The second-generation TKI dacomitinib, designed to treat NSCLC, is being evaluated in a clinical trial that will measure the drugâ€™s effectiveness as a first-line treatment.
Tony Mok, MD
The second-generation tyrosine kinase inhibitor (TKI) dacomitinib, designed to treat non-small-cell lung cancer (NSCLC), is being evaluated in an international phase III clinical trial that will measure the drug’s effectiveness as a first-line treatment in a genetic subset of patients with locally advanced or metastatic disease.
Dacomitinib blocks three of the four human epidermal growth factor receptor (HER) signaling pathways, which are implicated in cancer growth, survival, and metastasis. In NSCLC, at least one member of the HER family of receptors is expressed in 90% of solid tumors, with 60% of those tumors containing abnormalities in a HER family member that contribute to tumor development.1
In the phase III ARCHER 1050 trial now under way, dacominitib is being tested against gefitinib, a first-generation TKI, in patients with EGFR (HER1)-activating mutations, which affect 20% to 30% of Asians with NSCLC and up to 15% of Caucasians.1
“These are patients with advanced-stage adenocarcinoma with knownEGFRmutations. Obviously this is a potentially fatal disease if untreated,” said Tony Mok, MD, professor of Clinical Oncology at the Chinese University of Hong Kong and principal investigator for the trial. “The standard therapy is a first-generation EGFR TKI such as gefitinib or erlotinib. Tumor response rate is high and efficacy is good. However, resistance usually occurs within a year.”
In nearly half of all cases, acquired resistance is caused by a secondaryEGFRmutation, theT790Mbinding pocket mutation. The drug, developed by Pfizer, Inc., is designed to overcome or delay the impact of that mutation, said Joseph O’Connell, a senior director for Pfizer and the clinical lead for dacomitinib, who noted that the mutation alters the binding pocket’s conformation “and favors ATP (adenosine triphosphate) signaling, preventing the drugs from working.”
“Resistance in the other half of cases involves activation of other pathways that allow cancer cells to escape. Those mechanisms are less clear, however,” O’Connell said.
ARCHER 1050 is an open-label trial that will divide an estimated 440 patients at sites in Asia and Europe between two arms (Table). The first group will take dacomitinib 45 mg orally once daily, while the other group will take gefitinib 250 mg orally once daily. The study, which began in April, should be completed by December 2016. The primary outcome measure is progression-free survival (PFS). Overall survival (OS), including at 30 months, is a secondary measure.
The study was initiated on the basis of data obtained in a single-arm phase II trial (A7471017) of dacomitinib as first-line treatment for advanced NSCLC, including a cohort of patients with EGFR-activating mutations and another withHER2gene mutations or amplifications. Mok, who was a principal investigator for the earlier trial with Pasi Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, described the rates of PFS observed in that study as “relatively prolonged compared to historic data.”
CLINICALTRIALS.GOV IDENTIFIER: NCT01774721
Primary outcome measure:
PFS per independent radiologic review
Secondary outcome measures:
OS at 30 months; PFS by investigator
assessment; best overall response; duration
of response; overall safety profile; patient-reported
outcomes of health-related quality
of life; patient-reported outcomes by EQ-5D
Study start date:
Estimated study completion date:
18 years and older
SELECTED INCLUSION CRITERIA:
Evidence of pathologically confirmed, advanced NSCLC (with known histology) with the presence of EGFR activating mutation (exon 19 deletion or theL858Rmutation in exon 21)
Acceptable for subjects with the presence of the exon 20 T790M
mutation together with either EGFR activating mutation (exon 19 deletion
or the L858R mutation in exon 21) to be included
No prior treatment with systemic therapy for NSCLC
Adequate renal, hematologic, liver function
ECOG PS of 0-1
No evidence of mixed histology that includes elements of small cell or
carcinoid lung cancer
Any other mutation other than exon 19 deletion orL858Rin exon 21, with or without the presence of the exon 20T790Mmutation
Any history of brain metastases or leptomeningeal metastases
Dacomitinib (PF-00299804) 45-mg tablets, continuous oral daily dosing
Gefitinib 250-mg tablets, continuous oral daily dosing
Principal adverse events observed in the phase II study of dacomitinib (A7471017) were diarrhea and skin and nail changes
ECOG PS = Eastern Cooperative Oncology Group performance status; NSCLC = nonsmall cell lung cancer; OS = overall survival; PFS = progression-free survival.
Of the 53 participants identified with EGFR-activating mutations, the majority of whom were never-smokers, 74% remained progression-free at 1 year. Nearly all (96%) of a subset of patients with mutations inEFGRexons 19 and 21 were progression-free at 4 months, the primary endpoint of the study, and the preliminary median PFS for that group of 46 patients was 17 months.
The results, presented at the American Society of Clinical Oncology 2012 Annual Meeting, were from the EGFR cohort of the study. The HER2 cohort was recruiting patients at the time, and data were not yet available.
“To me, this is a very important study, as this may take us to the next stage of offering a ‘better’ TKI for our patients,” Mok added. “The new drug is promising for higher efficacy. However, we must note the potential toxicity, including skin rash, diarrhea, and mucositis. In my experience, it is essential to treat the toxicity early on; thus we have installed clear protocols for toxicity management.”
In the phase II study, there were 21 grade 3 adverse events and two grade 4 adverse events, but no treatmentrelated deaths. The most common side effects included diarrhea and skin and nail changes. Three out of 46 patients in the cohort of participants withEGFRexon 19 or 21 mutations discontinued dacomitinib due to treatmentrelated side effects.
A related phase II trial now under way, ARCHER 1042, is evaluating the effect of prophylactic intervention and an interrupted dosing schedule on the incidence of adverse events in patients treated with dacomitinib. That study, which began in December 2011, should be completed by August 2014.
Dacomitinib was designed as an irreversible inhibitor of the ATP binding site; the molecular bond it forms permanently blocks the binding site, inactivating HER receptor molecules by turning off the intracellular component of those cells that transmits the signaling that leads to growth, proliferation, and metastasis, O’Connell said.
“TKI inhibitors compete with ATP to enter the binding site and block it, like two people trying to go through the same doorway, whereas dacomitinib forms a covalent bond within the signaling pocket that prevents ATP from triggering further activity, like locking the doorway,” he said. First-generation TKIs such as gefitinib and erlotinib are reversible inhibitors.
Dacomitinib was also designed to block three of the four HER receptorsHER1 (EGFR), HER2 and HER4— which interact with each other in a variety of cancers, whereas first-generation EGFR inhibitors target only one receptor, O’Connell said.
Mok noted, for example, that HER2 is a partnering pathway with EGFR, forming chemical bonds (dimers) that activate the downstream pathway. The altered activity of a specific HER receptor can also be functionally compensated for by another HER receptor or other signaling pathways. The crosstalk can result in compensatory tumor signaling and growth, which can lead to drug resistance.2
Dacomitinib functions as a pan-HER inhibitor because there are enough similarities in the three HER binding sites it targets to enable it to bind with all three. By contrast, the HER3 receptor is “an important partner,” O’Connell said, but cannot be blocked by TKI small molecules because it lacks the ATP binding site.
“Irreversible inhibitors have not been a major focus of research and development to date, in part over concerns that they exacerbate toxicity, and so there are very few. This was really a theoretical concernbut what’s been found in practice is that the drugs are tolerable and comparable to other oral drugs and chemotherapy in terms of tolerability,” O’Connell said. “But they are part of a new push. With a better understanding about the molecular biology—elements like the ATP binding pocket and how it works in cell signaling—and why resistance develops, there has been a realization that stronger blockade of the signaling may be more effective.”
In a related phase III trial, ARCHER 1009, dacomitinib is compared with erlotinib, without a focus on patients with specific mutations (the study is no longer recruiting participants). The primary endpoint in that trial is also PFS. In an earlier phase II trial of dacomitinib versus erlotinib, 188 patients who had received one or two prior chemotherapy regimens were divided between a dacomitinib arm and an erlotinib arm. Median PFS was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib, and median OS was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib.3
O’Connell said that Pfizer is also looking at the role of dacomitinib in targeting the HER signaling pathway in gastrointestinal cancer, head and neck cancer, and glioblastoma. There are also ongoing preclinical studies of the drug in bladder and pancreatic cancers.