Poziotinib for Patients With HER2 Exon 20 Mutant Non–Small-Cell Lung Cancer: Results From a Phase II Trial

PURPOSE

Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a single-arm, open-label, phase II study.

PATIENTS AND METHODS

Patients with advanced HER2 exon 20 mutant NSCLC were enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The primary end point was objective response rate per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response.

RESULTS

Thirty patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed objective response rate was 27% (95% CI, 12 to 46). Responses were observed across HER2 exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI, 4.0 to not estimable). The median progression-free survival was 5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95% CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhea (20%). There was one possible treatment-related death because of pneumonitis.

CONCLUSION

Poziotinib showed promising antitumor activity in patients with HER2 exon 20 mutant NSCLC including patients who had previously received platinum-based chemotherapy.

INTRODUCTION

Human epidermal growth factor receptor 2 (ERBB2, HER2) mutations occur in 3% of lung cancers, and in non–small-cell lung cancer (NSCLC), 48% of all HER2 mutations including variants of unknown significance are exon 20 mutations.¹ Preclinical studies have demonstrated that HER2 exon 20 mutations are resistant to most currently approved covalent and noncovalent tyrosine kinase inhibitors (TKIs), including afatinib, neratinib, and dacomitinib,^2-4 with reported objective response rates (ORRs) of 0%-19%.^5-8 The current standard of care for this population remains cytotoxic chemotherapy with or without programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors, which have limited activity for these patients.^9-11 Therefore, there is a substantial need for new therapies for HER2 exon 20 mutant NSCLC.

CONTEXT

• Key Objective

• Currently, there are no targeted therapies approved for patients with human epidermal growth factor receptor 2 (HER2) exon 20 mutant non–small-cell lung cancer (NSCLC). This phase II single-arm investigator-initiated trial was designed to determine the antitumor activity of poziotinib, an irreversible covalent tyrosine kinase inhibitor, in patients with HER2 exon 20 mutant NSCLC.

• Knowledge Generated

• Poziotinib resulted in promising antitumor activity with an objective response rate of 27% in patients with advanced HER2 exon 20 mutant NSCLC. The most common poziotinib-related severe adverse events were skin rash and diarrhea.

• Relevance

• Our results show that HER2 exon 20 mutations can be targeted effectively using small tyrosine kinase inhibitors such as poziotinib. We conclude the poziotinib may be a new therapeutic option for patients with HER2 exon 20 mutant NSCLC including those who were previously treated with platinum-based chemotherapy and immunotherapy.

More recently, other HER2-directed approaches have been explored. The combination of anti-HER2 monoclonal antibodies trastuzumab and pertuzumab reported a 21% (95% CI, 5 to 51) ORR for patients with NSCLC.¹² In a study of patients with NSCLC harboring any HER2 mutation, ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC), 6 of 11 (54.5%) patients harboring HER2 exon 20 insertion mutations had a partial response.¹³ In preliminary results for another trastuzumab-based ADC, trastuzumab deruxtecan (Ds8201a), an ORR of 62% (95% CI, 46 to 76) was reported in patients with NSCLC bearing any HER2 mutation.¹⁴ Based on the last two clinical studies, the National Comprehensive Cancer Network guidelines have included T-DM1 and trastuzumab deruxtecan as treatment options for patients with HER2 mutant NSCLC.¹⁵ Finally, pyrotinib, an irreversible TKI, yielded a response rate of 30.0% (95% CI, 18.8 to 43.2) in patients with HER2 exon 20 mutant lung cancer.¹⁶

Poziotinib (HMB781-36B) is an orally available, irreversible covalent TKI. Although poziotinib shares a similar quinazoline backbone with afatinib and dacomitinib, because of the smaller size, increased halogenation, and flexibility of the drug, poziotinib can circumvent the steric hindrance in drug-binding pocket induced by HER2 or epidermal growth factor receptor (EGFR) exon 20 insertions.^1,17 The predicted activity of poziotinib was confirmed using in vitro and in vivo models demonstrating the potent antitumor activity of poziotinib in cells with these mutations.^1,17 Based on our preclinical findings, we initiated an investigator-sponsored multicohort phase II trial of poziotinib in patients with advanced solid tumors including NSCLC harboring HER2 or EGFR mutations. Herein, we report the primary results from a cohort of patients with NSCLC with HER2 exon 20 mutations treated as part of our trial.

PATIENTS AND METHODS

Patients and Study Design

This is a single-center, phase II, open-label, single-arm, multicohort, investigator-initiated trial. Patients with stage IV or recurrent HER2 exon 20 mutant lung cancer were eligible for the cohort reported here. Other cohorts of this trial not reported here include EGFR exon 20 mutant lung cancer, HER2 exon 19 solid tumors, and solid tumors, excluding lung cancer, with exon 20 EGFR or HER2 mutations (Appendix Fig A1, online only). HER2 exon 20 mutations were documented by one of the following Clinical Laboratory Improvement Amendments–certified tests: Oncomine Comprehensive Assay, Guardant360 Assay (using plasma), or FoundationOne Assay. In addition, patients were at least 18 years of age, had adequate organ function, and had measurable disease (using computed tomography [CT], positron emission tomography-CT, or magnetic resonance imaging) as defined by RECIST version 1.1 guidelines,¹⁸ Eastern Cooperative Oncology Group performance status 0 or 1. Patients with CNS metastases were eligible if the disease was asymptomatic, was treated with surgery and/or radiation, and was stable without requiring escalating corticosteroids or anticonvulsant medications for at least 4 weeks before the first dose of poziotinib. Key exclusion criteria included treatment with chemotherapy, investigational agent, or other anticancer drugs within 14 days of the first dose of poziotinib; and cardiac ejection fraction < 50% by either echocardiogram or multigated acquisition scan. Detailed inclusion and exclusion criteria are provided in the Protocol (online only).

The Protocol was approved by MD Anderson Cancer Center Institutional Research Ethics Board (IRB protocol ID 2016-0783). All patients provided written informed consent before study procedures, sampling, and analyses, and the study was done in accordance with the Declaration of Helsinki. This study is registered with ClinicalTrials.gov, NCT03066206.

Treatment and Assessment

Patients received poziotinib 16 mg orally once daily, until objective disease progression, and could continue beyond progression for as long as clinical benefit was observed, as judged by the investigator and in the absence of other discontinuation criteria (patient withdrawal and adverse event). Patients who discontinued poziotinib for reasons other than disease progression continued with tumor assessments until disease progression. Dose interruption or reduction occurred if patients had a grade 3 or more non–disease-related adverse event or unacceptable toxicity such as grade 2 diarrhea lasting for 7 or more days. If the adverse event resolved or reverted to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) grade 1, poziotinib treatment could be restarted at the same dose (16 mg) or a lower dose (12 mg). A second reduction of dose to 8 mg was allowed for reoccurrence of same toxicity. If toxicity recurred following two dose modifications, poziotinib was discontinued.

Tumor response according to RECIST version 1.1 was assessed by a thoracic radiologist using CT, positron emission tomography-CT, or magnetic resonance imaging scans taken at baseline, and every 8 weeks from the start of poziotinib. Confirmation of objective responses was required by a second scan more than 28 days after initial response was noted. During the treatment period, serum chemistry, hematology, vital signs, physical examination, weight, digital electrocardiogram, and Eastern Cooperative Oncology Group performance status were assessed every 4 weeks; left ventricular ejection fraction was assessed every 12 weeks; and adverse events (graded according to CTCAE version 4.03) were monitored continuously throughout the treatment period.

Outcomes

The primary end point was the proportion of patients who achieved an objective response as assessed by the investigator according to RECIST version 1.1 and was defined as the number of patients who had a complete or partial response. Secondary end points included progression-free survival (PFS), duration of response (DoR), disease control, overall survival (OS), and safety. PFS was defined as the time from date of first dose until the date of objective disease progression or death regardless of whether the patient discontinued poziotinib or received another anticancer therapy before progression. DoR was defined as the time from the date of first documented response (subsequently confirmed) until the date of documented progression or death in the absence of disease progression. Disease control was defined as the percentage of patients who have a best overall response (defined as complete response, partial response, or stable disease for 8 weeks or longer). OS was defined as the time from the date of first dose until death because of any cause.

Statistical Analysis

We hypothesized that poziotinib is an effective and well-tolerated targeted treatment for patients with ERBB2 exon 20 mutant lung cancer. This patient cohort was sized to recruit 30 patients. A sample size of 30 patients ensures that, if the trial is not terminated early, a posterior 90% credibility interval for ORR will have width of 0.266 at most, under the assumption of a 30% ORR. To ensure that the study could be terminated early in the event of the regimen being inefficacious or unsafe, the ORR and toxicity (as defined in the Protocol) were monitored simultaneously by every 10 patients according to the stopping boundaries calculated using the Bayesian approach of Thall et al^19,20 as extended by Thall and Sung.²¹ Patient demographics, disease characteristics, treatment information, and clinical outcomes were summarized through descriptive statistics. The rates of best overall response and disease control and their exact 95% confidence intervals were estimated. PFS, DoR, and OS outcomes were calculated using the Kaplan-Meier method. Data were analyzed using a March 01, 2021, data cutoff. Statistical software programs SAS 9.4 (SAS, Cary, NC) and S-Plus 8.0 (TIBCO Software Inc, Palo Alto, CA) were used for all the analyses.

RESULTS

Patients

Between March 30, 2017, and November 11, 2019, 35 patients were screened, of whom 30 started poziotinib treatment between September 18, 2017, and November 22, 2019 (Appendix Fig A2, online only). All treated patients are included in safety and efficacy analysis presented here. Baseline characteristics are shown in Table 1. The majority of patients had never smoked, and all patients had histologic features of adenocarcinoma. All but two of the patients (93%) had received prior therapy including 90% who received prior platinum-containing chemotherapy, 80% who received prior PD1 or PDL1 inhibitor, and 53% who had received two or more prior lines of therapy (Appendix Table A1, online only). The most common HER2 exon 20 mutation was Y772_A775dupYVMA (77%, n = 23), followed by G778_P780dupGSP (17%, n = 5). The median duration of treatment follow-up at the time of data analysis (data cutoff March 1, 2021) was 14 months (range, 2.0-43 months).

TABLE 1.

Patients Characteristics (n = 30)

Efficacy

The investigator-assessed ORR at 8 weeks was 43% (95% CI, 25 to 63, n = 13) and the disease control rate was 73% (95% CI, 54 to 88, Table 2). Among 13 patients who achieved a partial response, eight were confirmed at subsequent imaging resulting in a confirmed response rate of 27% (95% CI, 12 to 46, Fig 1). Responses were observed across HER2 exon 20 mutation subtypes (Appendix Table A2, online only). The median DoR was 5 months (95% CI, 4.0 to not estimable, Fig 2A), and the median PFS was 5.5 months (95% CI, 4.0 to 7.0, Fig 2B). The PFS rate at 6 and 12 months was 30% (95% CI, 17 to 52) and 10% (95% CI, 3.4 to 29), respectively. In the subset of patients who had previously received platinum-based chemotherapy (n = 27), the median PFS was 5 months (95% CI, 2.0 to 6.0), and the 8-week ORR was 47% (95% CI, 25 to 59) with a confirmed partial response rate of 26% (95% CI, 13 to 45). The median PFS in patients who received two or more prior lines of therapy (N = 16) was 4 months (95% CI,: 2.0 to 6.0), and the 8-week objective response was 31% (95% CI, 14 to 56) with confirmed partial response rate of 19% (95% CI, 7.0 to 43). The median duration of exposure (length of time on treatment with poziotinib, irrespective of dose interruptions) was 6 months (interquartile range, 3.0-8.0 months; range, 0.6-43 months; Fig 3). At data cutoff, two patients remained on treatment, one patient with a confirmed partial response and one patient with prolonged stable disease. Notably, both patients remain on poziotinib after more than 3 years from starting treatment. Eight patients continued poziotinib treatment beyond radiologic disease progression for a median of 2 months (range, 1.5-8.2 months). At the time of data cutoff, 16 patients (53%) had died. Of these, 15 (50%) deaths were considered related to cancer progression and one (3%) was considered possibly related to study drug adverse event. The median OS was 15 months (95% CI, 9.0 to not estimable, Appendix Fig A3, online only).

TABLE 2.

Best Response to Treatment by RECIST 1.1 Criteria

FIG 1.

Waterfall plot of best response. DCR, disease control rate; ORR, objective response rate.

FIG 2.

(A) Kaplan-Meier estimate of DoR. (B) Kaplan-Meier estimate of PFS. DoR, duration of response; NE, not estimable; PFS, progression-free survival.

FIG 3.

Swimmers plot of poziotinib treatment duration. Each bar denotes a single patient. P indicates patient received previous platinum-based therapy and I indicates patient received previous immunotherapy. Additional previous treatments for each patient can be found in Appendix Table A1.

Safety

With a median duration of exposure (length of time on poziotinib) of 6 months (interquartile range, 3.0-8.0 months; range, 0.6-43 months), the treatment-related adverse events (TRAEs) of any grade were reported in 29 patients (97%), most of them grade 1 or 2. The most common TRAEs were skin rash (83%), diarrhea (80%), paronychia (70%), oral mucositis (67%), and dry skin (63%). Grade 1 and 2 TRAEs that occurred in 10% or more of the patients and all grade 3 TRAEs are listed in Table 3.

TABLE 3.

Grade 1 and 2 Treatment-Related AEs Occurring in 10% or More of the Population Are Reported, and All Events of Grade 3

Severe treatment-related toxicities seen included grade 3 skin rash (47%), diarrhea (20%), and paronychia (20%). There was no grade 4 TRAEs. One patient had grade 5 pneumonitis. This was a 59-year-old woman with three prior lines of therapy who presented on day 12 of poziotinib treatment with dyspnea and cancer progression. CT scan of the chest demonstrated bilateral patchy groundglass opacities with differential diagnoses that included infection, lymphangitic spread of her cancer, or pneumonitis that was refractory to treatment with corticosteroids and antibiotics. The patient died 3 weeks later, and the death was attributed as possibly related to study drug. One patient (3%) discontinued poziotinib because of TRAE, 16 patients (53%) had one dose reduction, and six patients (20%) had two dose reductions.

DISCUSSION

In this phase II trial, poziotinib resulted in a 27% confirmed partial response rate and a median PFS of 5 months in patients with advanced HER2 exon 20 mutant lung cancer. We observed responses across HER2 exon 20 insertions subtypes. Furthermore, an additional 46% of patients achieved stable disease, for a disease control rate of 73%. The median OS reached 15 months. An independent multicenter phase II trial of poziotinib in HER2 exon 20 mutant previously treated metastatic NSCLC (ZENITH20 trial), which was initiated after our trial and was based on our findings, enrolled 90 patients, and preliminary reports from this study were similar with a confirmed partial response of 28% with a DoR of 5.1 months.²²

The majority of patients (93%) in this study had previously received at least one line of systemic therapy and more than half (53%) received two or more prior lines. In the subset of patients who had previously received platinum-based chemotherapy, the confirmed partial response rate was 26% with median PFS of 5 months. In comparison, in molecularly unselected patients with platinum-pretreated NSCLC, standard second-line chemotherapy, docetaxel, has an ORR of 7%-13% and median PFS of 2-4 months.^23,24 Similarly, retrospective studies have reported that patients with HER2 exon 20 mutant NSCLC had an ORR of 6% and median PFS of 1.9 months to second-line immune checkpoint (PD-1 or PDL-1) blockade.^9,11 Patients with NSCLC whose disease has progressed on two or more lines of therapy have no defined standard-of-care systemic therapy options, demonstrating the urgent and unmet clinical need for effective therapies for these patients. In our study, such patients had a clinically meaningful confirmed response rate of 19% and median PFS of 4 months.

A number of promising agents have been tested recently in clinical trials of patients with HER2 exon 20 mutant lung cancer. DESTINY-Lung01 was a phase II study of trastuzumab-deruxtecan (Ds8201a), an HER2-targeted ADC, which reported an ORR of 62% (95% CI, 46 to 76) with median PFS of 14 months in patients with HER2 mutant lung cancer.¹⁴ However, unlike the study presented here, which included only patients with HER2 exon 20 insertion, DESTINY-LUNG01 enrolled patients with any HER2 mutation. Moreover, unlike oral TKIs including poziotinib, trastuzumab-deruxtecan is administered intravenously, which may be less convenient for patients. The discontinuation rate because of drug-related adverse events in that study was 19%. Interstitial lung disease was reported in 12% of patients, leading to drug discontinuation in all patients affected except one patient who continued the study drug after dose interruption. Notably, in a pooled analysis of 234 patients with HER2-positive breast cancer who were treated in clinical trials of trastuzumab-deruxtecan, fatalities because of interstitial lung disease were seen in 2.6% of treated patients.^25,26 Similar to DESTINY-LUNG01, the aforementioned study of T-DM1 was not exclusive to HER2 exon 20 mutations and allowed any HER2 mutation with a resultant response rate of 44% (95% CI, 22 to 69). In the small subset of patients with HER2 exon 20 insertions (n = 11), the response rate was 54.5%. T-DM1 was well tolerated with no grade 3 or higher TRAEs apart from 6% grade 3 anemia.¹³

The response rate reported in a phase II study of pyrotinib in patients with HER2 mutant lung cancer was 30% with a median PFS of 6.9 months. Although our trial allowed any HER2 exon 20 insertion or point mutation, all patients treated had HER2 exon 20 insertions, which is distinct from the pyrotinib study, where 20% of patients enrolled had a HER2 exon 20 or 19 point mutation. Preclinical studies have shown that the majority of HER2 point mutations, with the exception of L755P, are more sensitive to HER2 TKIs than exon 20 insertion mutations.^1,17,27-31 Nevertheless, in the subset of patients with HER2 exon 20 insertion NSCLC treated in the pyrotinib trial (n = 49), the response rate was 30.6%, which is consistent with the outcomes reported in a prior smaller single-center phase II trial in which six (46%) of 13 patients with an exon 20 insertion achieved a partial response.³² Both our study and the pyrotinib trial reported comparable grade 3 diarrhea rate of 20%. However, in the poziotinib trial, we observed higher rates of grade 3 skin rash (47%) and grade 3 paronychia (20%), whereas no grade 3 skin rash or paronychia were reported with pyrotinib. The rate of grade 3 or higher deranged liver enzymes or liver function was 10% with pyrotinib compared with none in the current poziotinib study. Finally, the pyrotinib study was conducted in an Asian population, whereas the study presented here accrued North American population.

In our study, poziotinib toxicity was typical of EGFR TKIs with skin rash, diarrhea, and paronychia being the most common grade 3 TRAEs. Those adverse events were generally manageable with early symptom management and/or dose reductions. Topical steroids and oral tetracyclines proved particularly effective in symptom management of acneiform eruption with escalation to oral retinoids in patients with grade 3 rash. The use of prophylactic antidiarrheals, such as loperamides, may reduce the rate of severe diarrhea. Hydration with dose reduction and/or dose interruption was recommended for patients with grade 3 diarrhea. While the clinical Protocol provided guidance on management of adverse events (Protocol and the Appendix), investigators used their best clinical judgment. In this trial, 73% of patients required a dose reduction, which is comparable with what is reported in phase III trials of other quinazoline-based, US Food and Drug Administration–approved TKIs afatinib and dacomitinib where 67% and 52% of patients had dose reductions because of TRAEs, respectively.^33,34 More recent data suggest that an alternative dosing regimen may reduce the rates of TRAEs while maintaining or enhancing efficacy. The aforementioned ZENITH20 trial included a cohort that randomly assigned patients to twice daily dosing of poziotinib versus daily dosing. When administered at 8 and 6 mg twice daily, poziotinib resulted in grade 3 or higher TRAEs in 26% and 16% patients, respectively, which compared favorably with 50% of patients receiving it at 16 mg daily, and 44% of patients receiving 12 mg daily.³⁵ In terms of efficacy, patients on the 8-mg twice daily dose had an overall response rate of 31.6%.³⁶ Our study has several limitations, including the small sample size, single-center enrollment, and lack of control arm and of independent blinded radiologic review. To this end, a larger multicenter trial is currently enrolling (ClinicalTrial.gov NCT03318939).

In conclusion, poziotinib as a single agent showed promising antitumor activity in patients with HER2 exon 20 mutant NSCLC, including patients who had previously received platinum-based chemotherapy, where there are currently limited therapeutic options, and patients with heavily pretreated disease where there is no defined standard-of-care treatment. The optimal dosing of poziotinib is being investigated in a randomized study that compares twice daily dosing to once daily dosing.³⁵ The daily dose of 16 mg used in the current study was associated with significant but manageable toxicity and frequently required dose reduction. Poziotinib has been granted fast track designation for HER2 exon 20 mutant NSCLC by the US Food and Drug Administration and is undergoing further clinical development.

APPENDIX

FIG A1.

Trial schema. EGFR, epidermal growth factor receptor; DoR, duration of response; HER2, human epidermal growth factor receptor 2; NSCLC, non–small-cell lung cancer; ORR, objective response rate; OS, overall survival; PD, disease progression; PFS, progression-free survival.

FIG A2.

Trial profile. HER2, human epidermal growth factor receptor 2.

FIG A3.

Kaplan-Meier estimate of OS. NE, not estimable; OS, overall survival.

TABLE A1.

Previous Treatment History by Patient

TABLE A2.

Response by HER2 Exon 20 Mutation Subtype

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.21.01113.

AUTHOR CONTRIBUTIONS

Conception and design: Yasir Y. Elamin, Jacqulyne P. Robichaux, Brett W. Carter, John V. Heymach

Financial support: Yasir Y. Elamin, John V. Heymach

Administrative support: John V. Heymach

Provision of study materials or patients: Yasir Y. Elamin, Don L. Gibbons, Frank V. Fossella, Marcelo V. Negrao, Jianjun Zhang, Anne S. Tsao

Collection and assembly of data: Yasir Y. Elamin, Brett W. Carter, Mehmet Altan, Don L. Gibbons, Frank V. Fossella, Vincent K. Lam, Marcelo V. Negrao, Xiuning Le, Frank E. Mott, Jianjun Zhang, George Blumenschein Jr, Anne S. Tsao, John V. Heymach

Data analysis and interpretation: Yasir Y. Elamin, Jacqulyne P. Robichaux, Brett W. Carter, Anisha B. Patel, Marcelo V. Negrao, Xiuning Le, Jianjun Zhang, Lei Feng, Anne S. Tsao, John V. Heymach

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Poziotinib for Patients With HER2 Exon 20 Mutant Non–Small-Cell Lung Cancer: Results From a Phase II Trial

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).