Entrectinib Shows Dramatic Response in Rare Salivary Gland Tumor

Alexander Drilon, MD

The experimental targeted therapy entrectinib demonstrated a dramatic response in a patient with metastatic mammary analog secretory carcinoma (MASC), which is a rare form of salivary gland cancer, according to a case report published inAnnals of Oncology.¹

In the report, a 34-year-old female patient withNTRK3-rearranged MASC that had progressed following multiple lines of prior treatment, including chemotherapy and crizotinib, was given entrectinib in a phase I study. She experienced a dramatic response to entrectinib, with an 89% reduction in tumor burden. The patient is still alive, and has gone on to other therapy after 10 months on entrectinib, according to the lead author of the article Alexander Drilon, MD, attending oncologist at Memorial Sloan Kettering Cancer Center.

MASC is a novel form of cancer identified in 2010, which can be mistaken for acinic cell carcinoma (ACC), a slow-growing salivary gland tumor.²In fact, the patient in the case study was initially misdiagnosed with ACC.

The patient initially presented in January 2006 with a growing parotid mass, and surgery revealed a stage 3 cancer. The surgical margins were microscopically involved with tumor, and the patient received postoperative radiation. In August 2011, she was diagnosed with metastases to the lung, pleura, mediastinum, and chest wall.

Treatment continued with two palliative surgeries, and three different forms of chemotherapy. A surgery in February 2013 revealed a carcinoma that was morphologically similar to the patient’s initial salivary tumor, at which point next-generation sequencing was performed, revealing that the cancer expressed anNTRK3fusion. The tumor was then reclassified as MASC.

The patient was initially treated with crizotinib (Xalkori), a multikinase inhibitor that has modest in vitro activity against Trk. Imaging indicated a 2% reduction in her disease burden at 3 weeks, and a 19% reduction at 10 weeks. However, the disease progressed by week 18, and she was enrolled in the phase I STARTRK-1 trial of entrectinib in rare forms of cancer characterized by NRK, ROS1 and ALK molecular alterations (NCT02097810).

A dramatic response followed, with her reduction in tumor burden topping out at 89% after 21 weeks. After 7 months on entrectinib, the patient had developed a solitary lung tumor, but she was kept on therapy. After 10 months on treatment, the patient had developed several other lung nodules, characterized by a novelNTRK3G623R mutation, the case report said. Entrectinib was discontinued.

“We’re starting to find these targets, such as gene fusions, in small slices of the pie across different cancers, such as MASC, and it becomes very difficult to mount a clinical trial against a target you might find in 1% of cases,” said Drilon. “So we’ll select patients for a study regardless of their cancer type, as long as they have the appropriate targeted mutation.”

The STARTRK-1 trial is an example of this type of study. In addition to the patient with MASC, findings have also been presented for patients with non—small cell lung cancer, colorectal cancer, and other tissue types. While STARTRK-1 is ongoing, a similar phase II basket study of entrectinib was initiated in September 2015, STARTRK-2. This study will enroll subjects with not only NTRK rearrangements, but also ROS1 and ALK rearrangements.

“In targeted therapy, a phase II study could potentially be your pivotal study,” explained Jacob Chacko, MD, CFO of San Diegobased Ignyta, which is developing the drug. “There are a number of targeted therapies that have benefited from accelerated approval timelines by the FDA, including crizotinib for lung cancer and certain hedgehog inhibitors for basal cell carcinoma.”

“Given that entrectinib demonstrated responses across multiple tumor types in the Phase I study, we felt confident designing the Phase 2 study as a basket study with several different arms. Each basket is defined by the combination of a target of interest—NTRK, ROS, and ALK—with a histology of interest— NSCLC, colorectal, and all others,” he said, noting that MASC falls into the ‘other’ category. “Each basket of drug target and tumor histology could enroll at different speeds, and could be considered independently from the other baskets for purposes of a potential registration,” Chacko said.

Enrollment of MASC patients may face certain challenges, not only because the disease is rare but also because it is so frequently misdiagnosed. For example, a retrospective review of ACC cases at The Johns Hopkins Hospital found that 11 of 14 extraparotid ACCs were marked by a genetic translocation, and therefore reclassified as MASC.

While MASC, like ACC, has been described as a “low-grade” malignancy, findings that it responds to targeted therapies like entrectinib might make proper diagnosis important, from both a clinical and research perspective.

“One of the recommendations of the paper is that if you have a case of ACC or suspected MASC you should get a comprehensive molecular profiling done via next-generation sequencing,” said Drilon. “It’s worth it because not all fusions or other drivers can be detected easily by older generation sequencing or assays.”

Molecular analysis may be even more important, because the same mutations suspected of being drivers in MASC are also implicated in a number of other, seemingly unrelated, cancers. For example, another case study published last fall described a dramatic response, followed by acquired resistance, to entrectinib, in a metastatic CRC patient characterized by aNTRK1rearrangement.³

Another participant who showed a dramatic response to entrectinib was a 46-year-old patient with NTRK1-rearranged NSCLC who participated in STARTRK-1.⁴That patient had brain metastases, and was last described at 2015 European Cancer Congress.

NTRKrearrangements have also been identified in thyroid cancer and sarcoma, among other malignancies, according to the case study published this month in theAnnals of Oncology.

“In the old days, they might do a combination of FISH, realtime PCR, and immunohistochemistry, but the beauty of nextgeneration sequencing, like our in-house assay, is that you can test for more than 400 markers,” said Drilon. “And the more people who adopt comprehensive molecular profiling in the community, the more quickly we can accrue patients in these trials.”

The phase II STARTRK-2 study began enrolling in the fall of 2015. The last update on the phase I STARTRK-1 study was presented at the European Cancer Congress (ECC) in September 2015, and another update is anticipated at the AACR meeting coming up in New Orleans at the end of April. This update will discuss not only STARTRK-1 but also ALKA, the European phase I counterpart. Last year’s ECC presentation described a response rate of 72% in 18 patients who had not previously received a ALK- or ROS1-inhibitor, across a variety of solid tumors with NTRK, ROS1, or ALK rearrangements.⁵

References:

1. Drilon A, Li G, Drogan S, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC) [published online February 15, 2016].Annals of Oncology.doi:10.1093/ annonc/mdw042
2. Bishop J, Yonescu R, Batista D, et al. Most Nonparotid “Acinic Cell Carcinomas” Represent Mammary Analog Secretory Carcinomas.Am J Surg Pathol.2013;37:1053—1057.
3. Russo M, Misale S, Wei G, et al. Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer.Cancer Discov.2016;6(1):36-44.
4. Farago A, Le L, Zheng Z, et al. Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.Journal of Thoracic Oncology.2015;10(12):1670—1674.
5. Siena S, Drilon A, Ou S, et al. Entrectinib (RXDX-101), an oral pan-Trk, ROS1, and ALK inhibitor in patients with advanced solid tumors harboring gene rearrangements. Slides presented at ECCO/ESMO, Sept. 25-29, 2015.http://ignyta.com/wp-content/uploads/2015/10/ESMO- 2015-entrectinib_F.pdfAccessed April 1, 2016.