Transforming approaches to treating TRK fusion cancer: historical comparison of larotrectinib and histology-specific therapies

Figures & data

Table 1. Global incidence and NTRK gene fusion frequency amongst the 7 tumor types included in this analysis.

Tumor type	Global incidence, 2018^a,^17	NTRK gene fusion frequency (%)
NSCLC	2,093,876	0.2^18
CRC	1,800,977	0.5^19
Thyroid	567,233	2–26^b,^20–24
Gliomas	296,851	0.6–25^c,^19^,^25
Salivary gland cancer	NR	50^d,^26
Non-GIST STS	NR	0.97^19
IFS	NR	91^e,^27–30

^aAs reported in by IARC, Globocan 2018.

^bNTRK gene fusion frequency varies in thyroid cancer as patients with iodizing radiation exposure and pediatric patients appear to have a higher frequency of NTRK gene fusions.

^cNTRK gene fusion frequency varies in patients with gliomas as certain pediatric gliomas have been associated with a higher frequency of NTRK gene fusions (ranging from 5% to 25%); whereas the frequency of NTRK gene fusions in adult gliomas has been reported at <1% to-date.

^dIn an analysis of 30 tumor samples from patients with mammary analog secretory carcinoma of the salivary gland, 15 patients had ETV6-NTRK3 gene fusions, whereas 10 harbored ETV6-RET fusions and four cases had no result of rearrangements/fusions (1 result was unanalyzable).

^dIFS is characterized by the ETV6-NTRK gene fusion; however, recent data has shown that other genes may be involved, including other NTRK gene fusions.

Abbreviations. CRC, colorectal cancer; GIST, gastrointestinal stromal tumor; IARC, International Agency for Research on Cancer; IFS, infantile fibrosarcoma; NSCLC, non-small cell lung cancer; NTRK, neurotrophic receptor tyrosine kinase; STS, soft tissue sarcoma.

Table 2. Efficacy of historical tumor histology-specific treatments.

Tumor type	Historical treatments^a					Larotrectinib^3^,^31^,^32^,^33
	Treatment line	N	ORR (%)	Median PFS (months)	Median OS (months)	Data cutoff date: 30 July 2018^b		Data cutoff date: 19 February 2019^c
						N	ORR (%)	N	ORR (%)
NSCLC	Second^d					7	71	12	75
	Chemotherapy^34–57	19–625	2.7–24	2.5–4.2	4.7–12.2
	Chemotherapy + VEGF inhibitor^41^,^42^,^53^,^54	76–628	23–28.9	4.5–5.8	10.5–15.2
	Immunotherapy^34–40	135	20	3.5	9.2
	Second or further^e
	Chemotherapy^37–39^,^58–72	33–612	4.3–25.5	2.5–4.3	5.9–16
	Immunotherapy^37–39^,^58^,^61–63^,^66–69^,^73	76–613	13.7–19	2.3–not reached	12.2–not reached
CRC	First or further^f					6	33	8	50
	Chemotherapy^74	205	NR	NR	16.2–16.4
	Second^g
	Chemotherapy^75–82	17–614	11–28.5	3–10.5	4–15.5
	Chemotherapy + VEGF inhibitor^75^,^76^,^78–81^,^83	16–612	13.4–47.7	5.7–8.5	6.7–17
	Second or further^h
	Chemotherapy^84–89	24–291	0–28	1.4–6.2	9.2–14.3
	Chemotherapy + VEGF inhibitor^84	286	22.7	7.3	12.9
	VEGF inhibitor^90^,^91	134–505	1–3.3	1.9–3.2	6.4–10.2
	Third^i
	Chemotherapy^92	91–124	8–9	12.9–13.2	NR
	Third or further^j
	Chemotherapy^92–98	104–534	1–13	2–4.8	7.1–11.4
	VEGF inhibitor^99	136	4	3.2	8.8
Thyroid cancer	First^k					10	70	24	79
	VEGF inhibitor^100^,^101	24–207	12.2	8–11	30–not reached
	Chemotherapy^102–104	9–56	21.4–53	1.6	5.5–6.7
	Surgery + chemotherapy + XRT^105	12–18	55.6–61.1	4	7
	First or further^l
	VEGF inhibitor^106–110	10–17	0–64.8	2.8–18.3	3.7–not reached
	Chemotherapy^111^,^112	11–55	NR	1.6–3.3	4–5.2
	Chemotherapy + XRT^113	19	NR	NR	12
	Second or further^m
	VEGF inhibitor^114	20	NR	1.9	3.9
	Chemotherapy^115	23–34	0	NR	4.7–12.3
Gliomas	First or further^n					9	11	14	36^r
	VEGF inhibitor^116	119	NR	NR	5.2
	VEGF inhibitor + chemotherapy^116	55	NR	NR	11.3
	Second^o
	VEGF inhibitor^117	32	63	23 weeks	NR
	VEGF inhibitor ± chemotherapy^118	40	NR	3.8	6.9
	Second or further^p
	VEGF inhibitor + chemotherapy^119	22	95.2	3	4.6
	Chemotherapy^120–125	15–40	NR	4.6–28	7–19.6
	VEGF inhibitor + XRT^126	14	NR	NR	8.4
	Third or further^q
	VEGF inhibitor^127^,^128	20–31	NR	2.9–8.5	12
	Chemotherapy^129	9	NR	12.4	NR
Salivary gland cancer	First^s					17	88	20	90
	Chemotherapy^130	42	31	6	10
	Second^t
	Chemotherapy^130	18	5	3.5	4
Non-GIST STS	First^u					21	81	36	81
	Chemotherapy^131^,^132	12–34	17.2–44.4	NR	NR
	First or further^v
	Chemotherapy^133	175	13.2	9.4 weeks–26.9 weeks	48 weeks
	mTOR inhibitor^134	29	NR	15.4	NR
	Surgery + chemotherapy + XRT^135	6–8	NR	2.4–3.9	12.7–46.9
	Second or further^w
	VEGF inhibitor^136	5	NR	6.5	8.9
IFS	First^x					13	92	28	96
	Surgery + chemotherapy^137^,^138	6–20	71–88.9	NR	NR

^aTherapies targeted to a specific molecular alteration were excluded from this analysis on the basis that oncogenic drivers appear to be mutually exclusive.

^bTumor histology-specific response rate data from 30 July 2018 data cutoff date are drawn directly from the Vitrakvi (larotrectinib) summary of product characteristics and are independent review committee assessed.

^cTumor histology-specific response data from 19 February 2019 data cutoff date are drawn from Hong et al., 2020 for NSCLC, CRC, thyroid cancer, salivary gland cancer, STS, and IFS and from Drilon et al. 2019 and Doz et al. 2019 for gliomas; these data are investigator assessed.

^dNivolumab; docetaxel; docetaxel + ramucirumab; docetaxel + placebo; pemetrexed; gemcitabine.

^eNivolumab; docetaxel; pemetrexed; atezolizumab; pembrolizumab; BSC.

^fLeucovorin + fluorouracil; FOLFOX; FOLFIRI; investigator’s choice.

^gAflibercept + FOLFIRI; FOLFIRI + placebo; irinotecan; FOLFIRI; FOLFIRI + bevacizumab; ramucirumab + FOLFIRI; FOLFOX; FOLFOX + bevacizumab, bevacizumab; BSC + chemotherapy; chemotherapy + bevacizumab; leucovorin + fluorouracil; investigator’s choice chemotherapy.

^hRegorafenib + BSC; FOLFOX + bevacizumab; FOLFOX; bevacizumab; irinotecan + BSC; irinotecan; FOLFIRI; leucovorin + fluorouracil; oxaliplatin; irinotecan + oxaliplatin.

ⁱLeucovorin + fluorouracil; FOLFOX; FOLFIRI; investigator’s choice chemotherapy.

^jTAS-102 + BSC; regorafenib + BSC, TAS-102, leucovorin + fluorouracil, FOLFOX.

^kSorafenib; paclitaxel; surgery + radiotherapy + docetaxel.

^lSorafenib; lenvatinib; paclitaxel + valproic acid; paclitaxel; fosbretabulin + paclitaxel/carboplatin; paclitaxel/carboplatin; pazopanib; doxorubicin + radiotherapy.

^mSorafenib; fosbretabulin.

ⁿBevacizumab monotherapy; bevacizumab + irinotecan.

^oBevacizumab monotherapy; bevacizumab + carboplatin; bevacizumab + dasatinib; bevacizumab + irinotecan; bevacizumab + lomustine; bevacizumab + temozolomide.

^pRe-irradiation with external beam radiation therapy; bevacizumab + re-irradiation with external beam radiation therapy; temozolomide; carmustine; procarbazine, lomustine, + vincristine; bevacizumab; temozolomide + VT-122.

^qBevacizumab.

^rThe 24-week disease control rate (defined as complete response + partial response + stable disease) for this population with primary CNS tumors was 71%.

^sCisplatin + vinorelbine.

^tCisplatin + vinorelbine.

^uIfosfamide + doxorubicin; ifosfamide + etoposide; mesna + filgrastim + dexrazoxane; ifosfamide, vincristine, + dactinomycin; vincristine, dactinomycin, + cyclophosphamide; vincristine, dactinomycin, ifosfamide, + doxorubicin; cyclophosphamide monotherapy; methotrexate + vinblastine with or without dexamethasone; other systemic anti-inflammatory drugs.

^vMultiple interventions including surgery, radiotherapy, and chemotherapy.

^wPazopanib.

^xSurgery + chemotherapy; chemotherapy.

Abbreviations. BSC, best supportive care; CRC, colorectal cancer; FOLFIRI, fluorouracil, leucovorin, irinotecan; FOLFOX, fluorouracil, leucovorin, oxaliplatin; FUOX, high-dose fluorouracil plus oxaliplatin; IFS, infantile fibrosarcoma; NR, not reported; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; STS, soft tissue sarcoma; VEGF, vascular endothelial growth factor.

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Data availability statement

Review article; no data/results provided in this publication.