June 2018 Edition Vol.11, Issue 6

Tumor-Agnostic Trials: When The Patient, Not the Tumor, is the Target

By Christina Bennett, MS

The theme for the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting was Delivering Discoveries: Expanding the Reach of Precision Medicine, and one way precision medicine is expanding its reach is through tumor-agnostic trials.

“Things have changed over the last couple of years, and in specific situations, that focus has shifted from choosing patients based on cancer type to choosing them primarily based on a target,” said Alexander Drilon, MD, Clinical Director of Early Drug Development Service at Memorial Sloan Kettering Cancer Center.

Case in point, last year the first tumor-agnostic therapy, pembrolizumab, was granted accelerated approval for adult and pediatric patients with treatment-refractory advanced solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).1

In addition, on May 29, 2018, the U.S. FDA granted Priority Review for Loxo Oncology’s tumor-agnostic agent larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring an NTRK gene fusion. Larotrectinib has already been granted Breakthrough Therapy Designation, and the target action date set by the FDA is November 26, 2018.2

At ASCO, results from a variety of early phase studies investigating agents across a swath of tumor types were reported, but the ones to create a buzz were Loxo Oncology’s trial for LOXO-292 and the largest national signal-finding trial to date, NCI-MATCH.

LOXO-292 Hits Its Target

Last year during ASCO, Loxo Oncology grabbed headlines with their debut of larotrectinib, and this year they did it again with another agent in their pipeline: LOXO-292, a RET inhibitor. LOXO-292 demonstrated an overall response rate (ORR) of 77% for participants with RET fusion-positive cancers. Also, nearly half of participants with RET-mutant medullary thyroid cancer responded.3

RET fusions are found in 2% of non–small cell lung cancer (NSCLC) and 10% to 20% of papillary thyroid cancer, the most common form of thyroid cancer. Other tumor types, such as pancreatic cancer, salivary gland cancer, colorectal cancer, and ovarian cancer, can harbor RET fusions but only rarely. RET mutations are found in most medullary thyroid cancers, a rare form of thyroid cancer.

“Although these alterations are bona fide cancer drivers, unfortunately, the clinical activity of approved or investigational anti-RET multikinase inhibitors has thus far been limited,” said study presenter Dr. Drilon. He explained that in contrast to prior multikinase inhibitors, LOXO-292 is highly selective, with minimal inhibition of other targets. Also, preclinical evidence suggests LOXO-292 has activity in the brain.

The data reported were from the dose escalation portion of the open-label, first-in-human phase I LIBRETTO-001 trial, which is evaluating LOXO-292 in patients with advanced or metastatic solid tumors that were treatment refractory or intolerant to standard therapy. The second part of the trial, the dose expansion portion, focuses on patients with solid tumors that harbor a RET gene alteration.

Data were reported for 82 participants, 29 with RET-mutant medullary thyroid cancer and 49 with RET fusion-positive cancers, and 4 with no known RET alteration. Of those with RET fusion-positive cancers, 38 had NSCLC, 9 had papillary thyroid cancer, and 2 had pancreatic cancer. A total of 12 participants (15%) had brain metastases. About two-third of patients had received a prior multikinase inhibitor.

The agent showed durable activity, with 90% of patients with RET fusion-positive cancers and 93% of patients with RET-mutant medullary thyroid cancer still on therapy. All RET fusion-positive cancers with brain metastases at baseline remained on therapy.

“LOXO-292 was well tolerated,” said Dr. Drilon. “Only six treatment-emergent adverse events were observed in greater than or equal to 10% of patients.” Most treatment-related adverse events were grade 1 or 2, and only two treatment-related grade 3 adverse events were reported, tumor lysis syndrome and alanine aminotransferase, both of which were reversible. Maximum tolerated dose was not reached.

“The data on LOXO-292 were quite amazing and very exciting,” commented Marcia Brose, MD, PhD, Director of the Center for Rare Cancers and Personalized Therapy in Penn’s Abramson Cancer Center. Dr. Brose was also excited to see that LOXO-292 had activity in the brain because, while treatments are improving for brain disease, for patients who have multiple lesions, the only option after a certain point is to give whole-brain radiation. “That causes significant disruption and memory issues and other complications, and so it’s really great that we actually have systemic therapies that can treat tumors in the brain.”

The LIBRETTO-001 trial is currently in the dose expansion phase. Dr. Drilon said, “Within, hopefully, the next year we’ll have much more substantial data to talk about.”

Finding a MATCH

The NCI-MATCH trial, which includes nearly 40 single-arm phase II trials and counting, is designed to enroll participants and then assign a treatment based on the genetic changes in their tumors. Most treatment arms have 35 participants, though some arms have as many as 70 participants enrolled.4 The results from Arms I, W, and Q of the NCI-MATCH trial were reported at the meeting, and the response rates were all low. Two arms reported an ORR of 8% and the other 0%.

“What we actually see in MATCH is more of a mix of tumor types and a mix of patients who have been heavily pretreated,” said Dr. Brose. “That’s part of why some of the results were not quite as strong upfront.”

“What MATCH is doing is it’s really pulling out some rare cancers that likely will benefit from some of these agents, so I look at it as a win,” said Dr. Brose.

In Arm I, participants had PIK3CA-mutated tumors and were given PI3-kinase inhibitor taselisib.5 Breast cancer and squamous cell lung cancer were excluded because these cancer types were being evaluated with taselisib in other trials. Among the 65 participants, there were 36 distinct tumor histologies, and nearly 70% of participants had three or more prior lines of therapy.

No participants achieved a response, and about half had stable disease. The 6-month progression-free survival (PFS) rate was 24% and median PFS was 3.5 months.

“Taselisib monotherapy had only limited activity in a cohort of pretreated patients with PIK3CA-mutant cancers,” concluded the study presenter Ian Krop, MD, PhD, from Dana-Farber Cancer Center. “I think it’s safe to say that with these data, PIK3CA mutation alone without other data does not appear to be a sufficient predictor of taselisib clinical activity.”

Dr. Krop rationalized that the reason why more activity was not seen with taselisib despite strong preclinical and early clinical data may be participants were heavily pretreated and the population was heterogeneous. Also, PIK3CA mutations may not be the major driver in these particular tumors and other alterations may act as a bypass around the PI3-kinase inhibition.

In Arm W, participants had FGFR aberrations and were given agent AZD4547.6 Participants with gastric cancer and NSCLC were excluded. Fifty participants received the study agent, and participants were heavily pretreated, with half having received more than three lines of therapy. Common tumor types enrolled were breast, urothelial, cervical, and endometrial cancers.

The ORR was 8%, with 4 of 50 participants achieving a partial response and no complete responses. Nearly half of participants had stable disease. The partial responses were intrahepatic cholangiocarcinoma, transitional cell cancer of the renal pelvis, squamous cell carcinoma of the cervix, and transitional cell cancer of the bladder. Median PFS was 3.6 months.

“AZD4547 demonstrated modest activity across various solid tumors with aberrations in the FGFR pathway with acceptable toxicities,” said study presenter Young Kwang Chae, MD, Assistant Professor of Medicine at Northwestern University. “Further trials are warranted in tumors harboring FGFR fusions.”

Lastly, in Arm Q, participants had HER2-amplified tumors and received ado-trastuzumab emtansine.7 Those with breast or gastric cancers were excluded. Participants had a range of tumor types, with the most common being colorectal carcinoma, gynecologic malignancies, and NSCLC. Half of the participants had three or more lines of therapy.

The ORR was 8%, with three confirmed partial responses and no complete responses. Two of the participants with a partial response had parotid gland tumors and one had extramammary Paget’s disease of the scrotum. The 6-month PFS rate was 25%. The median time to progression was 2.9 months, and the participant with a parotid gland tumor that had a partial response was still on therapy at 16.5 months.

“This arm did not meet the pre-defined primary endpoint of overall response rate in this heavily pretreated population,” said study presenter Komal Jhaveri, MD, medical oncologist from Memorial Sloan Kettering Cancer Center. “Durable disease stabilization was seen in ovarian, endometrial, and colorectal cancers.”

The responses seen for parotid gland tumors in Arm Q were consistent with the results of another study reported at ASCO. The study showed complete responses for all 6 HER2-amplified salivary gland tumors treated with ado-trastuzumab emtansine; most salivary gland tumors are in the parotid glands.8 On the basis of this other study, Dr. Jhaveri concluded, “This warrants further study of [ado-trastuzumab emtansine] in such rare tumors.”

About Arm Q, Dr. Brose said, “These are cancer tumor types that are extremely hard to do any kind of clinical testing in, and historically what you would have had to do is a phase II in those arms and no drug company would ever support it because those cancers are so rare.” She continued, “Now we can go back with more hope and say ‘okay, these were winners, we should study them further.’”

References

  1. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm. Accessed June 11, 2018.
  2. FDA accepts larotrectinib New Drug Application and grants Priority Review. https://ir.loxooncology.com/press-releases/fda-accepts-larotrectinib-new-drug-application-and-grants-priority-review. Accessed June 11, 2018.
  3. Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol. 2018;36:(suppl; abstr 102).
  4. NCI-MATCH Trial (Molecular Analysis for Therapy Choice). https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match. Accessed June 11, 2018.
  5. Krop IE, Jegede O, Grilley-Olson JE, et al. Results from molecular analysis for therapy choice (MATCH) arm I: Taselisib for PIK3CA-mutated tumors. J Clin Oncol. 2018;36:(suppl; abstr 101).
  6. Chae YK, Vaklavas C, Cheng HH, et al. Molecular analysis for therapy choice (MATCH) arm W: Phase II study of AZD4547 in patients with tumors with aberrations in the FGFR pathway. J Clin Oncol. 2018;36:(suppl; abstr 2503).
  7. Jhaveri KL, Makker V, Wang XV, et al. Ado-trastuzumab emtansine (T-DM1) in patients (pts) with HER2 amplified (amp) tumors excluding breast and gastric/gastro-esophageal junction (GEJ) adenocarcinomas: Results from the National Cancer Institute (NCI) Molecular Analysis for Therapy Choice (MATCH) trial. J Clin Oncol. 2018;36:(suppl; abstr 100).
  8. Li BT, Makker V, Buonocore DJ, et al. A multi-histology basket trial of ado-trastuzumab emtansine in patients with HER2 amplified cancers. J Clin Oncol. 2018;36:(suppl; abstr 2502)

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