Novel Irreversible EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

Vincent A. Miller, MD
Memorial Sloan-Kettering Cancer Center, New York, New York

Despite the dramatic initial results seen with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non–small cell lung cancer (NSCLC) patients with activating EGFR mutations, relapse inevitably occurs. This is due to the development of "acquired resistance" that often arises from second EGFR kinase domain mutations such as T790M. In vitro and in vivo studies have shown that several small-molecule EGFR inhibitors can covalently bind to the EGFR and effectively inhibit growth of tumors harboring T790M, inducing regressions of established tumors in mice bearing mutations such as L858R/T790M. This overview summarizes clinical results obtained with several molecules for which preclinical data suggest activity in patients with acquired resistance.

BIBW2992

BIBW2992 is a potent, oral, irreversible inhibitor of EGFR (IC₅₀, 0.5 nM) and HER2 (IC₅₀, 14 nM) tyrosine kinases.⁹² BIBW2992 has activity against NSCLC cell lines with activating sensitive (IC50, 0.7 nM in the L858R-bearing H3255) and resistant EGFR TK domain mutations (IC₅₀, 99 nM in the L858R + T790M–bearing NCI 1975). Durable responses were observed in phase I trials of BIBW2992 in NSCLC patients with activating EGFR mutations, and the recommended phase II dose was 50 mg once daily. Preliminary results from a phase II study of BIBW2992 in patients with documented EGFR activating mutations were recently reported by Yang and colleagues.¹⁵

The primary endpoint in this phase II, open-label, single-arm, ongoing multicenter trial conducted in the United States and Taiwan is objective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points include disease control (clinical response [CR], partial response [PR], stable disease [SD]), time to objective response (OR), duration of OR, progression-free survival (PFS), overall survival, and safety. A 2-stage design was planned, and the study would continue only if 16 of the initial 40 patients achieved a complete or partial response (40% CR and PR) as determined by treating investigators.

BIBW2992 was given at a dose of 50 mg/day until disease progression or undue toxicity. Key eligibility criteria included pathologically confirmed stage IIIB, IV, or recurrent adenocarcinoma of the lung, and the presence of an activating mutation in exon 18, 19, 20, or 21 of the EGFR as determined by direct DNA sequencing. Patients must have experienced disease progression following first-line cytotoxic chemotherapy or developed recur rent disease after prior neoadjuvant or adjuvant chemotherapy.

At the time of presentation, 174 patients (Taiwan: 156; US:18) had been screened for mutations. EGFR mutations were identified in 64 patients from Taiwan (41%, 95% CI 37%–45%) and none from the US. Twenty-eight patients were treated with BIBW2992, and results of the first 24 of these were presented.¹⁵ Twenty-seven patients (42%) were identified with EGFR L858R, 26 (41%) with exon 19 del, 5 (7.8%) with an exon 20 insertion, and 1 patient each with G863V, L861P, K860E, L861Q, G719S+S768I, and G724S+S768I. A tumor sample insufficient for complete sequencing of the 4 exons was present in 34 cases. The median age was 60 (range, 38-82). Fourteen of 24 patients were female, and ECOG performance status (PS) was 0/1/2 in 15, 8, and 1 patient, respectively. Fourteen of 24 patients were never-smokers.

The investigators concluded that BIBW2992 is quite active, with 12 PRs (50%, 95% CI 30%–70%) in the first 24 patients, 10 of which were confirmed. The drug appeared to be fairly well tolerated in this enriched population, with rash and diarrhea as the most common clinically significant toxicities. Nine dose reductions were necessary in 7 patients: 5 for diarrhea, and 1 each for rash, mucositis, hand-foot syndrome, and transient renal insufficiency. Further evaluation of BIBW2992 is warranted in NSCLC patients genotypically and/or demographically enriched for the presence of EGFR mutations. A randomized phase II/III trial (LUX-Lung 1) has been initiated to study BIBW2992 in patients with NSCLC failing reversible EGFR inhibitors and enriched for T790M mutations.

Neratinib (HKI-272)

Neratinib (HKI-272), also an irreversible TKI, inhibits EGFR and HER2 tyrosine kinase activity through covalent binding to critical cysteine residues at the ATP binding site. Preclinically, neratinib inhibits growth in cell lines or xenografts that contain both EGFR sensitizing and resistance-associated mutations (e.g.,T790M).⁹³ Treatment also results in regression of murine tumors driven by EGFR kinase domain or VIII mutations.^94,95

In a prior phase I study of neratinib, 6 of 16 patients with advanced NSCLC and prior gefitinib or erlotinib treatment had SD for 24 weeks.⁹⁶ Thus, a 3-arm phase II trial was undertaken in patients with stage IIIB/IV recurrent NSCLC to further characterize the safety and efficacy of neratinib in populations clinically or molecularly enriched for EGFR sensitivity.¹⁶ EGFR mutations were analyzed by direct sequencing. Patients were enrolled and assigned to Arm A or B if they had disease progression following 12 weeks of erlotinib or gefitinib, and either EGFR mutation (Arm A) or EGFR wild-type tumors (Arm B). Patients were enrolled in Arm C if they had no prior EGFR-TKI treatment, adenocarcinoma, 20 pack-year smoking history, and were current non-smokers. The primary endpoint was overall response rate.

The investigators recently reported preliminary data for 165 patients (median age 60 years, 30% male, 37/59/4% with PS 0/1/2, and 64% with 1 prior chemotherapy regimen for metastatic disease).¹⁶ Patients initially received 320 mg neratinib daily, but the protocol was amended to lower the dose to 240 mg because of reported gastrointestinal adverse events (AEs). Diarrhea was the only grade 3 AE that occurred in 5% of patients (320 mg dose: 47%, 240 mg dose: 25%). Reasons for discontinuation included disease progression (78%), AEs (5%), and symptomatic deterioration (7%). Twelve of 165 (7%) patients had T790M mutations. Of the 28 patients in Arm C, 11 had EGFR mutations, 14 had no EGFR mutations, and the EGFR status of 3 patients was unknown. In Arm A, 2 patients had PR and 42 had SD (10 with clinical benefit (CR+PR+ SD 24 wks). In Arm B, 1 patient had a PR, 22 had SD, and 5 had clinical benefit 24 wks. In Arm C, 1 patient had PR, 11 had SD, and 6 experienced clinical benefit 24 wks. The overall objective response rate was 2% (4/165). None of the responders had T790M mutations. Median PFS was 11.6 weeks (Arm A), 14.7 weeks (Arm B), and 7.4 weeks (Arm C).

The investigators concluded that neratinib is reasonably tolerated, with diarrhea as the most common grade 3 AE. Eighteen (11%) NSCLC patients with prior erlotinib/gefitinib treatment had SD for 24 weeks. Exploratory analyses are ongoing to correlate out come with clinical and molecular parameters.

PF-00299804

PF-00299804 is an oral, irreversible small-molecule inhibitor of HER1, HER2, and HER4. Janne and colleagues recently reported results of the first-in-human (FIH) assessments, with special monitoring for left ventricular ejection fraction, corneal, and renal AEs.¹⁷This was a dose-escalation cohort study with an additional intrapatient dose-escalation scheme. Patients would remain on study until intolerable toxicity, progression, withdrawal of consent, or death. Two treatment schedules were investigated: Schedule A–once-daily (QD) dosing, and Schedule B–2 weeks QD/21-day cycle (at 133% QD, MTD 60 mg). At the MTD, 3 separate cohort expansions were undertaken: all patients to confirm tolerability, patients with refractory NSCLC (KRAS wild-type), and patients with HER1(EGFR), HER2, and/or HER3 amplification, and/or if NSCLC, HER1 and/or HER2 mutations.

At the time of data presentation, 43 patients with NSCLC had been enrolled. Median age was 57 years (range, 26-77); 95% of patients had received prior EGFR-TKIs, and 77% had prior chemotherapy. Fifty-three percent were never-smokers, and 24 (56%) had EGFR mutations, 4 of whom had T790M. Confirmed PRs were observed in 4 of 33 (12%) evaluable patients, who had remained on study 13+, 7.5, 5+, and 5+ months, respectively. An additional patient with SD remained on study drug for >11 months. The most common treatment-related AEs were diarrhea (22 patients) and rash and other skin-related events (20 patients). The investigators concluded that given the predictable safety profile and promising activity, particularly in patients with EGFR mutations thought to be resistant to reversible EGFR-TKIs (e.g., exon 20 insertions), additional clinical trials were warranted in untreated, clinically enriched populations and in patients who had failed prior EGFR-TKI therapy.

Conclusions and Future Directions

The identification of EGFR TK domain mutations in NSCLC and their association with sensitivity to EGFR-TKIs has been a watershed event in the treatment of this lethal cancer. Treatment may now be selected in some patients on a truly individual basis rather than empiricism. Although even the patients most sensitive to this strategy eventually relapse or progress, rebiopsy can establish the molecular basis of this phenomenon in about two thirds of cases. Treatment using second-generation irreversible EGFR-TKIs directed at T790M, the cause of acquired resistance in slightly more than 50% of cases, has now advanced to phase III study. However, only through careful examination of rebiopsy specimens or circulating tumor cells obtained at treatment failure can the basis of acquired resistance be more fully understood and more effective patient-specific treatment strategies be instituted.

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