Treatment Strategies With NTRK Gene Rearrangements Emerge in Lung and Other Solid Tumors

^1,2Neurotrophic tropomyosinrelated kinase (NTRK) gene rearrangements have recently been described in a small subset of ‘never smoker’ patients with lung cancer who do not have mutations in some of the more well-established drivers such as anaplastic lymphoma kinase (ALK) or epidermal growth factor receptor (EGFR) genes.^1,3Tyrosine kinase inhibitors (TKIs) that are specific for the Trk family, as well asALKandROS1, have recently shown activity in the subset of patients with solid tumors, including patients with lung cancer who harbor rearrangements in these genes.^4,5Three genes:NTRK1,NTRK2, andNTRK3code for three proteins: TrkA, TrkB, and TrkC, respectively. The relevance of these genetic alterations for patients with lung cancer, and the corresponding potential for Trk inhibitors to open a new line of treatment in lung cancer, are just beginning to be explored.^4-8A new phase II global trial of entrectinib, a potentTrk inhibitor, will add additional clinical interest in these genes beyond typicallung cancer clinical trialsin these genes.

IMPORTANCE OF TRK REARRANGEMENTS IN LUNG CANCER

Evidence for a role of the Trk family of kinases in lung cancer was reported in 2013, when Vaishnavi et al detected gene rearrangements within the kinase domain of theNTRK1gene in a sample of 36 patients with lung adenocarcinoma who did not have known genetic alterations.³One of the patients had a gene rearrangement of the 5’ portion of the myosin phosphatase Rho-interacting protein (MPRIP) gene fused to the 3’ portion ofNTRK1; the resultant protein (RIP-TrkA) encoded by this fusion could be found in a malignant pleural effusion, and in cultured cells from this patient, which showed autophosphorylation of the fusion protein at critical tyrosine residues, implying its constitutive activation. A second patient in this study was found to have a gene rearrangement between theCD74gene andNTRK1.³

Expression of these aberrant fusion proteins in different cell culture model systems showed that they indeed possessed oncogenic properties, inducing cytokine-independent proliferation, supporting anchorage-independent growth, and resulting in the formation of tumors in nude mice.³Moreover, when expressed in cells, autophosphorylation of the fusion proteins could be inhibited, as could their oncogenic properties, by the use of Trk-specific inhibitors. Collectively, the findings pointed to a likely role forNTRKrearrangementsin a small subset of patients (3/91 in the study, 3.3%) with lung cancer. 

IMPACT OF TRK EXPRESSION IN LUNG CANCER

Aberrant Trk expression, and/or activation, has also been associated with relevant biologic effects in lung cancer, including metastasis. In one study using an in vitro system to identify factors associated with lung cancer metastasis, TrkB (encoded by theNTRK2gene) was correlated with the ability of lung cancer cells to migrate to lymph nodes in response to a brain derived neurotrophic factor (BDNF) secreted by the lymph nodes.⁸As such, cell lines with loss of TrkB function were significantly impaired in their migratory and metastatic activity both in vitro and in vivo, and similar effects could be demonstrated with the use of Trk-specific inhibitor drugs.⁸In a murine model of lung cancer (KRASandp53knockout mice), mice that also had inactivation of theNTRK2gene had a significantly reduced capacity to form lymph node metastases compared with those with functionalNTRK2; similarly, in patient samples, TrkB expression was significantly correlated with development of distant metastasis.⁸Taken together, the findings implicated this member of the Trk family as an important mediator of lymph node metastasis, and may also implicate TrkB as a negative prognostic factor, because patients with TrkB expression were 2.2-fold more likely to develop metastases.⁸Interestingly, an analogous role for theNTRK3gene in facilitating tumor growth and metastasis had previously been found in breast cancer.⁹

PHASE I STUDIES: ENTRECTINIB

The 2015 American Society of Clinical Oncology (ASCO) Annual Meeting presented detailed phase I findings with entrectinib (formerly termed RXDX- 101), a pan-Trk/ROS1/ALK inhibitor in patients with solid tumors having the relevant molecular alterations.^4,5The data were from the ALKA-372-001 study and the STARTRK-1 study, which are the first-in-human studies targeting alterations responsive to targeted receptor kinases. Both trials were designed to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), as well as preliminary anticancer activity of single-agent entrectinib in patients with solid tumors with the relevant molecular alterations, specifically,NTRK1(encoding TrkA),ROS1orALKfor the ALKA-372-001 study, andNTRK1/2/3(encoding TrkA/TrkB/TrkC, respectively),ROS1orALKfor the STARTRK-1 study.^4,5

At the trial data cutoff point for the presentation, 67 patients with a range of solid tumors had been dosed across both clinical trials. Entrectinib was well tolerated, with no treatment-related serious adverse events (AEs).^4,5In the reported safety findings of the ALKA- 372-001 study, two grade 3 treatmentrelated AEs were observed, asthenia and muscle weakness, each of which subsided with dose reduction.⁴The most frequent AEs were paresthesia, nausea, myalgia, asthenia, dysgeusia, and vomiting.⁴In the reported safety findings of the STARTRK-1 study, three grade 3 treatment-related AEs were observed: neutropenia, which resolved with dose reduction, and two dose-limiting toxicities of reversible cognitive impairment and fatigue, both of which occurred at the 800-mg fixed dose, and resolved upon study drug interruption. The most frequent AEs were fatigue, dysgeusia, constipation, nausea, and paresthesia.⁵

Pharmacokinetic measurements showed dose-proportional increases in exposure across the daily dosing regimens evaluated, with a half-life compatible with once-daily dosing.^4,5Eleven patients across both clinical trials met the expected phase II eligibility criteria of the sponsor (Ignyta), which included: (1) presence ofNTRK1/2/3,ROS1, orALK; (2) ALK inhibitor and/or ROS1 inhibitor naïve; and (3) treatment at or above the RP2D of 400 mg/m². The response rate in the 11 patients that met these criteria across both studies was 91% (10 of 11 responses as assessed by the clinical sites), with 9 patients remaining on study treatment with durable responses of up to 16 treatment cycles. The responses included: three of three responses in patients withNTRK1/2/3gene rearrangements, including patients with non—small cell lung cancer (NSCLC), colorectal cancer, and acinic cell cancer; five of six responses, including one complete response, in patients withROS1gene rearrangments, all of which were in NSCLC; and two of two responses in patients withALKgene rearrangements, including one patient with NSCLC and one patient with another solid tumor. Results of these phase I trials thus support further clinical development of entrectinib.^4,5

AN EMERGING ROLE FOR TRK IN LUNG CANCER

At the 16th Annual International Lung Cancer Congress at Huntington Beach, California, in August 2015, Tony Mok, MD, of the Chinese University of Hong Kong, commented on the plannedSTARTRK-2phase II trial of entrectinib initiating this fall by Ignyta. “STARTRK-2 is actually intended as a registration study. This is the first time a basket study may serve as a registration study. This is very exciting, we’re transitioning from histologybased to molecular-based classification for treatment selection.”

Sai-Hong Ignatius Ou, MD, PhD, is a coinvestigator on the STARTRK-1 trial and clinical professor at the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center.Targeted Oncologyspoke with Ou about the emerging role ofNTRKrearrangements in lung cancer. “There are not a lot of studies that support it, but it’s going to be [an] important target,” he said. “It’s rearranged, just likeALKandROS, but at this point, it is case reports based on the phase I studies.”

Ou noted that the percentage of patients with NSCLC who have relevant mutations that might benefit from treatments like entrectinib is fairly low, probably not more than 3%, so finding patients to participate in drug trials will likely take some time. That said, as more people start looking for these molecular alterations inNTRKgenes (and with the growing availability of effective Trk-specific treatments), the demand will certainly increase. “Trk rearrangements and fusions are gradually being added to test menus at commercial labs, and it will take time to drive adoption. Tests are done when there is an inhibitor—you don’t do tests when there is no treatment, so when more and more inhibitors are in clinical trials—the Trk inhibitors—then there will be a need to look forNTRK,” Ou said.

Ou was also quick to cite other examples of mutations, and corresponding inhibitors, which have been down the same path. “The story is the same asROS1.ROS1was discovered in 2007, and nobody paid attention, because there was nothing to blockROS1, until we finished the crizotinib study onALK, and we started on the crizotinib-ROS1study, then suddenly everybody is testingROS1, because they thought there is an inhibitor, and you find more and moreROS1patients—this is going to be the same thing.NTRKrearrangement testing is largely occurring in the clinical trial setting, but once there are response data, people will demand it— when there is a need, they will have a test.”

Lung cancer is not the only major type of cancer likely to have NTRK rearrangements (and consequently would benefit from Trk inhibitors), according to Ou, who emphasized that the rearrangements are more commonly observed in central nervous system tumors, and sarcomas. Despite this, he believes that the clinical experience in lung cancer with molecular diagnostics and targeted therapies is well suited to studying the clinical relevance ofNTRKalterations and Trk inhibitors. “I don’t think lung cancer is the major tissue type that hasNTRKrearrangement; but the fact that it’s being tested in lung cancer is [because] most of the lung cancer doctors are ahead of the curve, and so they’re going after it. But I think if you want to see the tumor types that have the mostNTRKrearrangements, it will be, probably, the central nervous system tumors and the sarcomas. But those people are not testing as much at this point, because they are not used to doing testing.”

Ou remains optimistic about theNTRKmarker, and is confident that patients who might benefit from therapies such as entrectinib will ultimately be found, given the diversity of tumor types that showNTRKrearrangements.

“There is a market forNTRK, and for Trk inhibitors, for the patients who areNTRKpositive, but we’re not there yet,” he said. “The key is, it’s an emerging field—Trk will be an important target in lung, and probably more important in other tumor types. When you find the patients, and have the treatments, people will ask for it,” Ou said. In some ways, Ou draws a parallel between the present clinical picture withNTRKin lung cancer and Apple Computer’s latest offering. “Trk is kind of like the iWatch,” he said. “It’s not there yet, because the standard is the iPhone.” But, he maintained that, as was the case withALKandROS1(and with the iPhone, not all that long ago), once the need is created, more patients are tested and identified, and Trk-specific inhibitors progress through clinical development and ultimately become approved for use, “Well, then… boom!”

For more information on the phase II trial for entrectinib in patients withNTRK,ROS1, andALKgene rearrangements, please visitwww.startrktrials.com.

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