TAPUR study may identify new biomarker-based therapies for heavily-pretreated CRC

03 Feb 2020 bởiChristina Lau
TAPUR study may identify new biomarker-based therapies for heavily-pretreated CRC

The TAPUR study – the first clinical trial conducted by the American Society of Clinical Oncology (ASCO) – may help identify new biomarker-based therapies for patients with heavily-pretreated colorectal cancer (CRC) who have HER2-positive or BRAFV600E-mutated tumours or a high tumour mutation burden (TMB) and have no standard treatment options.

“The TAPUR study is a prospective, multibasket, phase II trial that aims to evaluate the performance of cancer therapies outside of their US FDA-approved indications in patients with advanced cancer not responding to standard treatment, and who have genomic alterations that can be targeted with a TAPUR study drug. The study was conducted using a disease-agonistic, biomarker-based approach,” said Dr Richard L. Schilsky, Chief Medical Officer of ASCO.

New data from three CRC cohorts of TAPUR, reported at ASCO’s 2020 Gastrointestinal Cancers Symposium (ASCO GI 2020), showed anti-tumour activity of various biomarker-based regimens in patients with heavily-pretreated advanced CRC harbouring the above-mentioned genomic alterations.

Pertuzumab + trastuzumab in HER2-positive CRC

One of the TAPUR CRC cohorts included 28 patients (median age, 54 years; 64 percent male; ECOG performance status 0–1, 97 percent) with HER2-positive advanced CRC, 79 percent of whom had received ≥3 prior treatment regimens. These patients, enrolled between November 2016 and September 2018, were treated with pertuzumab (420 mg intravenously [IV] over 30–60 minutes, Q3W) plus trastuzumab (6 mg/kg over 30–60 minutes, Q3W) in the study. [Gupta R, et al, ASCO GI 2020, abstract 132]

“HER2 amplification, overexpression or mutation is present in 5–7 percent of patients with CRC. Dual HER2 blockade with pertuzumab plus trastuzumab performed well in our cohort, demonstrating an objective response rate [ORR] of 14 percent and a disease control rate [DCR] of 50 percent, respectively,” reported investigator Dr Ranju Gupta of Lehigh Valley Health Network, Bethlehem, Pennsylvania, US.

“Four patients achieved partial response [PR], while 10 had stable disease [SD] for ≥16 weeks,” he added. “The median progression-free survival [PFS] was 17.2 weeks, while 1-year overall survival [OS] rate was 58 percent.”

One patient (4 percent) experienced grade 3 adverse events (AEs) of anaemia and infusion reaction, while another (4 percent) experienced a serious AE (SAE) of left ventricular dysfunction – an infrequent cardiac AE known to be associated with trastuzumab therapy.

“Our impressive results provide strong justification for comparing pertuzumab-trastuzumab combination therapy with chemotherapy in a phase III trial in patients with heavily-pretreated, HER2-amplified metastatic CRC [mCRC],” said Gupta.

“As RAS mutations could circumvent the effects of HER2 blockade, we are now investigating whether the presence of RAS mutations in CRC would influence response to pertuzumab and trastuzumab,” he added.

Cobimetinib + vemurafenib in BRAFV600E-mutated mCRC

In another cohort of 28 patients (median age, 62 years; 63 percent female; ECOG performance status 0–2) with BRAFV600E-mutated mCRC enrolled between August 2016 and August 2018, combination therapy with cobimetinib (60 mg orally QD for 21 days, 7 days off) and vemurafenib (960 mg orally BID) demonstrated an ORR of 29 percent and a DCR of 57 percent. Eight patients had PR, while eight had SD that lasted for ≥16 weeks. [Klute K, et al, ASCO GI 2020, abstract 122]

“The median PFS was 15.8 weeks, while median OS was 38.9 weeks, or approximately 9 months,” reported investigator Dr Kelsey Klute of the University of Nebraska Medical Center, Omaha, Nebraska, US.

“BRAFV600E mutation is found in approximately 10 percent of mCRC patients. These patients tend to have rapid disease progression after first-line therapy. With second- and third-line treatment, their response rates are below 5 percent while PFS is 2–2.5 months only,” she continued. “Our findings, in a cohort in which 63 percent of patients had received ≥3 prior systemic regimens, are certainly encouraging.”

In the cohort, 33 percent of patients experienced grade 3 AEs, while 20 percent experienced SAEs. The AEs, including elevated liver enzymes, decreased lymphocytes, dyspnoea, diarrhoea, fatigue, hypercalcaemia, hypophosphataemia, rash, photosensitivity, upper gastrointestinal haemorrhage, and vomiting, were consistent with those observed in melanoma patients treated with cobimetinib and vemurafenib.

“The recent phase III BEACON trial demonstrated significantly improved OS and ORR with the encorafenib-binimetinib-cetuximab and encorafenib-cetuximab combinations vs standard treatment with cetuximab plus chemotherapy in patients with BRAFV600E-mutated mCRC progressing after 1–2 previous regimens,” said Klute. [N Engl J Med 2019;381;1632-1643] “These results and data from our TAPUR cohort signal a need for additional studies to delineate the optimal role of combination therapies targeting MAPK and EGFR signalling, either alone or in combination with chemotherapy or immunotherapy, and to evaluate the tolerability, impact on quality of life, and financial toxicity of these regimens.”

Pembrolizumab in CRC with high TMB

Among a third cohort of 27 patients (median age, 59 years; 52 percent female; ECOG performance status 0–1) with advanced CRC who had high TMB, defined as ≥9 mutations/megabase by a FoundationOne test (n=26) or other approved tests (n=2), pembrolizumab (2 mg/kg or 200 mg IV over 30 minutes, Q3W) monotherapy demonstrated modest activity. [Meiri E, et al, ASCO GI 2020, abstract 133]

The patients, enrolled between June 2017 and November 2018, mostly had microsatellite-stable disease (n=25), while microsatellite status was ambiguous for one patient and not available for another patient. In this cohort, 78 percent of patients had received ≥3 prior systemic regimens.

“One PR was observed in a patient with microsatellite-stable disease with a TMB score of 10, while seven patients had SD lasting for ≥16 weeks. The ORR and DCR were 4 percent and 28 percent, respectively,” reported investigator Dr Eyal Meiri of the Cancer Treatment Centers of America, Atlanta, Georgia, US. “Median PFS was 9.3 weeks, while 1-year OS rate was 46 percent.”

Two patients (7 percent) in the cohort experienced grade 3 AEs, including abdominal infection, anorexia, colitis, diarrhoea, fatigue, nausea and vomiting. One patient also experienced a SAE of acute kidney injury.

“Additional phase II study in a larger group of patients is needed to better evaluate the efficacy of the PD-1 inhibitor in this population before proceeding with randomized trials,” suggested Meiri.

A remaining question is whether a certain TMB threshold would predict favourable response to pembrolizumab, he added. “This can help identify candidates for treatment with pembrolizumab as opposed to regorafenib or trifluridine/tipiracil, which are used in third-line or later settings in patients with microsatellite-stable disease,” he explained.

“It would be important to evaluate whether patients with a higher TMB would have better response to pembrolizumab,” commented Dr Johanna C. Bendell of Sara Cannon Research Institute, Nashville, Tennessee, US. “We see similar interesting data emerging from lung cancer studies, where it is becoming unclear whether TMB can be used as a predictive marker for benefit from immune checkpoint inhibitor therapy. In this case, the basket study is providing evidence that the biomarker may not be right.”