EGFR-mutant disease: strategies against sensitizing and resistance-mediating mutations

Targeting HER3: patritumab deruxtecan

EGFR tyrosine kinase inhibitors (TKIs) are the established first-line option in patients with EGFR-mutated NSCLC, although resistance inevitably develops in the long run. A wide variety of genomic alterations has been identified in the context of EGFR TKI resistance [1, 2]. HER3, which is expressed in 83 % of NSCLC tumors [3], is not known to confer resistance to EGFR TKI therapy in EGFR-mutant disease. Therefore, the antibody-drug conjugate patritumab derux­tecan (HER3-Dxd) that targets HER3 is a potentially active subsequent option after failure of EGFR TKI treatment.

The phase I U31402-A-U102 dose escalation and dose expansion study tested HER3-Dxd in patients with EGFR-TKI–resistant NSCLC. At ASCO 2021, Jänne et al. reported the pooled efficacy results for 57 patients treated with 5.6 mg/kg in the trial. Safety was presented for a total of 81 individuals; this group included all patients in dose escalation and in dose expansion Cohort 1 (i.e., pretreated patients with adenocarcinoma histology and EGFR mutations) [4]. The entire population had received a median of four prior treatment lines. Platin-based chemotherapy had been administered in 91 % and 80 % in the efficacy and safety populations, respectively.

Efficacy across resistance mechanisms

Despite being heavily pretreated, the patients experienced clinically meaningful, durable antitumor effects. HER3-Dxd gave rise to a confirmed ORR of 39 % and a disease control rate (DCR) of 72 %. Responses lasted for a median of 6.9 months, and median PFS was 8.2 months. The subgroup of patients pretreated with osimertinib and platinum-based chemotherapy demonstrated similar efficacy; here, ORR, DCR, and median PFS were 39 %, 68 %, and 8.2 months, respectively. HER3-Dxd proved active across diverse EGFR resistance mechanisms, as well as across the spectrum of baseline HER3 expression according to membrane H scores. HER3 was expressed in the tumors of all evaluable patients and showed no correlation with time since the last EGFR TKI dose. Moreover, the treatment was efficacious irrespective of the presence of CNS metastases.

Forty of the 57 patients in the efficacy population had detectable EGFR exon 19 deletions or L858R mutations in plasma at baseline. Early clearance of these aberrations at week 3 or 6, as compared to no clearance, was associated with improved best response (Figure 1) and prolonged PFS (8.3 vs. 4.4 months; HR, 0.33). HER3-Dxd showed a manageable safety profile. Treatment discontinuation rates due to treatment-emergent AEs (TEAEs) were low at 11 % and 9 % in the 5.6 mg/kg and all-doses populations, respectively. Among grade ≥ 3 TEAEs, decreases in platelet and neutrophil counts occurred most commonly. There was a low rate of treatment-related interstitial lung disease events (5 % in the total population), with none being grade 4/5. HER3-Dxd is being further assessed in the setting of EGFR-mutant NSCLC.

Figure 1: Improved patient responses observed with early clearance of exon 19 deletions and L858R mutations in ctDNA on treatment with patritumab deruxtecan

Figure 1: Improved patient responses observed with early clearance of exon 19 deletions and L858R mutations in ctDNA on treatment with patritumab deruxtecan

Amivantamab/lazertinib after osimertinib

In patients who have developed disease progression on treatment with the third-generation TKI osimertinib, resistance mutations are most commonly either EGFR-dependent (e.g., C797S mutation) or MET-dependent (e.g., MET amplification) [5, 6]. Other pathways such as PIK3CA or RAS/RAF may also be involved, although in 40-50 %, no resis­tance mechanisms can be identified. Co-occurrence of multiple mechanisms is common.

A potential treatment approach after osimertinib failure is the combination of amivantamab, a bispecific antibody targeting EGFR and MET, with the potent third-generation EGFR TKI lazertinib. Both agents have shown clinical activity across various EGFR mutations [7-11]. Based on these observations, 45 chemotherapy-naïve patients with EGFR exon 19 deletions or L858R mutations who had progressed on osimertinib were treated with amivantamab plus lazertinib in the dose-expansion phase of the phase I CHRYSALIS trial. Amivantamab was administered intravenously 2-weekly from cycle 2 at doses of 1,050 mg (< 80 kg body weight) or 1,400 mg (≥ 80 kg), while lazertinib 240 mg was taken orally every day.

The analysis presented at ASCO 2021 demonstrated durable responses of this combination [12]. After a median follow-up of 11.0 months, the ORR was 36 %, and 64 % of patients showed clinical benefit (i.e., complete or partial responses plus stable disease ≥ 11 weeks). Responses lasted for a median of 9.6 months; 69 % of patients responded for at least 6 months. Median PFS was 4.9 months. At the same time, the analysis revealed manageable safety of the regimen. The most common AEs were infusion-related reactions, rash, and paronychia, with the majority rated as grade 1 or 2. Treatment-related dose reductions and discontinuations occurred in 18 % and 4 %, respectively.

Patient selection according to NGS and IHC

The design of the CHRYSALIS trial included biomarker analyses using next-generations sequencing (NGS) and immunohistochemistry (IHC). According to NGS, 17 of 45 patients had EGFR- or MET-based resistance. Among the remaining 28 patients, 12 had identifiable alterations such as the PIK3CA E545K mutation or CCND1 amplification. Those with EGFR/MET-based resistance, compared to those without, fared better regarding ORR, duration of response, clinical benefit rate, and PFS (Table 1). However, NGS did not identify half of the confirmed responders.

In 20 cases, tumor biopsies were sufficient for IHC staining after NGS. Here, 10 patients had combined EGFR/MET H scores ≥ 400, and this group experienced excellent outcomes (Table 1). IHC was shown to identify patients regardless of the underlying genetic resistance mechanisms. The authors therefore suggested that EGFR/MET expression according to IHC might be used as an alternative approach to identify potential responders. The phase I/Ib CHRYSALIS-2 study will seek to validate these biomarkers prospectively in a new osimertinib-pretreated cohort (NCT04077463).

Table 1 Outcomes obtained with amivantamab/lazertinib in patients with and without EGFR/MET-based resistance and in patients with MET/EGFR expression

MET amplification: comparison of strategies

Although MET amplification is an important mechanism of acquired resis­tance to EGFR TKI therapy, no treatment standard for progressive disease based on this aberration exists. Three strategies are commonly administered: EGFR-TKI and MET-TKI combination therapy, MET-TKI monotherapy, or chemotherapy. A real-world study compared these three approaches in 70 patients with EGFR-mutant NSCLC and acquired MET amplification [13]. Treatment consisted of either EGFR TKI therapy plus crizotinib (n = 38), crizotinib alone (n = 10), or chemotherapy (n = 22).

The combination showed the most favorable results across the entire cohort. Compared to chemotherapy, significant superiority was observed with respect to ORR (p = 0.026), DCR (p = 0.016), and PFS (p = 0.036). OS was comparable across the three groups. Moreover, the EGFR TKI plus crizotinib approach showed activity in patients with concurrent TP53 mutations or EGFR amplification, which were the most common concurrent mutations in the three cohorts. As the authors noted, combined EGFR and MET inhibition might be a preferred option in this subset of patients.

Favorable findings for sequential afatinib-osimertinib

The T790M mutation emerges as the predominant resistance mechanism after failure of first- and second-generation EGFR TKIs in approximately 50-70 % of cases [14-17]. As is known, T790M can be targeted effectively using osimertinib. Sequential administration of afatinib and osimertinib has been shown to facilitate prolonged, chemotherapy-free treatment in patients with T790M resistance [18]. Real-world data from South Korea reported at ASCO 2021 assessed time on treatment in four groups of patients receiving first-line afatinib therapy: those in whom subsequent osimertinib was prescribed based on the presence of T790M (Cohort A; n = 116); those with other subsequent treatments in the absence of T790M (Cohort B; n = 143); those with other treatments and unknown T790M status (Cohort C; n = 111); and patients treated with afatinib only who had not received any second-line therapy yet (Cohort D; n = 367) [19].

Median time on treatment (TOT) was 23.42 months in the total study population. For Cohorts A-C, median TOTs in the first-line setting were 17.43, 14.19 and 7.13 months, respectively, thus demonstrating the most favorable outcome for the afatinib-osimertinib sequence. TOT in Cohort D was 42.61 months, which suggests that first-line afatinib allows certain patients to maintain long-term, chemotherapy-free disease control. In the second line, Cohort A again showed the best outcome with a TOT of 11.04 months; for Cohorts B and C, these were 3.32 and 2.43 months, respectively.

Similarly, response rates were highest in Cohort A in the first and second lines. Among the patients who progressed on afatinib treatment, rebiopsy was performed in 70.81 %. Here, the detection rate of T790M was 44.27 %. According to the conclusion of the authors, afatinib followed by osimertinib after the acquisition of the T790M resistance mutation is a feasible and effective strategy.

Outcomes in patients with exon 20 insertion

Among EGFR mutations, exon 20 insertion mutations (Exon20ins) are the third most common alterations, occurring in up to 12 % of cases [20, 21]. At present, no approved targeted therapies are available for lung cancer patients with Exon20ins in the metastatic setting. Limited activity has been observed for EGFR TKIs, platinum-based chemotherapy, docetaxel, and immunotherapies [22-28].

The retrospective real-world study conducted by Chouaid et al. described treatment patterns and clinical outcomes of patients with advanced non-squamous NSCLC harboring EGFR Exon20ins [29]. The data source was the French Epidemiological Strategy and Medical Economics Advanced and Metastatic Lung Cancer Data Platform. Among a total of 13,737 patients, four cohorts were defined based on EGFR mutation status: Exon20ins without exon 19 deletion/L858R mutation (n = 61); common EGFR mutation (i.e., exon 19 deletion or L858R without Exon20ins; n = 1,049); other EGFR mutation(s) (n = 439); wild-type EGFR mutation or not tested (n = 12,188).

The group with Exon20ins represented 3.9 % of the total, which confirmed that this is a rare aberration in NSCLC patients. In this cohort, first-line chemotherapy was administered in 74.1 %, EGFR TKI treatment in 13.7 %, and immunotherapy in 8.6 %. Patient prognosis was similar to that of the group who had wild-type EGFR mutation or had not been tested, which was worse than prognosis for those with common or other EGFR mutations (Table 2). Compared to patients with common EGFR mutations, median OS was significantly shorter (24.3 vs. 35.4 months; p = 0.049), as was median PFS (7.0 vs. 8.9 months; p = 0.0167). The authors pointed out that these observations highlight the need for therapeutic advancements in patients with exon 20 insertion mutations.

Table 2 Inferior overall survival and progression-free survival in patients with EGFR exon 20 insertion mutations compared to those with other mutations

Mobocertinib following platinum pretreatment

The oral, first-in-class, irreversible EGFR TKI mobocertinib has been developed to inhibit EGFR Exon20ins and other EGFR mutations with or without T790M. Mobocertinib is undergoing clinical assessment in a total of seven cohorts included in a phase I/II study. At ASCO 2021, Ramalingam et al. reported updated primary efficacy results for platinum-pretreated patients (PPP; i.e., patients with Exon20ins-positive metastatic NSCLC after platinum therapy who receive mobocertinib 160 mg/d in the dose-escalation, expansion, or the EXCLAIM cohort) and the EXCLAIM cohort (i.e., previously treated patients with Exon20ins-positive metastatic NSCLC who receive mobocertinib 160 mg/d) [30]. The PPP and EXCLAIM cohorts comprise 114 and 96 individuals, respectively.

Mobocertinib induced deep and durable responses. ORR was 28 % and 25 % according to independent review committee for the PPP and EXCLAIM cohorts, respectively. Almost 80 % in both groups achieved disease control (78 % and 76 %, respectively). In the PPP cohort, median duration of response was 17.5 months, while this had not been reached in the EXCLAIM cohort yet. Median PFS and OS in the PPP cohort amounted to 7.3 and 24.0 months, respectively.

Responses occurred independent of pretreatment and across Exon20ins subtypes regardless of their frequency or position from the C-helix. Consistent with the known safety profile of EGFR TKIs, the AEs elicited by mobocertinib mainly included manageable gastrointestinal and cutaneous events. Dose reductions due to AEs occurred in 25 % and 22 % in the PPP and EXCLAIM cohorts, respectively. In 17 % and 10 %, respectively, treatment had to be discontinued.

Patient-reported outcomes were assessed in the EXCLAIM cohort using the EORTC QLQ-LC13 and EORTC QLQ-C30 questionnaires. This showed that clinically meaningful improvements from baseline for dyspnea, cough, and chest pain were evident in cycle 2 and were maintained throughout the treatment. Likewise, mean global health status/quality of life scores were maintained over the study period despite worsening in gastrointestinal-related symptom scores during treatment. In their summary, the authors stated that mobocertinib appears to have a favorable risk-benefit profile in patients with previously treated EGFR Exon20ins-positive metastatic NSCLC and might provide a meaningful treatment option in this population that has a high unmet need.

Amivantamab in Exon20ins-positive disease

In the CHRYSALIS trial, amivantamab monotherapy has shown durable responses in patients with advanced NSCLC and EGFR Exon20ins [8, 9]. Minchom et al. evaluated the efficacy of amivantamab versus physician’s choice of anticancer treatment in the real-world setting in lung cancer patients with Exon20ins who had received prior platinum-based chemotherapy [31]. To this end, the investigators compared an efficacy analysis set of 81 post-platinum patients from the Exon20ins population included in CHRYSALIS with an external control analysis set (n = 174) derived from three real-world US-based datasets. The control patients met relevant eligibility criteria for the CHRYSALIS study. Their most common therapies were non-platinum-based chemotherapies, immunotherapies, platinum-containing regimens, and EGFR TKIs.

Compared to the real-world cohort, amivantamab-treated patients experienced a 53 % reduction in the risk of progression (median PFS, 8.3 vs. 2.9 months; HR, 0.47) and a 51 % mortality reduction (median OS, 22.8 vs. 12.8 months; HR, 0.49). Time to next treatment was prolonged by 10 months (14.8 vs. 4.8 months; HR, 0.40; Figure 2). As the authors noted, the poor performance of the external controls reflected the ineffectiveness of currently available real-world treatments and highlights the urgent need to identify more targeted treatments for patients with advanced NSCLC and EGFR Exon20ins.

Figure 2: Time to next treatment with single-agent amivantamab in patients with EGFR exon 20 insertion mutations compared to real-world outcomes from three databases

Figure 2: Time to next treatment with single-agent amivantamab in patients with EGFR exon 20 insertion mutations compared to real-world outcomes from three databases

Uncommon mutations in the real world

EGFR mutations classified as uncommon, i.e., those that are not deletion 19 or L858R mutation, are estimated to represent 7 %-23 % of the EGFR mutation pool [32]. “Major” uncommon mutations sensitive to TKI therapy include G719X, S768I, and L861Q. Exon20ins mutations are considered resistant to EGFR TKIs, although this is a highly heterogeneous group. T790M is known to confer resistance to first- and second-generation TKIs. For other uncommon mutations, little data have been obtained on TKI sensitivity. In addition, up to one third of EGFR-mutant tumors harbor compound mutations. It can be expected that the growing use of sensitive sequencing-based detection methods and liquid biopsy will increase the frequency of uncommon mutations detected in real-world clinical practice [33].

The real-world cohort study UpSwinG that was conducted in nine countries across Europe and Asia investigated the treatment and outcomes of patients who had ≥ 1 uncommon EGFR mutation and received EGFR TKIs (afatinib, gefitinib, erlotinib, osimertinib) in the first or second line [34]. Overall, 246 individuals were included in the analysis. Most were Asian, and less than 10 % had brain metastases, as active brain metastases constituted an exclusion criterion.

The analysis showed that EGFR TKIs were generally the first-line treatment of choice (91.9 % vs. chemotherapy in 8.1 %). Afatinib was the most commonly used index therapy (54.1 %), followed by gefitinib (28.7 %), erlotinib (14.3 %) and osimertinib (2.9 %). TKI therapy conferred encouraging results for the primary endpoint of time to treatment failure (TTF), OS, and ORR. TTF was 11.3 and 8.8 months for afatinib and first-generation TKIs, respectively, and OS was 24.5 and 24.2 months, respectively. With first-line treatment in general, partial responses were obtained in 43.9 %, and stable disease was seen in 41.7 %. Responses to second-line treatment included partial responses and stable disease in 22.2 % and 49.1 %, respectively.

Patient fitness was largely maintained over time; at the start of first-line therapy, half of patients had an ECOG performance status of 1, and at the start of second-line therapy, this proportion had only slightly decreased (45.7 %). Clinical outcomes varied according to the mutation category; TTF and ORRs were generally most favorable in the subgroups with major uncommon mutations and compound mutations. The authors concluded that treatment with an EGFR TKI should be considered for most patients whose tumors harbor uncommon EGFR mutations.

First-line benefit of aumolertinib

Aumolertinib is a novel, irreversible, third-generation EGFR TKI that selectively inhibits both sensitizing and resistance EGFR mutations. Approval of this drug was granted in China in 2020 based on the APOLLO trial, which demonstrated robust efficacy in patients with EGFR-mutated NSCLC who had progressed on first- or second-generation EGFR TKIs after developing the T790M mutation [35]. In the first-line setting, the randomized, double-blind, phase III AENEAS trial tested aumolertinib 110 mg/d (n = 214) against gefitinib 250 mg/d (n = 215) in patients with locally advanced or metastatic NSCLC harboring exon 19 deletion or L858R mutation [36].

Compared to gefinitib, aumolertinib gave rise to marked PFS improvement (median PFS, 19.3 vs. 9.9 months; HR, 0.463; p < 0.0001; Figure 3). At 12 months, PFS rates were 69.5 % vs. 46.3 %, and at 24 months, 32.5 % vs. 12.9 %. PFS benefits were preserved across subgroups relating to type of EGFR mutation, presence of brain lesions, gender, age, smoking history, and ECOG performance score. Median OS had not been reached in either arm yet (HR, 0.82). No difference resulted for ORR (73.8 % vs. 72.1 %), although duration of response was significantly longer in the experimental arm (18.1 vs. 8.3 months; HR, 0.38; p < 0.0001).

Aumolertinib was generally well tolerated. Most commonly, patients experienced creatine phosphokinase elevations, transaminase elevations, and cytopenia. Rash was observed less frequently with aumolertinib than with gefitinib (23.4 % vs. 41.4 %), which also applied to diarrhea (16.4 % vs. 35.8 %). QTc prolongation was seen in 10.7 % with aumolertinib (grade ≥ 3, 0.9 %) vs. 8.8 % with gefitinib (grade ≥ 3, 1.9 %). Interstitial lung disease occurred in 0.9 % vs. 0.5 % (no grade ≥ 3 events in either arm).

In their summary, the authors noted that based on these results, they will pursue discussions with global regulatory authorities with the goal of facilitating a markedly less costly global access pricing structure. Global trials of aumolertinib with chemotherapy and selected targeted agents as well as assessment of the drug in the adjuvant setting are ongoing or planned.

Figure 3: AENEAS trial: first-line superiority for aumolertinib vs. gefitinib regarding progression-free survival

Figure 3: AENEAS trial: first-line superiority for aumolertinib vs. gefitinib regarding progression-free survival


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