Tucatinib Active in Heavily Pretreated HER2+ Breast Cancer

Rashmi K. Murthy, MD, MBE

Tucatinib used in combination with capecitabine, trastuzumab (Herceptin), or both agents showed promising antitumor activity in heavily pretreated women with HER2-positive breast cancer with or without brain metastases, according to findings published in The Lancet Oncology.¹

In phase Ib results from a nonrandomized, open-label study, 83% (5/6) of patients with measurable disease treated with tucatinib/capecitabine had an objective response, as did 40% (6/15) of patients receiving tucatinib/trastuzumab. Sixty-one percent (14/23) of patients treated with the combination of all 3 drugs had an objective response.

The median duration of response was 8.9 months (range, 1.4-8.9) in the tucatinib/trastuzumab arm, 5.2 months (range, 2.1-7.6) in the tucatinib/capecitabine arm, and 11.0 months (range, 2.9-18.6) with the triplet.

“Up to 50% of women with HER2-positive metastatic breast cancer experience CNS metastases. When they arise, they can compromise survival and impact quality of life for patients,” first author Rashmi K. Murthy, MD, MBE, an assistant professor in the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said in a January 2018 interview with OncLive.

“There remains an unmet medical need for patients with HER2-positive metastatic breast cancer whose disease has metastasized to the brain,” she added. “The current systemic therapies do not penetrate the blood-brain barrier well, so there is a need for anti-HER2 agents that successfully do cross over.”

Sixty patients were recruited at 5 sites in the United States from January 2014 to December 2015. All patients had received prior trastuzumab, 55% had received lapatinib (Tykerb), 65% had received pertuzumab (Perjeta), and 97% had received ado-trastuzumab emtansine (T-DM1; Kadcyla). The median number of unique HER2-targeted treatments was 3 (range, 3-4).

Eight patients were assigned to 350 mg of twice-daily tucatinib and 52 were assigned to 300 mg twice daily. Maximum-tolerated dose recommended phase II dose for tucatinib in combination were the primary objectives.

Investigators observed no dose-limiting toxicities (DLTs) in the dose-escalation and expansion cohorts in either doublet when tucatinib was administered at the 300-mg dose level. There was a single DLT in the 300-mg dose level in the dose-escalation and expansion triplet cohort (n = 27). The DLT was a grade 4 cerebral edema occurring in a patient with an untreated brain metastasis. The patient had not been treated with corticosteroids before the DLT.

The recommended phase II dose of tucatinib was set at 300 mg twice daily.

The median progression-free survival (PFS) was 7.8 months (95% CI, 4.1-12.5) in the triplet arm, 7.1 months (95% CI, 4.4-9.7) in the tucatinib/capecitabine arm, and 5.5 months (95% CI, 1.5-10.2) in the tucatinib/trastuzumab arm (n = 18). The clinical benefit rate was 74% in the triplet arm.

At baseline, 29 (56%) patients treated at the recommended phase II dose had brain metastases, 12 (41%) of whom had measurable metastases. Seventeen (59%) were either treatment-naïve or had progressed despite prior treatment.

In the triplet arm, the median PFS was 6.7 months (95% CI, 1.4-12.5) for patients with brain metastases (n = 11).

Investigators used modified RECIST criteria permitting a bicompartmental separation of body and brain to conduct an exploratory analysis assessing the efficacy of all 3 combinations in patients with brain metastases. One patient with measurable brain metastases had untreated asymptomatic brain metastases and 11 had treated progressive metastases.

Of those, 5 (42%) had brain-specific objective response, 5 had stable disease, and 1 had progressive disease. One patient was not evaluable.

Five (8%) patients, all assigned to 300 mg of tucatinib, died of disease progression within 30 days of their last tucatinib dose. There were no treatment-related deaths reported.

Twenty (33%) patients experienced serious adverse events (AEs), 3 (5%) of which were related to the study drug: 1 cerebral edema in the triplet arm with tucatinib administered at 300 mg, 1 incidence of nausea in the 350 mg of tucatinib/capecitabine arm, and 1 incidence of vomiting in the 350 mg of tucatinib/trastuzumab arm.

At the recommended phase II dose, the most common (≥5%) grade ≥3 treatment-emergent AEs in all patients were fatigue (8%), diarrhea (7%), and palmar-plantar erythrodysesthesia (7%). There were 4 (15%) incidents of grade 3 diarrhea in the triplet arm and 1 (4%) incident of grade 4. There was 1 grade 3 diarrhea in the tucatinib/capecitabine arm and none in the tucatinib/trastuzumab arm. There was no incidence of grade 4 diarrhea in either doublet arm.

“[Tucatinib] is such a pure small molecule inhibitor that doesn’t have some of the side effects that are problematic for patients, including the most problematic one, which is diarrhea,” study coauthor Kimberly L. Blackwell, MD, medical oncologist, Duke Cancer Institute, said in a March 2018 interview with OncLive.

“It is a very exciting drug because it appears to work and get into the blood-brain barrier space. It looks like its toxicity profile is quite nice, with very low incidence of diarrhea and rash. The low side effect profile is going to make this a very exciting drug to combine with standard chemotherapy, as well.”

In an accompanying editorial, Luca Gianni, MD, department of Medical Oncology, Ospedale San Raffaele—IRCCS, Milan, Italy, wrote that tucatinib is attractive because of its “improved tolerability profile.” He noted that it would be “remarkable” if tucatinib was shown to have a lower incidence of diarrhea with drugs other than capecitabine.²

“The second feature that makes tucatinib appealing is the pattern of antitumor activity,” he wrote. “The new tucatinib regimens had good or even outstanding activity in women with disease progression who had run out of conventional anti-HER2 options with monoclonal antibodies, trastuzumab emtansine, and other TKIs. This result alone deserves further research that is indeed ongoing in a placebo-controlled trial.”

“So, is there the room and need for yet another HER2-directed drug?” he asked. “The evidence suggests that there is, provided that the new candidate makes the difference in areas of medical need left behind by the rich armamentarium of HER2-directed drugs that are already available. Tucatinib is a potentially first-in-class HER2-selective TKI that could make that difference.”

Investigators are evaluating the triplet combination versus placebo in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with a taxane, trastuzumab, pertuzumab, and T-DM1 in the phase II HER2CLIMB trial (NCT02614794). The trial is currently recruiting patients, with an expected primary completion date of September 2020.

References

1. Murthy R, Borges VF, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study [published online May 24, 2018]. Lancet Oncol. doi: 10.1016/ S1470-2045(18)30256-0.
2. Gianni L. Is there room for another HER2-targeting drug? [published online May 24, 2018]. Lancet Oncol. doi: 10.1016/ S1470-2045(18)30405-4.