NEW YORK (GenomeWeb) – A multi-basket trial launched by the American Society of Clinical Oncology three years ago has reported out the first positive data from two arms demonstrating activity for Pfizer's palbociclib (Ibrance) and Merck's pembrolizumab (Keytruda) in biomarker-defined cancers.
Additionally, the study, called the Targeted Agent and Profiling Utilization Registry (TAPUR), is also opening its first tissue-agnostic cohort in line with pharmaceutical companies' growing interest in exploring such strategies, and may open more pan-cancer arms in the future.
ASCO began enrolling advanced cancer patients in the TAPUR study in 2016 in order to investigate if already marketed drugs were effective in other molecularly defined cancers. As of this week, TAPUR has screened more than 2,000 patients and enrolled 1,500 patients who are enrolled across 420 biomarker-defined treatment arms. In order to evaluate the safety and efficacy of the drugs in TAPUR cohorts, at least 10 and up to 28 patients have to be enrolled, and ultimately a signal of activity is declared if tumors shrink or stop growing in seven out of 28 patients for at least 16 weeks.
The study has previously reported out arms where a molecularly targeted strategy failed to show activity in patients, but last month ASCO announced the first two positive arms — palbociclib in non-small cell lung cancer characterized by CDKN2A alterations and pembrolizumab in metastatic breast cancer with high tumor mutational burden. In the cohort involving palbociclib, out of 28 advanced NSCLC patients with CDKN2A loss or mutation, one experienced tumor shrinkage and six had stable disease for at least 16 weeks. Ten patients had at least one grade 3 or grade 4 adverse event.
In the cohort involving pembrolizumab, 10 out of 28 metastatic breast cancer patients with high tumor mutational burden either saw their tumor shrink or had stable disease for 16 weeks or longer. Although there is no definitive biomarker for predicting response to immunotherapy, in this cohort high TMB status suggested that advanced breast cancer patients may respond to a checkpoint inhibitor.
Studies have shown that TMB cut-offs are likely to be histology-specific, but in the TAPUR cohort patients had high TMB status established by assays with different cut-offs. Twenty patients had their TMB levels established with Foundation Medicine's FoundationOne test (based on a cut-off of nine muts/Mb), and the rest received tests approved by the TAPUR molecular tumor board. The TMB levels for enrolled patients ranged between nine muts/Mb to 37 muts/Mb.
Ajjai Alva, from the University of Michigan and the lead investigator of this TAPUR cohort, said that there has been interest from pharma and patient advocacy groups in expanding the metastatic breast cancer cohort to explore this signal further. However, after an arm reads out positive, ASCO leaves it up to the sponsor to decide whether to follow it up in a larger study.
The University of Michigan has enrolled 10 percent of patients currently partaking in multiple cohorts within TAPUR. Ultimately, Ajjai sees TAPUR as not only a way to learn about tumor biology and drug signals, but also as a way for his patients who are out of therapy options to gain access to drugs that they otherwise may not be able to obtain or afford. "Instead of waiting for FDA to approve this indication in breast cancer, which will take years, larger trials, and billions of dollars, 28 patients had access to the drug," he said. "It's an enormous resource. It's like accelerated access."
In addition to these first two positive cohorts, Richard Schilsky, senior VP and CMO of ASCO, said that TAPUR's data safety monitoring board has released early readouts from additional cohorts that are looking positive and will be reported later in 2019 or early 2020. Meanwhile, other TAPUR cohorts have failed to find an efficacy signal. For example, in April, researchers reported that breast cancer and NSCLC patients without KRAS, NRAS, or BRAF mutations likely will not derive benefit from Eli Lilly's cetuximab (Erbitux).
But negative findings are also important for the field's collective understanding of tumor biology and for clinical practice. "We think it's very important for oncologists to have that information [about negative cohorts]," said Schilsky. "We don't want them prescribing drugs off label when there is data to suggest that doing so doesn't help."
While some TAPUR cohorts are enrolling and reporting out safety and efficacy data relatively quickly, many of the arms will take a very long time to enroll because the biomarkers of interest are so rare in the population. In an effort to still look for an efficacy signal, the leaders of TAPUR may decided to combine some of the arms that are investigating the same drug and biomarker but in different histologies and create a pan-cancer cohort.
For example, currently there are seven cohorts investigating the activity of AstraZeneca's olaparib (Lynparza) in different tumor types with BRCA1 or BRCA2 mutations, and within TAPUR the hope is to enroll these individual cohorts in search of a signal. However, BRCA1/2 mutations occur infrequently in tumors making it challenging to enroll studies. For example, in order to enroll 152 patients in the Phase III POLO study evaluating olaparib in metastatic pancreatic cancer, molecular testing firm Myriad Genetics had to screen more than 3,300 patients.
In TAPUR, instead of trying to evaluate the activity of olaparib in BRCA-mutated cancers histology by histology, "you could also ask, ‘Well, is there a histology-agnostic, BRCA-altered, olaparib cohort that includes all those different cohorts?'" Schilsky said. "And of course, the answer is yes. We can collapse them all into one gigantic cohort and analyze it in a histology-agnostic way."
Currently, TAPUR's protocol is not written to include tissue-agnostic cohorts as a primary analysis, but this could be a secondary analysis investigators perform. Alternatively, AstraZeneca could decide to combine the different arms in that way and present that to a regulatory body for a histology-agnostic indication for olaparib, Schilsky suggested.
TAPUR was initially launched to explore drug safety and efficacy in histology-specific cohorts, because at the time drugmakers were concerned that genomic alterations may not behave the same way across tumor types. Schilsky is seeing more pharma interest in this strategy now that the FDA has approved two tissue-agnostic drugs, Merck's pembrolizumab and Loxo Oncology's larotrectinib (Vitrakvi).
The study also recently added its first tissue-agnostic arm, which will study Boehringer Ingelheim's afatinib (Gilotrif) in patients with cancers driven by NRG1 fusions, which occur in less than 1 percent of solid tumors. Before joining the study, for several years the drugmaker had been receiving case reports from around the world of patients with NRG1-positive cancers who responded to afatinib. Preclinical studies had also shown that afatinib's mode of action impacts NRG1-positive cancers in that NRG1 alterations activate the ERBB2/ERBB3 pathway, and afatinib is a pan-ERBB inhibitor.
"That created some body of spontaneously generated evidence," said Victoria Zazulina, Boehringer Ingelheim's global head of medicine in oncology. "We thought about how we can more formally get better assessments and understanding of response, may be even publish it, and bring it to the broader world of investigators and researchers."
Boehringer is not prepared to say whether it would seek a tissue-agnostic indication for afatinib at this time, but it is hoping that TAPUR will improve understanding of the drug's response rate in this subset of patients. "If the data are great, I'm sure that will open the door for discussions with the FDA" and at which point, it will be determined what additional evidence may be needed for a regulatory filing, Zazulina said.
Recognizing that pan-cancer modalities are a way to give patients treatment options who otherwise wouldn't have any, the FDA has been encouraging drugmakers to pursue tissue-agnostic indications and has said it plans to issue guidance on this topic. This realization is also what's guiding Boehringer, according to Zazulina.
"Our drug [afatinib] has a unique mode of action that's very relevant for this [NRG1-positive cancer] population, [and] currently there is nothing in terms of a targeted treatment for them," she said. By joining TAPUR, Boehringer also hopes to raise awareness of the NRG1-positive cancer population so that more labs can test for the rare biomarker and more patients can be identified.
TAPUR allows any CLIA-certified, CAP-accredited lab to screen patients for TAPUR in order to make it as easy as possible for patients to gain access to testing. According to Schilsky, approximately 60 percent of the testing done in TAPUR is performed by Foundation Medicine, 20 percent is done by Caris Life Sciences, and the remaining 20 percent is done by other labs, including Guardant Health, and at hospitals and cancer centers.
Caris, for example, recently launched a whole transcriptome test that can gauge gene fusions like the NRG1 fusions of interest in this cohort. Investigators from the lab and several of its partner cancer centersalso searched through 22,000 samples of patients the lab had tested and reported that they identified NRG1 fusions in multiple tumor types, representing 0.2 percent of cancers.
However, NRG1 fusions aren't on all labs' radar. "That's a problem because if they don't report it out then our clinical sites aren't going to be able to identify patients who can potentially receive the treatments," said Schilsky, adding that he plans to reach out to labs doing screening for TAPUR to inform them of the need to test for this biomarker.