Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths, accounting for 18.4% of all cancer deaths.1 The most common lung cancer is non–small cell lung cancer (NSCLC), which occurs in 85% of patients with lung cancer, and the most common NSCLC is adenocarcinoma, which represents 40% of all lung cancer diagnoses. A large proportion of NSCLC adenocarcinoma is mutation-driven, and genomic profiling of these tumors revolutionized the treatment of NSCLC by improving identification of genetic alterations and providing options for targeted molecular therapies to individualize treatment.
Because of the number of mitogenic driver mutations present in NSCLC, these tumors are now classified into molecular subsets on the basis of mutation status.2,3 The most frequently altered genes in NSCLC are EGFR (10%–35%), KRAS (25%–30%), FGR (20%), ALK (3%–7%), MET (2%–4%), BRAF (1%–3%), ROS1 (1%–3%), and RET (1%–3%).2,3 For many of the molecular subsets, including EGFR, ROS1, ALK, NTRK, KRAS, BRAF, MET, and RET, there are approved targeted therapies available for treatment. In addition, there are several investigational therapies in development for other molecular subsets, including EGFR exon 20 insertions, exon 18 alterations, and HER2-amplified NSCLC.
EGFR Mutations
The EGFR signaling pathways influence angiogenesis and the activation and regulation of cellular proliferation, underscoring the importance of EGFR mutations in NSCLC.4 Upregulation of EGFR signaling due to kinase-activating mutations or increased EGFR expression results in powerful proto-oncogenic functions, causing rapid and uncontrolled proliferation and expansion of mutated tumor cells.5 Identified in 20% to 30% of patients with NSCLC worldwide, EGFR mutations are more common in adenocarcinomas, never-smokers, women, and Asians.6,7 EGFR mutations are located primarily in the tyrosine kinase domain at exons 18 to 21, with exon 19 deletions and exon 21 L848R mutations representing the majority of EGFR mutations. It is important to identify the specific EGFR mutation, including sensitive mutations, primary resistance mutations, and de novo and acquired resistance mutations. Molecular testing of EGFR mutations is the standard of care for the diagnostic evaluation of NSCLC, and the presence or absence of EGFR mutations greatly influences treatment selection.8
Studies have shown that 12% to 34% of patients with NSCLC with EGFR mutations carry atypical or uncommon EGFR mutations.9–11 Uncommon EGFR mutations are diverse and include a variety of point mutations and insertions on exons 18 through 21. The most common of these are exon 20 insertions (9%) and the point mutations G719S/A/C (collectively known as G719×; 11.5%) on exon 18, S768I (5.5%) on exon 20, and L861Q (5.85%) on exon 21. Although therapy with tyrosine kinase inhibitors (TKIs) has been shown to benefit patients with NSCLC with some of these uncommon mutations, such as the G719×, A768I, and L861Q point mutations, other uncommon EGFR mutations often are not sensitive to TKI treatment.12 For example, patients with EGFR exon 20 insertions, which account for approximately 9% of EGFR mutations, are often resistant to standard EGFR TKIs. Patients who carry these alterations have poor responses to early TKIs, with objective response rates (ORRs) ranging from 11% with afatinib to 0% with gefitinib/erlotinib and median progression-free survival (PFS) of ≤2 months.11 Additionally, similar to patients who carry other NSCLC driver mutations, such as ALK, KRAS, and common EGFR mutations, patients with uncommon EGFR mutations have poor outcomes on immune checkpoint inhibitor therapy (immunotherapy). The median PFS for patients with known NSCLC driver mutations receiving immunotherapy is 2.8 months, and the median PFS is 2.7 months in patients with EGFR exon 20 insertions.13,14 It is important, therefore, to identify therapeutically relevant oncogenic drivers to determine which targeted treatments the mutations may be sensitive to, identify primary resistance mechanisms, or identify de novo and acquired resistance mutations.6,8
NCCN Guidelines for Biomarker Testing in Metastatic NSCLC
Molecular Testing for Rare EGFR Mutations
Biomarker testing is recommended to determine the specific EGFR mutation for guiding the selection of targeted therapy. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer recommend biomarker testing in eligible patients with metastatic NSCLC once the histologic subtype is identified (Table 1).15 The NCCN Guidelines recommend testing for a broad array of biomarkers, including EGFR, ALK, ROS1, KRAS, BRAF, RET, MET exon 14 skipping, NTRK 1/2/3, and PD-L1 in patients with nonsquamous histology.15 ASCO also recommends performing mutation testing in any patient with nonsquamous NSCLC, any tissue with an adenocarcinoma component, and/or clinical/demographic features suggestive of the presence of a biomarker-driven malignancy (eg, age ≤50 years, never or light smoker).16 The initial recommended biomarker testing is for EGFR, ALK, ROS1, and BRAF, and if these are negative then the next step is a broad biomarker testing panel that includes KRAS, RET, MET, and HER2.16 However, use of a broad biomarker panel for initial testing is preferred, because this allows for identification of less-common EGFR variants.
Testing for EGFR mutations may be performed using either tissue or blood, although there are advantages and disadvantages for both approaches. Testing of biopsy tissue from patients with NSCLC is highly sensitive, although sensitivity does not reach 100%, and these tests can often be done in-house. Additionally, for newly diagnosed patients, biopsy tissue is often readily available. Ideally, a full next-generation sequencing panel should be ordered because it can detect rare and previously uncharacterized alterations in the sequenced genes, whereas a request for a single gene test may only determine common EGFR mutations. The disadvantages of tissue testing are that the tissue sample may be inadequate or not demonstrate cellularity, tissue samples are often not reflective of tumor heterogeneity, and it can take 2 to 4 weeks to perform a complete DNA sequencing panel once the tissue is received. Mutation testing of blood samples is a rapid and noninvasive way to evaluate patients for EGFR mutations. A major advantage of this approach is that it can easily detect both common and uncommon mutations. The major disadvantages of blood testing are that it is less sensitive than tissue testing, it is dependent on DNA shedding into the peripheral circulation, and it can be costly and there are often barriers to full insurance coverage.
Liquid biopsy testing offers an alternative to standard procedures when tissue biopsy specimens are insufficient or cannot be obtained. It also provides a rapid assessment of emerging resistance mechanisms. A panel convened by the International Association for the Study of Lung Cancer (IASLC) developed a set of guidelines for using liquid (blood/plasma) testing for determining therapeutic targets in treatment-naïve patients with advanced NSCLC.17 The guidelines recommend testing a surgical specimen (biopsy) if available and treating with standard-of-care therapy based on the presence or absence of oncogenic drivers. In testing tissue specimens, it is strongly suggested to use a tissue-sparing approach. If the tissue biopsy specimen is not sufficient for molecular testing, the molecular analysis should be performed on a liquid biopsy for circulating tumor cell DNA. A full next-generation sequencing panel is preferred if available, but if not, the IASLC recommends that testing should include EGFR, ALK, ROS1, and BRAF at a minimum.17 If the therapeutic target is positive, the patient should be treated with standard-of-care therapy based on the presence or absence of oncogenic drivers. Due to a higher rate of false-negatives associated with liquid biopsies, if the therapeutic target is negative, the tissue should be rebiopsied and the molecular analysis performed on the biopsy specimen. It is recommended that all NSCLC tissue specimens be tested for PD-L1 by immunohistochemistry.
Advances in Targeted Therapy for Rare EGFR Mutations
An understanding of the biology of rare EGFR mutations in NSCLC has ushered in the development of targeted therapy for specific types of mutations. Three generations of TKIs that target EGFR point mutations (G719×, S768I, and L861Q) are available or in development, as well as treatments for exon 20 insertions. Treatments that target exon 18 and HER2 mutations are also in development. Clinical data for the newer EGFR-targeted therapies are discussed.
EGFR Point Mutations
Afatinib
Afatinib is a second-generation irreversible ErbB blocker that was initially approved by the FDA for patients with EGFR exon 19 deletions or exon 21 substitutions that have progressed after platinum-based chemotherapy. In January 2018, this approval was broadened to include treatment of 3 atypical EGFR point mutations (S768I, L861Q, and/or G719×) in patients with metastatic NSCLC.18,19 The approval was based on a pooled analysis from studies that included 32 patients with the following mutations: G719× with S, A, C, D substitutions; S768I; and L861Q, which also can present in combination with other point mutations.18 The patients, who were treated with afatinib at 40 mg or 50 mg daily, had a confirmed ORR of 66% (95% CI, 47–81). Among the 21 responders, 52% had a response duration of ≥12 months and 33% had a response duration ≥18 months.
A post hoc analysis of the phase II LUX-Lung 2 and the randomized phase III LUX-Lung 3 and LUX-Lung 6 clinical trials of afatinib treatment of EGFR mutation–positive advanced (stage IIIb–IV) lung cancers found that 12% (75/600 patients) had uncommon EGFR mutations.10 Uncommon EGFR mutations detected in patients in group 1 (n=38) included point mutations or duplications in exons 18 to 21 (L861Q, G719S, G719A, G719C, S768I) alone or in combination. Uncommon EGFR mutations in group 2 patients (n=14) included de novo T790M mutations in exon 20 alone or in combination with other mutations, and exon 20 insertions were the uncommon mutation in group 3 patients (n=23). Group 1 patients showed the most active response to afatinib treatment: ORR, 71.1% (23/38 patients); median PFS, 10.7 months; and median overall survival (OS), 19.4 months.
A later pooled analysis assessed the clinical efficacy of afatinib in 693 patients with NSCLC harboring uncommon EGFR mutations treated in randomized clinical trials, compassionate use and expanded access programs, phase IIIb or noninterventional trials, and case series.20 The analysis found that afatinib showed strong activity against major uncommon (G719×, L861Q, S768I) and compound EGFR mutations in patients who were EGFR TKI–naïve. The ORRs were 60% in patients with major uncommon mutations (n=110) and 77% in those with compound mutations (n=35). The respective time to treatment failure was 10.8 and 14.7 months.
Osimertinib
Osimertinib is a third-generation irreversible EGFR TKI that is approved by the FDA for multiple indications for the treatment of NSCLC. It is approved in patients with EGFR-mutated metastatic NSCLC whose tumors have developed T790M mutations after initial EGFR inhibitor treatment, and it is approved for both first-line metastatic treatment and adjuvant therapy after tumor resection in patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. The ASCO and Ontario Health (Cancer Care Ontario) guidelines recommend osimertinib for first-line treatment of patients with exon 19 deletion, exon 21 L858R, and exon 20 T790M EGFR mutations.21
The phase I AURA trial included immunohistochemical analyses to assess key pathways and tumor markers, including phospho-EGFR, phospho-S6, phospho-AKT, PD-L1, and CD8.22 The AURA trial showed that osimertinib modulated key EGFR signaling pathways and led to increased immune cell infiltration. The phase III AURA3 trial compared osimertinib versus platinum-pemetrexed chemotherapy in 419 patients with metastatic NSCLC whose tumors had developed EGFR T790M mutations following first-line treatment with an EGFR TKI.23 Osimertinib resulted in a significant improvement in median PFS, from 4.4 months with chemotherapy to 10.1 months with osimertinib (hazard ratio [HR], 0.30; P<.001). The ORR was also better in patients treated with osimertinib versus chemotherapy (71% vs 31%; P<.001). Importantly, osimertinib was associated with an improvement in median PFS in patients with central nervous system metastases. Rates of grade ≥3 adverse events were lower in patients treated with osimertinib versus platinum-pemetrexed chemotherapy.
The phase III, double-blind FLAURA trial of osimertinib randomized 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC to treatment with osimertinib at 80 mg/d orally or to a standard EGFR TKI (gefitinib, 250 mg/d orally or erlotinib, 150 mg/d orally).24,25 Median PFS was significantly longer with osimertinib than with the comparator standard TKI therapy (18.9 vs 10.2 months; HR for disease progression or death, 0.46; 95% CI, 0.37–0.57; P<.001).24 The ORR was similar for osimertinib and the comparator group (80% and 76%, respectively), and the respective median durations of response were 17.2 and 8.5 months. The median duration of treatment exposure was 20.7 and 11.5 months in the osimertinib and comparator groups, respectively, at the time of data cutoff, and 22% of patients treated using osimertinib versus 5% of those treated using the comparator continued to receive their assigned treatment.25 Median OS, a secondary endpoint, was 38.6 months (95% CI, 34.5–41.8) in the osimertinib group and 31.8 months (95% CI, 26.6–36.0) in the comparator group (HR for death, 0.80; 95% CI, 0.64–1.00; P=.046). OS rates and the number of patients continuing to receive first-line trial therapy were consistently higher with osimertinib at 12, 24, and 36 months. Grade ≥3 adverse events occurred less frequently with osimertinib (42% vs 47%).
Based on its efficacy against multiple EGFR mutations, osimertinib is currently being evaluated as a potential treatment option for patients with uncommon EGFR point mutations. A phase II study of 36 patients with metastatic or recurrent NSCLC harboring uncommon EGFR mutations was conducted in Korea.26 The study evaluated outcomes in patients with the G719× (n=19), L861Q (n=9), and S768I (n=8) mutations treated using osimertinib. The ORRs were 53%, 78%, and 38% with the G719×, L861Q, and S768I mutations, respectively, and the respective PFS were 8.2, 15.2, and 12.3 months.
Exon 20 Insertions
EGFR exon 20 insertions, the second most common EGFR mutation after classic mutations, account for 10% to 12% of all observed EGFR mutations.11,27 They are largely resistant to first-, second-, and third-generation EGFR TKIs, because exon 20 insertion mutations induce steric hindrance of the drug-binding pocket. Insertions at the C-terminal end of p shift it into the drug-binding pocket, forcing a rigid placement of the α−C helix in the inward, activated position. In addition, the phosphate-binding loop is shifted into the drug-binding pocket of both receptors.11 These findings indicate that small, flexible quinazoline derivatives (eg, afatinib) may be capable of inhibiting exon 20 insertions because they have the ability to fit into the sterically hindered binding pocket, whereas drugs with a large, inflexible group (eg, erlotinib) cannot reach the C797 residue and cannot inhibit exon 20 insertions.11
Patients with NSCLC with exon 20 insertions have a worse prognosis compared with those with other EGFR mutations, and current TKI targeted therapies are less effective for exon 20 insertions than for classic EGFR mutations.28,29 A phase II study evaluated the third-generation EGFR TKI osimertinib at 160 mg/d in 21 patients with NSCLC with exon 20 insertions.30 The study showed that osimertinib had some activity against exon 20 insertions, with an ORR of 25% and a median PFS of 9.7 months (95% CI, 4.07–NA). Exon 20 mutations are associated with superior outcomes from immune checkpoint inhibitors compared with classic EGFR mutations on exons 19 and 21.31 However, the role for immunotherapy in patients with exon 20 insertions is limited because the benefit associated with these therapies is small (a median PFS of approximately 2 months) and the risk of treatment-related adverse events is high.
Although numerous treatments have been evaluated in patients with exon 20 insertions, until recently the standard of care for front-line treatment of NSCLC with exon 20 insertions remained platinum-based chemotherapy.29 Improved understanding of the biology surrounding these mutations has led to the development of numerous targeted therapies that have efficacy against exon 20 insertions, leading to the approval of the first exon 20 insertion–targeted therapy, amivantamab, which has been approved as second-line therapy.32
Amivantamab
Amivantamab, a fully humanized, bispecific IgG1 antibody targeting EGFR and cMET receptors, is the first treatment approved by the FDA as second-line therapy for adult patients with exon 20 insertion mutation NSCLC. It is an EGFR-targeted therapy with immune cell–directing activity that is associated with a significant clinical benefit in EGFR-driven NSCLC, including TKI-resistant tumors. Amivantamab targets activating and resistant EGFR and cMET mutations and amplifications through an Fc-dependent monocyte/macrophage-mediated antitumor mechanism, with trogocytosis contributing to tumor cell receptor degradation.33,34
Amivantamab monotherapy has shown antitumor activity in patients with diverse EGFR mutation disease, including EGFR exon 19 deletions; L858R, T790M, and C797S mutations; exon 20 insertions; and MET amplification.35,36 A phase I study reported that 30% of patients (32/108) with EGFR-mutant NSCLC had a best response of partial response across diverse EGFR mutations, including exon 20 insertions, T790M, C797S, and cMET amplification.35 The ongoing phase I/II CHRYSALIS study is evaluating amivantamab treatment in patients with metastatic/unresectable NSCLC with exon 20 insertion mutations whose disease has progressed on platinum-based chemotherapy (Figure 1).37 In the dose-escalation portion of the study, the intravenous monotherapy recommended phase II doses (RP2D) of 1,050 mg in patients <80 kg and 1,400 mg in patients ≥80 kg were established. The safety and efficacy of the RP2D doses are currently being established in the dose expansion phase. The primary efficacy endpoint is the ORR per RECIST 1.1.
CHRYSALIS study design: post-platinum exon 20 insertion patient population.37
Abbreviations: C1, cycle 1; C2+, cycle 2 and beyond; Exon20ins, exon 20 insertions; NSCLC, non–small cell lung cancer; RP2D, recommended phase II dose.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
CHRYSALIS study design: post-platinum exon 20 insertion patient population.37
Abbreviations: C1, cycle 1; C2+, cycle 2 and beyond; Exon20ins, exon 20 insertions; NSCLC, non–small cell lung cancer; RP2D, recommended phase II dose.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
CHRYSALIS study design: post-platinum exon 20 insertion patient population.37
Abbreviations: C1, cycle 1; C2+, cycle 2 and beyond; Exon20ins, exon 20 insertions; NSCLC, non–small cell lung cancer; RP2D, recommended phase II dose.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
The efficacy population for the CHRYSALIS study comprises 81 patients with a median time from initial diagnosis to study entry of 17 months who were previously treated with platinum-based doublet chemotherapy, and 25% of whom had received EGFR TKI therapy.37 Among this cohort, the median age is 62 years, 59% are female, and the patients are predominantly Asian (49%) or White (37%). Initial results from this study have indicated the efficacy of amivantamab in this population. The ORR determined by blinded independent review was 40% (95% CI, 29–51), and the median duration of response was 11.1 months (95% CI, 6.9–not reached). The clinical benefit rate, defined as complete response, partial response, or stable disease for at least 2 disease assessments, was 74% (95% CI, 63–83).
Amivantamab has shown activity for all of the 25 distinct exon 20 insertion variants identified by next-generation sequencing from 63 evaluable patient samples (Figure 2).37 At the time of data cutoff, 15 of 32 patients remained on amivantamab treatment and 20 of 32 had responses lasting ≥6 months. The median PFS was 8.3 months (95% CI, 6.5–10.9), and the median OS was 22.8 months (95% CI, 14.6–not reached). The safety profile of amivantamab was consistent with the inhibition of the EGFR and MET pathways. Treatment-related adverse reactions related to EGFR inhibition included rash (86%), paronychia (42%), stomatitis (18%), pruritus (17%), and diarrhea (10%). Rash caused 2% of patients to discontinue treatment. Grade ≥3 adverse reactions were reported in 39% of patients, with the most common being diarrhea (3.5%), rash (3%), and infusion-related reactions (2%). Infusion-related reactions that were considered treatment-related occurred in 65% of patients; 94% of these reactions occurred with the first infusion and rarely impacted the ability of patients to continue treatment.
Best ORR by insertion region of exon 20 (detected by ctDNA).37
Abbreviations: CBR, clinical benefit rate; ctDNA, circulating tumor cell DNA; ORR, objective response rate; SoD, sum of diameters.
aOne patient in the efficacy population discontinued before any disease assessment and is not included in the plot.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
Best ORR by insertion region of exon 20 (detected by ctDNA).37
Abbreviations: CBR, clinical benefit rate; ctDNA, circulating tumor cell DNA; ORR, objective response rate; SoD, sum of diameters.
aOne patient in the efficacy population discontinued before any disease assessment and is not included in the plot.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
Best ORR by insertion region of exon 20 (detected by ctDNA).37
Abbreviations: CBR, clinical benefit rate; ctDNA, circulating tumor cell DNA; ORR, objective response rate; SoD, sum of diameters.
aOne patient in the efficacy population discontinued before any disease assessment and is not included in the plot.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
Mobocertinib
Mobocertinib (TAK-788) is an oral, selective EGFR/HER2 TKI with selective preclinical activity against activating EGFR and HER2 mutations, including exon 20 insertions, without inhibiting wild-type EGFR.38–40 A phase I/II study reported a confirmed ORR of 43% in 28 evaluable patients with advanced NSCLC refractory to standard therapy and ECOG performance status 0–1 who were treated with mobocertinib at 160 mg/d during dose escalation.38,39 The median (range) best percentage change in target lesion measurements was –32.6% (–100% to 26.3%), and the median PFS was 7.3 months (95% CI, 4.4–15.6).40
The design and patient cohorts for the ongoing 3-part open-label, multicenter study of mobocertinib (phase I, dose escalation; phase II, dose expansion; EXCLAIM extension cohort) are shown in Figure 3.41 Approximately two-thirds of patients were of Asian descent and female, and the median number of prior systemic anticancer regimens was 2 for the platinum pretreated patient (PPP) cohort and 1 for the EXCLAIM cohort. The confirmed ORR per an independent review committee for mobocertinib was 26% (95% CI, 19–35) in the PPP cohort and 23% (95% CI, 15–33) in the EXCLAIM cohort. The median duration of response to mobocertinib treatment per an independent review committee was 17.5 months (95% CI, 8.3–not estimable) in the PPP and not estimable in the EXCLAIM cohorts. More than 50% of responses were ongoing in both cohorts at the time of data cutoff. Median PFS per an independent review committee was 7.3 (95% CI, 5.5–10.2) in both patient cohorts. Other results showing meaningful clinical benefit from mobocertinib treatment are shown in Table 2.41 A similar proportion of patients in each cohort had a reduction from baseline in the sum of the target lesion diameter: 82% (94/114) and 80% (77/96) in the PPP and EXCLAIM cohorts, respectively. Treatment-related adverse events occurring in ≥30% of patients were diarrhea (90% of patients; grade ≥3 in 21% of PPP and 16% of EXCLAIM cohort patients), rash (45%), paronychia (35%), decreased appetite (∼30%), nausea (∼30%), and dry skin (30%).
Design and patient cohorts in the phase I/II and EXCLAIM extension study of mobocertinib in patients with NSCLC previously treated with platinum.41
Locations: United States only for phases I and II; United States, European Union, and Asia for phase II extension cohort. Abbreviations: CNS, central nervous system; NSCLC, non–small cell lung cancer; ORR, overall response rate; PK, pharmacokinetics; PS, performance status; TKI, tyrosine kinase inhibitor.
aActive or measurable (but not both) CNS metastases permitted. Active CNS metastases: untreated or treated and progressing; measurable CNS metastases: ≥10 mm in longest diameter by contrast-enhanced MRI.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
Design and patient cohorts in the phase I/II and EXCLAIM extension study of mobocertinib in patients with NSCLC previously treated with platinum.41
Locations: United States only for phases I and II; United States, European Union, and Asia for phase II extension cohort. Abbreviations: CNS, central nervous system; NSCLC, non–small cell lung cancer; ORR, overall response rate; PK, pharmacokinetics; PS, performance status; TKI, tyrosine kinase inhibitor.
aActive or measurable (but not both) CNS metastases permitted. Active CNS metastases: untreated or treated and progressing; measurable CNS metastases: ≥10 mm in longest diameter by contrast-enhanced MRI.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
Design and patient cohorts in the phase I/II and EXCLAIM extension study of mobocertinib in patients with NSCLC previously treated with platinum.41
Locations: United States only for phases I and II; United States, European Union, and Asia for phase II extension cohort. Abbreviations: CNS, central nervous system; NSCLC, non–small cell lung cancer; ORR, overall response rate; PK, pharmacokinetics; PS, performance status; TKI, tyrosine kinase inhibitor.
aActive or measurable (but not both) CNS metastases permitted. Active CNS metastases: untreated or treated and progressing; measurable CNS metastases: ≥10 mm in longest diameter by contrast-enhanced MRI.
Citation: Journal of the National Comprehensive Cancer Network 19, Suppl_2; 10.6004/jnccn.2021.0200
Poziotinib
Poziotinib, a novel EGFR TKI inhibitor, is smaller and more flexible than first- and second-generation TKIs, which allows it to bind to the sterically hindered drug-binding pocket of exon 20 insertion mutants.11,42 In genetically engineered mouse models of NSCLC driven by exon 20 insertion, poziotinib-treated mice had an 80% reduction in tumor volume, whereas afatinib treatment resulted in a 35% increase in tumor volume. In a phase II study with 44 evaluable patients who had EGFR exon 20–NSCLC, poziotinib showed efficacy with an ORR (best response) rate of 55% and an ORR (confirmed) of 43%.43
A phase II study evaluated the safety and efficacy of oral poziotinib at 16 mg/d in 115 previously treated patients with NSCLC and EGFR exon 20 insertion mutations (ZENITH20).44 The median age of patients was 61 years, and the median number of lines of prior therapy was 2. Results for the total population and the evaluable patients are shown in Table 3. In the evaluable patients, the ORR was 19.3% (95% CI, 11.7–29.1), the median duration of response was 7.4 months (95% CI, 3.7–9.7), and the median PFS was 4.1 months (95% CI, 3.7–5.5). The most common treatment-related grade ≥3 adverse events were rash (28%), diarrhea (26%), stomatitis (9%), and paronychia (6%).
Clinical Activity of Poziotinib in Patients With NSCLC Harboring EGFR Exon 20 Insertions: ZENITH20 Study44
Management of Adverse Events
In addition to indicating efficacy in the treatment of patients with NSCLC harboring uncommon EGFR mutations, newer targeted therapies have shown a manageable toxicity profile.37,41,44,45 The most frequent treatment-related adverse events of grade ≥3 severity associated with these agents are diarrhea and rash. In clinical trials of these novel targeted therapies, <20% of patients discontinued treatment because of an adverse event, and many adverse events were managed by a reduction in the drug dose.
Management of the rash associated with EGFR TKI targeted therapies (mobocertinib, poziotinib, afatinib, osimertinib) includes topical emollients, topical steroids, and early referral to dermatology. Early and aggressive use of antidiarrheal agents (eg, loperamide, diphenoxylate hydrochloride-atropine sulfate) and hydration are useful to manage diarrhea. In addition, monitoring of serum electrolytes (potassium, sodium), renal function (serum creatinine), and liver function tests are recommended. Dose reductions decrease the risk of treatment-related adverse events, particularly with afatinib.46
The most common adverse event with the EGFR antibody amivantamab is an infusion-related reaction, which is characterized by dyspnea, flushing, chills, and nausea.37 It occurs in 65% of patients, but grade 3 reactions occur in <2% of patients. The vast majority (94%) of infusion-related reactions occur on cycle 1, day 1 of therapy, have a median time to onset of 44 minutes, and occur after cycle 2, day 1 of therapy in <1% of patients. Infusion-related reactions may be mitigated by holding the drug infusion and reinitiating it at a reduced rate.47 Administration of steroids, analgesics, and/or antihistamines can lessen the risk and severity of an infusion-related reaction.
Future Directions in EGFR-Targeted Therapy
Although exon 20 insertions and point mutations in exons 18 to 21 are the best studied of the uncommon EGFR mutations, several other EGFR and EGFR/ERBB family mutations occur less frequently, and effective targeted therapies are needed for these. Currently, ongoing studies are evaluating therapies for both exon 18 mutations and HER2 mutations and amplifications in patients with NSCLC. Of the major uncommon EGFR mutations in NSCLC, exon 18 mutations account for up to 5% of the variants. Limited clinical evidence suggests that the EGFR TKIs afatinib and osimertinib have modest activity against exon 18 mutations.48 Mutations of the ERBB2/HER2 gene, another member of the ERBB/EGFR family, occur most frequently in the kinase domain exons 18 to 21.42 Response to HER2-targeted TKIs and HER2 monoclonal antibodies are variable by both cancer type and mutation. In nonsquamous NSCLC, HER2 mutations occur in approximately 2.3% of patients, and an additional 1.4% of patients carry HER2 amplifications.2
Exon 18 Mutations
In an in vitro study, NSCLC EGFR exon 18 mutations were highly sensitive to neratinib, an irreversible pan-HER TKI, in contrast to first-generation TKIs.49 The phase II SUMMIT basket trial is evaluating neratinib monotherapy in these patients. Patients in this study are receiving oral neratinib at 240 mg/d in addition to mandatory loperamide prophylaxis for the first 8 weeks.50 Of the initial 11 evaluable patients, the median age is 67 years, 55% are male, 91% are White, and 55% have an ECOG performance status of 1. Patients had received a median of 2 prior lines of therapy, and most had complex G719× mutations. The first best response was partial response in 6 patients, stable disease in 4, and progressive disease in 1. Responses were noted regardless of single or complex G719× mutations. The confirmed ORR was 40%, the duration of response was 7.5 months, and the median PFS was 9.1 months. No grade 3 diarrhea was reported. The neratinib SUMMIT trial is continuing to enroll patients with EGFR exon 18–mutant NSCLC.
HER2 Mutations
Although HER2 mutations and amplifications are common in breast and gastric cancers, they are relatively uncommon in NSCLC.51 And while numerous HER2-targeted therapies have been approved in other cancer types, none have yet been approved in NSCLC, although several studies are ongoing evaluating these agents.
Ado-trastuzumab emtansine is an HER2-targeted antibody–drug conjugate that was initially studied for the treatment of HER2 metastatic breast cancers.51 A phase II trial evaluated ado-trastuzumab emtansine (3.6 mg/kg intravenously every 21 days) in a cohort of 18 patients (median age, 64 years) with HER2-mutant lung cancer who were followed for a median of 10 months. The median number of prior systemic therapies was 2, and 50% of patients had received prior HER2-targeted therapy. The ORR was 44%, and the median PFS was 5 months.51 The longest PFS was >11 months in a patient with stable disease as the best response with –27% tumor shrinkage. Adverse events, including infusion reactions, thrombocytopenia, elevated liver enzymes, fatigue, and nausea, were grade 1 or 2. The results of this study were positive.
In a phase I trial, 11 patients with HER2-mutated NSCLC who received trastuzumab deruxtecan, an antibody–drug conjugate, had a confirmed ORR of 72.7%.52 An ongoing phase II trial, DESTINY-Lung01, is evaluating trastuzumab deruxtecan (6.4 mg/kg intravenously every 3 weeks) in patients with nonsquamous NSCLC overexpressing HER2 or containing a HER2-activating mechanism.53 Early results from 42 patients (median age, 63 years; median number of prior therapies, 2) with HER2 mutations primarily in the kinase domain (90.5%) showed a confirmed ORR of 61.9% and a disease control rate of 90.5% with trastuzumab deruxtecan treatment. The estimated median PFS was 14 months; median OS had not been reached. All patients had treatment-emergent adverse events (64.3% were grade ≥3), which led to dose interruption in 59.5% of patients, dose reduction in 38.1%, and discontinuation of therapy in 23.8%. Trastuzumab deruxtecan showed promising clinical activity.
In addition to HER2-directed therapies, trials are ongoing evaluating other EGFR-targeted TKIs in patients with HER2 mutations. Poziotinib at 16 mg/d orally showed activity in HER2 exon 20 insertion NSCLC in a phase II clinical trial.11,42 The confirmed ORR in the first 12 evaluable patients was 42%, and the median PFS was 5.6 months. The multinational, phase II ZENITH20 study included a patient cohort with HER2 exon 20 insertion mutations (ZENITH20-2, n=90) who were treated with poziotinib at 16 mg/d orally.54 The cohort had a median age of 60 years, 64% were female, and 66% were nonsmokers, and patients had received a median of 2 prior therapies. In the 74 evaluable patients, the confirmed ORR was 35.1% (27.8% in all 90 patients) and median PFS was 5.5 months. Tumor reduction was noted in 74% (67/90) of patients, and the median tumor reduction was 22%. Poziotinib met efficacy expectations in this cohort, and further study of the drug is ongoing.
Summary
Mutations in the EGFR signaling pathway are common in NSCLC, the most common lung cancer. EGFR mutations are primarily located in the tyrosine kinase domain at exons 18 to 21. Some of the mutations, particularly exon 20 insertion mutations, do not respond well to TKIs and are therefore difficult to treat. The advent of genomic profiling has identified many of the mitogenic driver mutations in NSCLC and improved the selection of targeted therapy. Biomarker testing using either tissue or blood is recommended as standard practice to guide the selection of therapy to target the specific mutation. The TKIs afatinib and osimertinib have shown activity in the treatment of 3 atypical EGFR point mutations (G719×, S768I, and L861Q), and several novel therapies, including the IgG1 antibody amivantamab and the EGFR TKIs mobocertinib and poziotinib, are being studied for the treatment of exon 20 insertion mutations. Other uncommon EGFR mutations for which targeted therapies are being investigated include exon 18 mutations (neratinib) and HER2 mutations (ado-trastuzumab emtansine and trastuzumab deruxtecan). As the understanding of the biology of genetic mutations in NSCLC and molecular testing for mutations evolve, options for targeted therapy to individualize NSCLC treatment will be better defined and lead to improved outcomes.
References
- 1.↑
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424.
- 2.↑
Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov 2017;7:596–609.
- 3.↑
Aran V, Omerovic J. Current approaches in NSCLC targeting K-RAS and EGFR. Int J Mol Sci 2019;20:5701.
- 4.↑
Fang S, Wang Z. EGFR mutations as a prognostic and predictive marker in non-small-cell lung cancer. Drug Des Devel Ther 2014;8:1595–1611.
- 5.↑
Voldborg BR, Damstrup L, Spang-Thomsen M, et al. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 1997;8:1197–1206.
- 6.↑
Wang J, Wang B, Chu H, et al. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations. OncoTargets Ther 2016;9:3711–3726.
- 7.↑
Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016;7:78985–78993.
- 8.↑
Shea M, Costa DB, Rangachari D. Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther Adv Respir Dis 2016;10:113–129.
- 9.↑
Castellanos E, Feld E, Horn L. Driven by mutations: the predictive value of mutation subtype in EGFR-mutated non-small cell lung cancer. J Thorac Oncol 2017;12:612–623.
- 10.↑
Yang JC-H, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830–838.
- 11.↑
Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med 2018;24:638–646.
- 12.↑
Wu JY, Yu CJ, Chang YC, et al. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812–3821.
- 13.↑
Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30: 1321–1328.
- 14.↑
Negrao MV, Skoulidis F, Montesion M, et al. BRAF mutations are associated with increased benefit from PD1/PDL1 blockade compared with other oncogenic drivers in non-small cell lung cancer. J Thorac Oncol 2019;14(Suppl 10):S257–258.
- 16.↑
American Society of Clinical Oncology. Molecular testing guidelines for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors. Accessed September 15, 2021. Available at: https://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/documents/2018-lung-markers-endorsement-table.pdf
- 17.↑
Rolfo C, Mack PC, Scagliotti GV, et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): a statement paper from the IASLC. J Thorac Oncol 2018;13:1248–1268.
- 18.↑
U.S. Food & Drug Administration. FDA broadens afatinib indication to previously untreated metastatic NSCLC with other non-resistant EGFR mutations. Accessed June 10, 2021. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-broadens-afatinib-indication-previously-untreated-metastatic-nsclc-other-non-resistant-egfr
- 19.↑
Guo G, Li G, Liu Y, et al. Next-generation sequencing reveals high uncommon EGFR mutations and tumour mutation burden in a subgroup of lung cancer patients. Front Oncol 2021;11:621422.
- 20.↑
Yang JCH, Schuler M, Popat S, et al. Afatinib for the treatment of NSCLC harboring uncommon EGFR mutations: a database of 693 cases. J Thorac Oncol 2020;15:803–815.
- 21.↑
Hanna NH, Robinson AG, Temin S, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol 2021;39:1040–1091.
- 22.↑
Thress KS, Jacobs V, Angell HK, et al. Modulation of biomarker expression by osimertinib: results of the paired tumor biopsy cohorts of the AURA phase 1 trial. J Thorac Oncol 2017;12:1588–1594.
- 23.↑
Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629–640.
- 24.↑
Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113–125.
- 25.↑
Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020;382:41–50.
- 26.↑
Cho JH, Lim SH, An HJ, et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09). J Clin Oncol 2020;38:488–495.
- 27.↑
Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci 2016;107:1179–1186.
- 28.↑
Girard N, Bazhenova L, Minchom A, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Presented at the 22nd World Conference on Lung Cancer of the International Association for the Study of Lung Cancer; January 28–31, 2021; Singapore.
- 29.↑
Naldoo J, Sima CS, Rodriguez K, et al. Epidermal growth factor receptor exon 20 insertions in advanced lung cell adenocarcinomas: clinical outcomes and response to erlotinib. Cancer 2015;121:3212–3220.
- 30.↑
Piotrowska Z, Wang Y, Sequist LV, et al. ECOG-ACRIN 5162: a phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 9513.
- 31.↑
Negrao MV, Reuben A, Robichaux JP, et al. Association of EGFR and HER-2 exon 20 mutations with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 9052.
- 32.↑
U.S. Food & Drug Administration. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. Accessed July 8, 2021. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer
- 33.↑
Yun J, Lee SH, Kim SY, et al. Antitumor activity of amivantamab (JNJ-61186372), an EGFR-Met bispecific antibody, in diverse models of EGFR exon 20 insertion-driven NSCLC. Cancer Discov 2020;10: 1194–1209.
- 34.↑
Vijayaraghavan S, Lipfert L, Chevalier K, et al. Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMET bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis. Mol Cancer Ther 2020;19:2044–2056.
- 35.↑
Haura EB, Cho BC, Lee JS, et al. JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2019;37(Suppl): Abstract 9009.
- 36.↑
Park K, John T, Kim SW, et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 9512.
- 37.↑
Sabari JK, Shu CA, Park K, et al. Amivantamab in post-platinum EGFR exon 20 insertion mutant non-small cell lung cancer. J Thorac Oncol 2021;16:S108–109.
- 38.↑
Doebele X, Riely GJ, Spira K, et al. First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non-small cell lung cancer [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 9015.
- 39.↑
Neal J, Doebele R, Riely G, et al. Safety, PK, and preliminary antitumor activity of the oral EGFR/HEER2 exon 20 inhibitor TAK-788 in NSCLC. J Thorac Oncol 2018;13:S599.
- 40.↑
Janne PA, Neal JW, Camidge DR, et al. Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 9007.
- 41.↑
Zhou C, Ramalingam S, Li B, et al. Mobocertinib in NSCLC with EGFR exon 20 insertions: results from the EXCLAIM and pooled platinum- pretreated patient populations. J Thorac Oncol 2021;16:S108.
- 42.↑
Robichaux JP, Elamin YY, Vijayan RSK, et al. Pan-cancer landscape and functional analysis of ERBB2 mutations identifies poziotinib as a clinically active inhibitor and enhancer of T-DM1 activity. Cancer Cell 2019;36:444–457.e7.
- 43.↑
Heymach J, Negrao M, Robichaux J, et al. A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC) [abstract]. J Thorac Oncol 2018;13(Suppl):S323–324. Abstract OA02.06.
- 44.↑
Le X, Goldman JW, Clarke JM, et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients [abstract]. J Clin Oncol 2020;38(Suppl): Abstract 9514.
- 45.↑
Cornelissen R, Garassino MC, Le X, et al. Updated efficacy, safety and dosing management of poziotinib in previously treated EGFR and HER2 exon 20 NSCLC patients. Presented at the 22nd World Conference on Lung Cancer of the International Association for the Study of Lung Cancer; January 28–31, 2021; Singapore.
- 46.↑
Harvey RD, Adams VR, Beardslee T, et al. Afatinib for the treatment of EGFR mutation-positive NSCLC: a review of clinical findings. J Oncol Pharm Pract 2020;26:1461–1474.
- 47.↑
Roselló S, Blasco I, García Fabregat L, et al. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol 2017;28(Suppl 4):iv100–118.
- 48.↑
Passaro A, Mok T, Peters S, et al. Recent advances on the role of EGFR tyrosine kinase inhibitors in the management of NSCLC with uncommon, non exon 20 insertions, EGFR mutations. J Thorac Oncol 2021;16:764–773.
- 49.↑
Kobayashi Y, Togashi Y, Yatabe Y, et al. EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs. Clin Cancer Res 2015;21:5305–5313.
- 50.↑
Cummings AL, Boni V, Dooms C, et al. Neratinib efficacy in patients with EGFR exon18-mutant non-small lung cancer (NSCLC): findings from the SUMMIT Basket trial. Presented at the IASLC 2021 Targeted Therapies of Lung Cancer Meeting, Worldwide Virtual Event; February 20, 2021. Abstract S12.02.
- 51.↑
Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol 2018;36:2532–2537.
- 52.↑
Tsurutani J, Park H, Doi T, et al. Updated result of phase 1 study of DS-8201A in HER2-expressing or -mutated advanced non-small-cell lung cancer. Presented at the International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer; September 24, 2018; Toronto, Canada.
- 53.↑
Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; D-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01 [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 9504.
- 54.↑
Socinski MA, Cornelissen R, Garassino MC, et al. ZENITH20, a multinational, multi-cohort phase II study of poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations. Ann Oncol 2020;31(Suppl 4):S1142–1215.
