RE:Publication of Positive Poziotinib Data in Cancer Cell excerpts
While Food and Drug Administration (FDA)-approved targeted therapies exist for cancers harboring ERBB2 amplifications, there are no approved targeted therapies for tumors having ERBB2 mutations. However, the National Comprehensive Cancer Network guidelines for non-small cell lung cancer (NSCLC) recommend that newly diagnosed patients undergo broad molecular profiling to detect ERBB2 mutations.
Studies have demonstrated that exon 20 mutants have extensive resistance to most noncovalent and covalent TKIs (Nagano et al., 2018; Robichaux et al., 2018), including neratinib, afatinib, and dacomitinib, although some uncommon HER2 exon 20 mutants demonstrated sensitivity (Kosaka et al., 2017). More recently, we reported that poziotinib effectively inhibited HER2 exon 20 insertion mutants at concentrations achievable in patients, and poziotinib treatment induced a radiological response in one patient whose lung cancer harbored an ERBB2 exon 20 mutation (Robichaux et al., 2018).
ERBB2 overall mutations occurred most frequently in bladder (8.3%), bile duct (5.3%), and stomach (4.5%) cancers (Figure 1A), whereas ERBB2 exon 20 mutations occurred most frequently in cancers of the small intestine (1.8%), lung (1.5%), and breast (0.9%) (Figure 1B). ERBB2 Mutations Occur Most Frequently in the Tyrosine Kinase Domain-Coding Region, and Mutational Hotspots Vary by Malignancy. We analyzed the frequency of mutations within the various regions of HER2 reported in cBioPortal and at MDACC. Across all cancers, ERBB2 mutations occurred most frequently in the tyrosine kinase domain (46%), which included mutations in exon 20 (20%), exon 19 (11%), and exon 21 (9%) (Figure 2A).
Poziotinib Was the Most Potent TKI Tested and Inhibited the Most Common HER2 Mutants In Vitro…
HER2 Mutant Human Cell Lines Showed Enhanced Sensitivity to Poziotinib…
Poziotinib Has Antitumor Activity in Patients with NSCLC Harboring ERBB2 Mutations…
Combination of Poziotinib and T-DM1 Treatment Potentiates Antitumor Activity…
DISCUSSION Our pan-cancer analysis reveals that ERBB2 mutational hotspots vary by cancer type and have differential sensitivity to HER2 TKIs in vitro, which likely affect clinical efficacy. In the SUMMIT trial, neratinib was most effective in breast cancer patients, with the majority of responders having tumors with L755S, V777L, or L869R (Hyman et al., 2018). In our in vitro screening, these mutations correlated with low IC50 values. In contrast, patients with colorectal cancer did not respond to neratinib (Hyman et al., 2018). We found that the V842I mutation is the most common ERBB2 mutation in colorectal cancers and that this mutant was not sensitive to neratinib in vitro. These data suggest that different TKI sensitivities between malignancies may be, in part, explained by cancer-specific mutational hotspots, which directly affect drug sensitivity. Data from the SUMMIT trial showed that while specific exon 20 insertions were associated with neratinib sensitivity in breast cancer patients, these identical mutations were associated with resistance in other cancer types, demonstrating that there may be other mechanisms underlying these tumor-type-specific differences that merit further investigation. Exon 20 insertion mutations and the exon 19 L755P mutation are resistant to most HER2 TKIs. MDS revealed that these mutations induce conformational changes that affect the overall size and shape of the drug-binding pocket. Collectively, these in vitro and in silico findings are consistent with the clinical observations that patients with ERBB2 exon 20 insertion mutations historically have had poor responses to TKIs. In NSCLC, where exon 20 insertions frequently occur, patients harboring ERBB2 exon 20 insertion mutations had response rates of 0% (Hyman et al., 2018), 11.5% (Kris et al., 2015), and 18.2% (Mazieres et al., 2016) to 18.8% (Peters et al., 2018) to neratinib, dacomitinib, and afatinib, respectively. Moreover, while L755S mutations have been shown to respond to neratinib, L755P mutations are profoundly resistant to both TKIs and ADCs (Hyman et al., 2018; Li et al., 2018; Mazieres et al., 2016). Our testing of a panel of covalent and non-covalent EGFR and HER2 TKIs against the most common HER2 mutants revealed that poziotinib has activity against the most common HER2 variants, including exon 19 and 20 mutants that are resistant to other HER2 TKIs. We have previously reported that exon 20 insertions have a sterically hindered drug-binding pocket, and that the size and flexibility of poziotinib can overcome this challenge (Robichaux et al., 2018). Likewise, in silico modeling of the L755P variant in the current report indicates that this alteration reduces the volume of the drug-binding pocket, which is predicted to limit the binding of drugs with larger terminal groups oriented toward the aC helix such as neratinib and osimertinib. In contrast, due to the terminal halogenated benzene group of poziotinib, the drug can bind deeply within the hydrophobic cleft created by A751, K753, L796, and T798 in HER2 (Robichaux et al., 2018). This interaction of the terminal benzene group with the hydrophobic cleft results in the alignment of the quinazoline core with residues at the back of the drug-binding pocket, maintaining receptor binding. Previous pre-clinical data in lung cancer (Robichaux et al., 2018) and current pre-clinical models of breast and colon cancer demonstrate that poziotinib has broad antitumor effects in multiple ERBB2 mutant cancer types and across exons. In a recent report, two of five (40%) patients with NSCLC harboring ERBB2 exon 20 insertions treated with poziotinib (12 mg or 8 mg) had a partial response (Oh et al., 2018). A recent case study reported that poziotinib induced a radiological response and clinical improvement in a heavily pretreated patient with ERBB2 mutant (G778dupGSP) breast cancer (Pandey and Brufsky, 2018). In the first 12 patients of clinical trial NCT03066206 with ERBB2 exon 20 mutant disease, we observed a confirmed ORR of 42% and a mPFS of 5.6 months. In addition, a patient with an L755P mutation, treated on a compassionate care use protocol, demonstrated a durable minor response to poziotinib lasting more than 7 months. Collectively, these data strongly suggest that poziotinib has activity against the most frequent ERBB2 variants and across diverse malignancies harboring ERBB2 mutations. In comparison, previous studies have reported that patients with ERBB2 mutant NSCLC had an ORR of 6% and mPFS of 1.9 months to second-line immune checkpoint (PD-1/ PDL-1) blockade (Negrao et al., 2018); an ORR of 10% and mPFS of 4.3 months to second-line non-HER2-targeted therapies (Mazieres et al., 2016); or an ORR of 7% and mPFS of 3.4 months to second-line HER2-targeted agents, neratinib, lapatinib, or afatinib (Mazieres et al., 2016). Furthermore, in the general platinum-refractory NSCLC population, standard second-line chemotherapy, docetaxel, has an ORR of 7%–13% and mPFS of 2–4 months (Hanna et al., 2004; Herbst et al., 2016; Horn et al., 2017; Rittmeyer et al., 2017; Shepherd et al., 2000). Toxicity of poziotinib was comparable with that of other quinazoline-based, FDA-approved TKIs afatinib and dacomitinib (Mok et al., 2018; Sequist et al., 2013). In the phase III study of afatinib for EGFR mutant NSCLC (Lux-lung 3, Sequist et al., 2013) and in the phase III study of dacomitinib for EGFR mutant NSCLC (Archer1050, Mok et al., 2018), 52% and 67% of patients had dose reductions due to AEs, respectively. Of the first 12 patients in our study receiving poziotinib, 67% of patients received dose reductions. Furthermore, in the Lux-lung 3 study and Archer1050 study, 8% and 10% of patients discontinued treatment due to AEs. In the first 12 patients receiving poziotinib, no patients discontinued treatment due to AEs. Previous studies of lapatinib in ERBB2-amplified breast cancer showed that lapatinib caused accumulation of HER2 on the cell surface, which enhanced trastuzumab binding and antitumor effects (Scaltriti et al., 2009). Furthermore, meta-analysis of several clinical trials found that combination of lapatinib and trastuzumab significantly increases pathological complete responses of HER2-positive breast cancers regardless of hormone receptor status (Baselga et al., 2012a; Xu et al., 2017). We find that poziotinib upregulates mutant, but not WT, HER2 on the cell surface and that combination of poziotinib with T-DM1 decreases cell viability in vitro and causes complete regression of HER2 exon 20 mutant NSCLC tumors in mice. Together, these data suggest that the high affinity and specificity of poziotinib for HER2 mutants make poziotinib a good candidate for combination with T-DM1 by enhancing mutant, but not WT, HER2 on the cell surface for targeting with T-DM1. Furthermore, these data highlight the need for clinical trials testing the efficacy of poziotinib and T-DM1 combination therapy in ERBB2 mutant malignancies.
