Commentary

‘Cancer-agnostic’ NTRK inhibitor approval ushers in paradigm of personalized genomics-guided therapeutics

On Nov. 26, the FDA announced the accelerated approval of larotrectinib as the first small molecule inhibitor for use in a “cancer-agnostic” manner, in pediatric and adult human cancers that harbor neurotrophic receptor tyrosine kinase gene fusions.

This marks an important milestone in the history of targeted drug development. This landmark approval has been touted as ushering in a new paradigm in genomics-guided molecular therapeutics.

The neurotrophic receptor tyrosine kinase (NTRK) genes NTRK1, NTRK2 and NTRK3 encode the tropomyosin receptor kinase (TRK) proteins TRKA, TRKB and TRKC, respectively. NTRK gene expression is primarily limited within the human nervous system after embryogenesis. The TRKA kinase regulates pain and thermoregulation; TRKB regulates movement, memory, mood and appetite; and TRKC regulates proprioception.

Incidence

Aligning with the recent emerging theme that oncogenic kinase fusions are more common and important in solid tumors than previously understood, NTRK fusions have been found to be ubiquitous in diverse human cancer types, including both pediatric and adult cancers. The resultant TRK-fusion oncoproteins become overexpressed and constitutively activated to dysregulate downstream cellular signaling, acting as a “driver” in an oncogene-addictive fashion.

Patrick C. Ma
Patrick C. Ma

NTRK fusion is indeed quite rare, accounting for only up to about 1% of all solid cancers. However, it is implicated in up to 20 different cancer types, albeit in low frequencies of NTRK-fusion occurrence (less than 5%), with many cancer types being quite common — eg, lung adenocarcinoma, large cell neuroendocrine cancer of the lung, colorectal cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, sarcoma, melanoma and brain cancers.

Yet interestingly enough, NTRK fusions can also be found highly enriched (more than 75%) in some rare cancer types — eg, infantile fibrosarcoma, mammary analog secretory carcinoma of the salivary gland and secretory breast cancer. NTRK fusions can be found in 5% to 25% of papillary thyroid cancer, congenital mesoblastic nephroma, Spitz tumor and pontine glioma cases.

Thus, in laymen’s terms, NTRK fusion is a unique orphan molecular entity in that although “it is rare, it can be also found everywhere.” This has immense implications impacting our modern-day practice of cancer genomics-guided molecular targeted therapy.

Cancer genomics of NTRK

Aberrations in NTRK genes include gene fusions, mutations, genomic amplifications and protein overexpression.

NTRK amplification has been reported in 31% of neuroendocrine prostate cancers, 19% of pancreas cancers, 9% of breast and liver cancers, and 6% of lung adenocarcinomas. NTRK mutations have also been found in 36% of cutaneous squamous cell carcinomas, 18% of melanomas, 13% of lung adenocarcinomas and 2% of breast cancers, according to data in cBioPortal.

NTRK gene fusions have been reported in sarcoma at an 0.8% incidence rate, bladder cancer at 0.5% and lung adenocarcinoma at 0.2%, among others. To date, among all of the aberrations, NTRK fusion is the most validated mechanism of oncogenic transformation.

Multiple fusion partners have been identified in NTRK fusion. Reported examples include ETV6-NTRK3, EML4-NTRK3, STRN-NTRK2, TPM3-NTRK1, LMNA-NTRK1, TPR-NTRK1 and SQSTM-NTRK1, to name a few.

New paradigm of drug development

FDA based the approval of larotrectinib (Vitrakvi; Bayer, Loxo Oncology) on the integrated analysis of three multicenter, open-label, single-arm clinical studies — a phase 1 study involving adults with advanced solid tumors (LOXO-TRK-14001; n = 8), a pediatric phase 1/phase 2 study (SCOUT; n = 12), and phase 2 “basket” study involving adolescents and adults (NAVIGATE; n = 35).

Drilon and colleagues reported results of the pooled analysis of the first 55 consecutive patients enrolled in these studies, with ages ranged from 4 months to 76 years. The population comprised 17 diverse cancer types. A majority of patients had NTRK1 and NTRK3 fusions, which researchers identified with next-generation sequencing or fluorescence in situ hybridization.

The overall response rate was 75% according to independent review and 80% according to the investigators’ assessment, with a 13% complete response rate and a 62% partial response rate. Seven patients (13%) had stable disease. The median time to response was 1.8 months.

The FDA approval statement cited a complete response rate of 22% and partial response rate of 53%. Median PFS and duration of response had not been reached. Fifty-five percent of all patients remained progression free at 1 year. The drug was found to be very tolerable.

FDA granted accelerated approval to larotrectinib as a treatment for adults and children with solid tumors that have NTRK gene fusions without a known acquired resistance mutation; that are metastatic or where surgical resection is likely to result in severe morbidity; and that have no satisfactory alternative treatments or have progressed following treatment. Thus, in the appropriate clinical setting, larotrectinib can be used within FDA indication as first-line therapy.

This is the first small molecule-targeted therapeutic that is approved by FDA for use in a “cancer-agnostic” biomarker-guided fashion. Another similar scenario is the approval of the PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda, Merck) for patients with cancer with a biomarker of DNA mismatch-repair deficiency.

Implications, impact on targeted therapy, tumor molecular profiling

The approval of larotrectinib provides new insights into the development of personalized cancer genomics-guided molecular-targeted therapy.

We now witness a novel paradigm-changing drug approval of larotrectinib as treatment for NTRK fusion-positive solid tumors with remarkable efficacy and durable responses. There are likely more similar molecular “driver” targets awaiting further discovery.

Larotrectinib’s approval also lends further support to the relevance of molecular-genomic classification in addition to histologic/anatomic cancer classification. Importantly, the observed responses in the larotrectinib registration clinical studies were found “agnostic” to age, sex, anatomic/histologic cancer types and molecular fusion partners of NTRK.

The recognition of the high frequency of NTRK fusions in some rare forms of orphan cancer types certainly is a game-changer for these patients at the dawn of this landmark FDA approval of larotrectinib.

Conversely, the fact that NTRK fusions — as highly “actionable” drivers — can be found in diverse and common cancer types, albeit at low frequencies as an orphan target, strongly argues for adoption of comprehensive tumor molecular profiling as part of standard of care.

The FDA should also be applauded for the highly adoptive performance, not only in catching up with the new paradigm of molecular oncology and therapeutics development, but also for demonstrating leadership in implementing regulatory and approval evolutionary changes to ensure our cancer patients receive beneficial therapeutics for their disease at the earliest time and in the best possible manner.

References:

André F, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1716821.

Doebele RC, et al. Cancer Discov. 2015; doi:10.1158/2159-8290.CD-15-0443.

Drilon A, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1714448.

Farago AF and Azzoli CG. Transl Lung Cancer Res. 2017;doi:10.21037/tlcr.2017.08.02.

Le DT, et al. N Engl J Med. 2015; doi:10.1056/NEJMoa1500596.

For more information:

Patrick C. Ma, MD, MSc, is director of the lung cancer program and co-leader of the Sara Crile Allen and James Frederick Allen Lung Cancer Program at West Virginia University Cancer Institute and Mary Babb Randolph Cancer Center of WVU Medicine. He can be reached at West Virginia University, 64 Medical Center Drive, P.O. Box 9300, HSS 1814, Morgantown, WV 26506; email: pcma@hsc.wvu.edu.

Disclosure: Ma reports advisory board/committee roles with AstraZeneca, Caris Life Sciences, Cymeta Biopharmaceutical and Takeda; speakers bureau roles wtih AstraZeneca, Bayer, Bristol-Myers Squibb, Merck and Takeda; and research funding to his institution from AbbVie, AstraZeneca, Bristol-Myers Squibb, CBT Pharmaceuticals, Cymeta Biopharmaceutical, EpicentRx, Incyte, Loxo Oncology, MedImmune, Pfizer, Spectrum, Tesaro and Xcovery.

On Nov. 26, the FDA announced the accelerated approval of larotrectinib as the first small molecule inhibitor for use in a “cancer-agnostic” manner, in pediatric and adult human cancers that harbor neurotrophic receptor tyrosine kinase gene fusions.

This marks an important milestone in the history of targeted drug development. This landmark approval has been touted as ushering in a new paradigm in genomics-guided molecular therapeutics.

The neurotrophic receptor tyrosine kinase (NTRK) genes NTRK1, NTRK2 and NTRK3 encode the tropomyosin receptor kinase (TRK) proteins TRKA, TRKB and TRKC, respectively. NTRK gene expression is primarily limited within the human nervous system after embryogenesis. The TRKA kinase regulates pain and thermoregulation; TRKB regulates movement, memory, mood and appetite; and TRKC regulates proprioception.

Incidence

Aligning with the recent emerging theme that oncogenic kinase fusions are more common and important in solid tumors than previously understood, NTRK fusions have been found to be ubiquitous in diverse human cancer types, including both pediatric and adult cancers. The resultant TRK-fusion oncoproteins become overexpressed and constitutively activated to dysregulate downstream cellular signaling, acting as a “driver” in an oncogene-addictive fashion.

Patrick C. Ma
Patrick C. Ma

NTRK fusion is indeed quite rare, accounting for only up to about 1% of all solid cancers. However, it is implicated in up to 20 different cancer types, albeit in low frequencies of NTRK-fusion occurrence (less than 5%), with many cancer types being quite common — eg, lung adenocarcinoma, large cell neuroendocrine cancer of the lung, colorectal cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, sarcoma, melanoma and brain cancers.

Yet interestingly enough, NTRK fusions can also be found highly enriched (more than 75%) in some rare cancer types — eg, infantile fibrosarcoma, mammary analog secretory carcinoma of the salivary gland and secretory breast cancer. NTRK fusions can be found in 5% to 25% of papillary thyroid cancer, congenital mesoblastic nephroma, Spitz tumor and pontine glioma cases.

Thus, in laymen’s terms, NTRK fusion is a unique orphan molecular entity in that although “it is rare, it can be also found everywhere.” This has immense implications impacting our modern-day practice of cancer genomics-guided molecular targeted therapy.

Cancer genomics of NTRK

Aberrations in NTRK genes include gene fusions, mutations, genomic amplifications and protein overexpression.

NTRK amplification has been reported in 31% of neuroendocrine prostate cancers, 19% of pancreas cancers, 9% of breast and liver cancers, and 6% of lung adenocarcinomas. NTRK mutations have also been found in 36% of cutaneous squamous cell carcinomas, 18% of melanomas, 13% of lung adenocarcinomas and 2% of breast cancers, according to data in cBioPortal.

PAGE BREAK

NTRK gene fusions have been reported in sarcoma at an 0.8% incidence rate, bladder cancer at 0.5% and lung adenocarcinoma at 0.2%, among others. To date, among all of the aberrations, NTRK fusion is the most validated mechanism of oncogenic transformation.

Multiple fusion partners have been identified in NTRK fusion. Reported examples include ETV6-NTRK3, EML4-NTRK3, STRN-NTRK2, TPM3-NTRK1, LMNA-NTRK1, TPR-NTRK1 and SQSTM-NTRK1, to name a few.

New paradigm of drug development

FDA based the approval of larotrectinib (Vitrakvi; Bayer, Loxo Oncology) on the integrated analysis of three multicenter, open-label, single-arm clinical studies — a phase 1 study involving adults with advanced solid tumors (LOXO-TRK-14001; n = 8), a pediatric phase 1/phase 2 study (SCOUT; n = 12), and phase 2 “basket” study involving adolescents and adults (NAVIGATE; n = 35).

Drilon and colleagues reported results of the pooled analysis of the first 55 consecutive patients enrolled in these studies, with ages ranged from 4 months to 76 years. The population comprised 17 diverse cancer types. A majority of patients had NTRK1 and NTRK3 fusions, which researchers identified with next-generation sequencing or fluorescence in situ hybridization.

The overall response rate was 75% according to independent review and 80% according to the investigators’ assessment, with a 13% complete response rate and a 62% partial response rate. Seven patients (13%) had stable disease. The median time to response was 1.8 months.

The FDA approval statement cited a complete response rate of 22% and partial response rate of 53%. Median PFS and duration of response had not been reached. Fifty-five percent of all patients remained progression free at 1 year. The drug was found to be very tolerable.

FDA granted accelerated approval to larotrectinib as a treatment for adults and children with solid tumors that have NTRK gene fusions without a known acquired resistance mutation; that are metastatic or where surgical resection is likely to result in severe morbidity; and that have no satisfactory alternative treatments or have progressed following treatment. Thus, in the appropriate clinical setting, larotrectinib can be used within FDA indication as first-line therapy.

This is the first small molecule-targeted therapeutic that is approved by FDA for use in a “cancer-agnostic” biomarker-guided fashion. Another similar scenario is the approval of the PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda, Merck) for patients with cancer with a biomarker of DNA mismatch-repair deficiency.

Implications, impact on targeted therapy, tumor molecular profiling

The approval of larotrectinib provides new insights into the development of personalized cancer genomics-guided molecular-targeted therapy.

PAGE BREAK

We now witness a novel paradigm-changing drug approval of larotrectinib as treatment for NTRK fusion-positive solid tumors with remarkable efficacy and durable responses. There are likely more similar molecular “driver” targets awaiting further discovery.

Larotrectinib’s approval also lends further support to the relevance of molecular-genomic classification in addition to histologic/anatomic cancer classification. Importantly, the observed responses in the larotrectinib registration clinical studies were found “agnostic” to age, sex, anatomic/histologic cancer types and molecular fusion partners of NTRK.

The recognition of the high frequency of NTRK fusions in some rare forms of orphan cancer types certainly is a game-changer for these patients at the dawn of this landmark FDA approval of larotrectinib.

Conversely, the fact that NTRK fusions — as highly “actionable” drivers — can be found in diverse and common cancer types, albeit at low frequencies as an orphan target, strongly argues for adoption of comprehensive tumor molecular profiling as part of standard of care.

The FDA should also be applauded for the highly adoptive performance, not only in catching up with the new paradigm of molecular oncology and therapeutics development, but also for demonstrating leadership in implementing regulatory and approval evolutionary changes to ensure our cancer patients receive beneficial therapeutics for their disease at the earliest time and in the best possible manner.

References:

André F, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1716821.

Doebele RC, et al. Cancer Discov. 2015; doi:10.1158/2159-8290.CD-15-0443.

Drilon A, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1714448.

Farago AF and Azzoli CG. Transl Lung Cancer Res. 2017;doi:10.21037/tlcr.2017.08.02.

Le DT, et al. N Engl J Med. 2015; doi:10.1056/NEJMoa1500596.

For more information:

Patrick C. Ma, MD, MSc, is director of the lung cancer program and co-leader of the Sara Crile Allen and James Frederick Allen Lung Cancer Program at West Virginia University Cancer Institute and Mary Babb Randolph Cancer Center of WVU Medicine. He can be reached at West Virginia University, 64 Medical Center Drive, P.O. Box 9300, HSS 1814, Morgantown, WV 26506; email: pcma@hsc.wvu.edu.

Disclosure: Ma reports advisory board/committee roles with AstraZeneca, Caris Life Sciences, Cymeta Biopharmaceutical and Takeda; speakers bureau roles wtih AstraZeneca, Bayer, Bristol-Myers Squibb, Merck and Takeda; and research funding to his institution from AbbVie, AstraZeneca, Bristol-Myers Squibb, CBT Pharmaceuticals, Cymeta Biopharmaceutical, EpicentRx, Incyte, Loxo Oncology, MedImmune, Pfizer, Spectrum, Tesaro and Xcovery.

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