14 CLINICAL STUDIES

The efficacy of VITRAKVI was evaluated in pediatric and adult patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label, single-arm clinical trials: Study LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease.

Adult patients received VITRAKVI 100 mg orally twice daily and pediatric patients (18 years or younger) received VITRAKVI 100 mg/m2 up to a maximum dose of 100 mg orally twice daily until unacceptable toxicity or disease progression. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) (89%), fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR). NTRK gene fusions were inferred in 14 patients who had a documented ETV6 or NTRK 3 translocation identified by FISH. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.

The assessment of efficacy was based on 339 patients with solid tumors with an NTRK gene fusion enrolled across the three clinical trials. Baseline characteristics were: median age 38 years (range: 18 days to 90 years); 39% <18 years of age; 51% female; 57% White, 28% Asian, 2.4% Black or African American; 6% Hispanic or Latino and ECOG performance status (PS) 0-1 (88%) or 2 (10%). Sixty-three percent of patients had metastatic disease, including patients with brain metastases, and 22% had locally advanced, unresectable disease. Ninety-two percent of patients had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy, including RAI. Seventy percent of all patients had received prior systemic therapy in the unresectable or metastatic setting excluding RAI; 30% were treatment naive, 33% had received 1 prior therapy and 37% percent had received 2 or more prior therapies with a median of one prior systemic regimen.

Efficacy results are summarized in Tables 5, 6, and 7.

Table 5 Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions
Efficacy Parameter	VITRAKVI N = 339
+ Denotes ongoing response.
* 5% were pathological complete response. Patients undergoing a surgical resection whose post-operative pathologic assessment showed no viable tumor cells and negative margins were pathological complete responders provided that no other sites of disease were present. † Kaplan-Meier estimates ‡ NE: Not evaluable
Overall response rate (95% CI)	60% (55%, 65%)
Complete response rate	24%*
Partial response rate	36%
Duration of response (DOR)	N = 204
Median (months) (95% CI)	43.3† (32.5, NE‡)
Range (months)	0.0+, 73.7+
% with Observed DOR> 12 months	64%
% with Observed DOR> 24 months	45%

Table 6 Efficacy Results by Tumor Type
Tumor Type	Patients (N=339)	ORR		DOR Range (months)
Tumor Type	Patients (N=339)	%	95% CI	DOR Range (months)
NA = not applicable due to small numbers or lack of response; NE = not evaluable; SD = stable disease; PD = progressive disease. + Denotes ongoing response.
* Observed values at data cutoff, not a range. † Colorectal Tumor Type includes 23 colon cancers and 1 rectal cancer.
Soft tissue sarcoma	70	70%	(58%, 80%)	0.0+, 72.7+
Infantile fibrosarcoma	49	94%	(83%, 99%)	1.6+, 73.7+
Primary CNS	49	27%	(15%, 41%)	1.9+, 57.5+
Lung	30	70%	(51%, 85%)	1.9+, 56.2+
Thyroid	30	63%	(44%, 80%)	3.7, 72.4+
Differentiated	23	78%	(56%, 93%)	4.9, 72.4+
Non-differentiated	7	14%	(0%, 58%)	3.7*
Salivary gland	25	84%	(64%, 95%)	7.4, 65.2+
MASC	14	79%	(49%, 95%)	7.7, 59.1
Colorectal†	24	46%	(26%, 67%)	3.9, 45.2+
Breast	14	57%	(29%, 82%)	7.4, 58.2+
Secretory	6	83%	(36%, 100%)	11.1, 58.2+
Non-secretory	8	38%	(9%, 76%)	7.4, 12.5+
Melanoma	11	45%	(17%, 77%)	1.9+, 23.2+
Pancreas	7	14%	(0%, 58%)	5.8*
Gastrointestinal stromal tumor	5	80%	(28%, 99%)	9.5, 50.4+
Cholangiocarcinoma	4	2 SD, 2 NE	NA	NA
Bone sarcoma	3	33%	(1%, 91%)	9.5*
Gastric	3	2 PD, NE	NA	NA
Cancer of unknown primary	2	100%	(16%, 100%)	5.6, 7.4
Congenital mesoblastic nephroma	2	100%	(16%, 100%)	32.9, 44.5
Prostate	2	SD, PD	NA	NA
Appendix	1	SD	NA	NA
Cervix	1	SD	NA	NA
Duodenal	1	PD	NA	NA
Esophageal	1	PD	NA	NA
External auditory canal	1	100%	(3%, 100%)	33.8+*
Hepatic	1	NE	NA	NA
Thymus	1	PD	NA	NA
Urothelial	1	PD	NA	NA
Uterus	1	NE	NA	NA

The ORR for patients with NTRK1 fusions (n=142) was 59% (95% CI: 51, 67), NTRK2 fusions (n=44) was 32% (95% CI: 19, 48) and NTRK3 fusions (n=142) was 67% (95% CI: 59, 75).

Table 7 Efficacy Results by NTRK Fusion Partner
NTRK Partner*	Patients (N=339)	ORR		DOR Range (months)
NTRK Partner*	Patients (N=339)	%	95% CI	DOR Range (months)
PD = progressive disease; SD = stable disease; NA = not applicable. + Denotes ongoing response.
* Includes fusion partners which are represented by 3 or more patients in the efficacy analysis set. Does not represent all potential fusion partners. † Observed values at data cutoff, not a range.
ETV6-NTRK3	102	80%	(71%, 88%)	0.0+, 66.7+
TPM3-NTRK1	63	67%	(54%, 78%)	0.8+, 73.7+
LMNA-NTRK1	29	69%	(49%, 85%)	3.4, 70.7+
Inferred ETV6-NTRK3	14	93%	(66%, 100%)	1.6+, 73.4+
TPR-NTRK1	10	60%	(26%, 88%)	3.0+, 38.7+
EML4-NTRK3	6	50%	(12%, 88%)	7.9, 40.7+
IRF2BP2-NTRK1	4	100%	(40%, 100%)	3.7, 47.8+
BCR-NTRK2	3	67%	(9%, 99%)	9.2+, 11.0
GKAP1-NTRK2	3	2 SD, 1 PD	NA	NA
NACC2-NTRK2	3	33%	(1%, 91%)	3.7†
RBPMS-NTRK3	3	67%	(9%, 99%)	3.3+, 23.0
SQSTM1-NTRK1	3	67%	(9%, 99%)	9.9, 12.9+