On Friday 16th August Roche announced the accelerated approval of it’s pan-solid tumour indicated product Rozlytrek (entrectinib) which targets both NTRK (Neurotrophic Tyrosine Receptor Kinase) gene fused solid tumours and ROS-1/ NTRK gene fused positive NSCLC [1]. This is the third FDA approval of indications  based on the presence of particular tumour biomarker, as opposed to traditional tumour location based indication, after Merck & Co.'s Keytruda, (indicated for microsatellite instability-high or mismatch repair deficiency in any solid tumour, 23/05/17 [2]) and Loxo Oncology's Vitrakvi, (indicated for any solid tumour with NTRK gene fusion without resistance, 26/11/18, accelerated approval [3]). Rozlytrek is the second product to receive an accelerated approval for solid tumours exhibiting an NTRK gene fusion, which highlights two interesting factors, choice of mechanism of action and approval landscape of pan-tumour based indications.

NTRK genes 1, 2 and 3 encode for TRK transmembrane protein receptors, A B and C, expressed in neuronal cells. Upon specific extracellular neurotrophin binding to the receptor, autophosphorylation of intracytoplasmic kinase domains occurs. This results in the activation of signalling cascades PI3K-AKT (inhibition of apoptosis), RAS-MEK (cell growth and differentiation) and PLCγ-MEK (cell growth and differentiation). These pathways are vital in cell differentiation, growth and survival (see fig 1). Rearrangements in NTRK genes make them ideal oncogenes as they exhibit pro-proliferative and antiapoptotic characteristics due to constant activation of the aforementioned signalling pathways [5]. NTRK fusion alterations are most commonly present in tumours situated in the thyroid at ~2.34%; in other solid tumours rates vary from 0% to 1% dependent tumour location and histopathology, however in small subpopulations, such as secretory carcinoma of the salivary gland and secretory breast carcinomas, NTRK fusion rates can reach as high as ~80% [6].

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Rozlytrek acts as a competitive inhibitor of ATP binding sites on the kinase domain of TRKA-B, thereby preventing autophosphorylation of these domains in NTRK gene fusion activated TRK proteins; this stops the activation of signalling cascades which promote oncogenic characteristics (anti-apoptosis, differentiation and cell growth).

Selection of this therapeutic target in two out of the three currently approved pan-tumour products is no coincidence. NTRK gene alterations, (more specifically gene fusions) are a well-studied area of onco-genealogy, the first NTRK fusion in a tumour cell having been found in a colon carcinoma patient in the 1980’s [5]; the historically quantified rarity of this gene alteration across multiple tumour types defines a small eligible patient population. This means that a NTRK gene fusion targeting drug would have to prove efficacy against multiple tumour types in order to have a large enough population to be economically viable.

Moreover, the Rozlytrek indication further specifies that patients have no resistance mutations to NTRK targeting therapy, be unresectable and pre-treated with no alternative satisfactory therapy. This niche patient population with a clear high un-met need qualified the product for an accelerated approval with a small clinical trial cohort. Due to the small and anatomically heterogeneous trial population efficacy vs standard of care regimen was not required.  The trials on which the approvals were based exceeded the required overall response rates dictating trial success, with a cohort size of 52 patients an objective response was recorded in 32 patients (60%) with a complete response in 4 (7%) and a response duration ranging from ~ 2 to ~26+ months [7]. It is also important to note that the trial design and implementation for both Rozlytrek and the earlier approval of Vitrakvi were developed whilst in conversations with regulators to determine what they would deem acceptable a seemingly vital step for any company looking for a pan-tumour label, particularly in rare mutations.

References:

[1] https://www.roche.com/investors/updates/inv-update-2019-08-16.htm Accessed: 19/11/2019 at 11:05

[2] https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s065lbl.pdf Accessed: 19/11/2019 at 13:05

[3] https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210861s000lbl.pdf Accessed: 19/11/2019 at 13:10

[4] Amatu, A et al. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open; 1(2);e000023. 2016.

[5] Vaishnavi, A et al. TRKing down an old oncogene in a new ear of targeted therapy. Cancer Discovery; 5(1); 25-34. 2015.

[6] Okamura, R et al. Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics. JCO Precis Oncol;

[7] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc Accessed: 19/11/2019 at 12:00