatric patients with advanced or metastatic solid tumors including CNS tumors, and patients with anaplastic large cell lymphoma, with ALK, ROS1 or NTRK alterations. Prior to enactment of FDARA, FDA would not have been able to require a study in pediatric patients, as PREA would require an indication-based study, e.g., in NSCLC, which occurs very rarely in children and would be considered infeasible. Therefore, this required study of repotrectinib under FDARA is an example of the enhanced ability of the FDA to require evaluation of relevant targeted therapies in children with cancer.²⁴

Conclusion

Repotrectinib is the first approval of a targeted therapy for patients with ROS1-positive NSCLC that formally includes a dedicated assessment in patients who have received prior ROS1 TKI therapy in labeling. In addition, repotrectinib has been shown to have clinically meaningful activity in patients with CNS metastasis and common ROS1 resistance mutations. This approval provides an important treatment option for patients with metastatic and advanced ROS1-positive NSCLC with or without CNS metastasis or resistance mutations and who have received prior ROS1 TKI therapy, addressing a significant unmet medical need in this rare disease population.