Multiple Resistance Mechanisms Thwart Efficacy for Third-Generation TKIs in NSCLC

Targeted Therapies in OncologyMarch II, 2024
Volume 13
Issue 4
Pages: 59

An important clinical strategy that focuses on improved frontline EGFR TKI regimens may help combat acquired EGFR TKI resistance and further streamline treatment options in subsequent lines, according to Balazs Halmos, MD.

Balazs Halmos, MD

Balazs Halmos, MD

The emergence of multiple resistance mechanisms associated with third-generation tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) poses a serious conundrum for clinicians. An important clinical strategy that focuses on improved frontline EGFR TKI regimens may help combat acquired EGFR TKI resistance and further streamline treatment options in subsequent lines, according to Balazs Halmos, MD.

“Resistance, which has become fairly simple in the case of first-generation EGFR TKIs, has become extremely complex in the context of third-generation potent drugs, such as osimertinib [Tagrisso], [with] multiple mechanisms of resistance…potentially in the same patient limiting the efficacy of second-line strategies,” Halmos said in a presentation during the 21st Annual Winter Lung Cancer Conference, sponsored by Physicians’ Education Resource, LLC.1 “For us to be more successful, we need to do better up front to prevent that resistance or delay it at least to the maximum amount of time.”

In his presentation, Halmos highlighted research evaluating the potential benefits of combining EGFR TKIs with VEGF TKIs or radiotherapy, the clinical implications of the phase 3 FLAURA2 (NCT04035486) and MARIPOSA (NCT04487080) trials, and the importance of including patients in the treatment decision-making process. Halmos is a professor in the Department of Oncology (Medical Oncology) and a professor in the Department of Medicine (Oncology & Hematology), and associate director of clinical science at the Montefiore Einstein Comprehensive Cancer Center at Albert Einstein College of Medicine in the Bronx, New York.

EGFR/VEGF Targeting

Halmos began his discussion of investigational EGFR-targeted combinations by noting interim findings from a phase trial (NCT03909334), which were presented atat the European Society for Medical Oncology (ESMO) Congress 2023 in Madrid, Spain. In the findings, the EGFR inhibitor osimertinib in combination with ramucirumab (Cyramza) led to an investigator-assessed median progression-free survival (PFS) improvement of 9.2 months over that seen with osimertinib monotherapy in patients with TKI-naive EGFR-mutated metastatic NSCLC (HR, 0.55; 95% CI, 0.32-0.93; log rank P =.026 ).2 These data were complicated by findings from the phase OSIRAM-1 trial (jRCT2080224085), also presented at ESMO Congress 2023, in which osimertinib plus ramucirumab elicited a less favorable blinded independent central review (BICR)–assessed median PFS benefit of 4 months vs that seen with osimertinib monotherapy in patients with EGFR-mutated nonsquamous NSCLC (HR, 1.054; 95% CI, 0.674-1.648; P =.46).3

Furthermore, findings from the phase 2 ATLAS trial (NCT04966676) showed no benefit associated with adding the VEGF inhibitor bevacizumab (Avastin) plus the immunotherapy agent atezolizumab (Tecentriq) to a chemotherapy backbone for patients with EGFR- or ALK-mutated NSCLC.4 “We continue to be challenged as to whether VEGF targeting is helpful,” Halmos said.1

EGFR Inhibitors Plus Radiotherapy

Commenting briefly on the potential for combining EGFR-directed agents with radiotherapy in the frontline EGFR-mutated NSCLC setting, Halmos explained that findings from the phase 3 Sindas trial (NCT02893332) demonstrated the PFS and overall survival (OS) benefit of adding radiation therapy to a first-generation EGFR TKI in patients with treatment-naive oligometastatic EGFR-mutated disease.5

“[Sindas was a] reasonably small study, and it would be nice to have these findings validated in a different context and different setting but these findings are intriguing for] individualizing treatment for some patients with limited metastatic disease,” Halmos noted.

EGFR Inhibitors in Combination: FLAURA2

Although the clinical use of EGFR inhibitors plus VEGF TKIs and radiotherapy has yet to be determined, the future of EGFR-directed agents in combination with chemotherapy is growing increasingly clear, as supported by data from FLAURA2 and MARIPOSA. FLAURA2 evaluated osimertinib with or without chemotherapy in patients with EGFR-mutated advanced NSCLC.6 The treatment arms were balanced, and 41% of patients in the overall population had baseline central nervous system (CNS) metastases. The trial met its primary end point of investigator-assessed PFS, which was 25.5 months (95% CI, 24.7-not calculable) with the combination vs 16.7 months (95% CI, 14.1-21.3) with osimertinib monotherapy (HR, 0.62; 95% CI, 0.49-0.79; P <.001). The PFS by BICR also favored the combination, with a median PFS improvement of 9.5 months over that seen with osimertinib monotherapy (HR, 0.62; 95% CI, 0.48-0.80).

The PFS benefit with osimertinib plus chemotherapy was observed across all prespecified patient subgroups although the most notable benefit was seen in the subgroup with baseline CNS metastases, in which the combination elicited a median PFS improvement of 11.1 months over that seen with osimertinib monotherapy (HR, 0.47; 95% CI, 0.33-0.66). Conversely the PFS benefit was 6.6 months with the combination vs osimertinib monotherapy in patients without CNS metastases (HR, 0.75; 95% CI, 0.55-1.03).

“[In] the patients without CNS metastases, that [PFS] improvement is less impressive, calling into question whether the added toxicity of chemotherapy is meaningful for many patients,” Halmos said. “Patients with measurable brain metastases seemed to benefit the most."

The OS data from FLAURA2 are still immature, and early readouts have not shown a significant OS benefit with osimertinib plus chemotherapy over osimertinib monotherapy, with an HR of 0.90 (95% CI, 0.65-1.24; P =.5238).6 Furthermore, Halmos noted that the adverse effect (AE) profile of the combination appears less favorable than that of osimertinib alone because intensive chemotherapy was added in the combination arm.1 However, he explained that most AEs associated with the combination in FLAURA2 were manageable and occurred within the first 3 months of therapy.

EGFR Inhibitors Plus Chemotherapy: MARIPOSA

Another frontline trial, MARIPOSA, randomly assigned patients with EGFR-mutated advanced NSCLC in a 2:2:1 ratio to receive amivantamab-vmjw (Rybrevant) plus lazertinib, osimertinib monotherapy, or lazertinib monotherapy.7

“The reason lazertinib monotherapy was assessed in the trial was] to understand the added value of the bispecific antibody [amivantamab],” Halmos explained.1 “This is important [to note] as we read the study results. The survival curves with lazertinib and osimertinib are practically identical, so the benefit is indeed derived from the bispecific antibody added to the thirdgeneration backbone.”

In MARIPOSA, baseline characteristics were balanced among the arms, and 41%, 40%, and 40% of patients in the amivantamab/lazertinib, osimertinib monotherapy, and lazertinib monotherapy arms, respectively, had a history of brain metastases.7 The median PFS by BICR was 23.7 months (95% CI, 19.1-27.7) with amivantamab plus lazertinib vs 16.6 months (95% CI, 14.8-18.5) with osimertinib monotherapy (HR, 0.70; 95% CI, 0.58-0.85; P <.001 ) and 18.5 months (95% CI, 14.8-20.1) with lazertinib monotherapy.

Although the PFS benefit with the combination was observed across all prespecified subgroups, Halmos emphasized that “what we don't see is a more impactful benefit in any particular cohort of patients, so when it comes to individualization, the current data do not help identify the specific group of patients who might benefit from this combination more than others.... That includes patients with brain metastases.”1 In patients with a history of brain metastases, the HR for PFS between the amivantamab/lazertinib and osimertinib monotherapy arms was 0.69 (95% CI, 0.53-0.92).7 In patients without a history of brain metastases, the HR was also 0.69 (95% CI, 0.53-0.89).

MARIPOSA findings demonstrated a trend toward improved OS with the combination vs osimertinib monotherapy, at 22 months, the interim OS HR was 0.80 (95% CI, 0.61-1.05; P =.11). As with FLAURA2, the AE profile of amivantamab plus lazertinib needs to be considered because of the toxicities associated with adding a bispecific to treatment with an EGFR TKI, Halmos noted.1 The most common treatment-emergent AEs in the combination arm of the trial were rash (grade ≥3, 15%) paronychia (grade grade ≥3, 11%) infusion-related reactions (grade ≥3, 6%) and hypoalbuminemia (grade ≥3, 5%). “I'm hopeful [that these AEs] will be mitigated over time as we’re learning about how to manage [them and]…support patients [and] moving from an intravenous to a subcutaneous [administration] strategy,” Halmos said.1

Future Directions in the First Line and Beyond

In the wake of data from FLAURA2 and MARIPOSA, which both indicate improved efficacy with combination EGFR-targeted strategies over single-agent osimertinib, additional treatment regimens must be developed and administered to patients who will derive the most benefit with the lowest risk of added AEs. Acknowledging the limitations of cross-trial comparisons, Halmos emphasized that current data would lead him to choose the FLAURA2 regimen for patients with brain metastases. He also noted that although the advent of several combination strategies in the first-line NSCLC setting has widened the scope of available treatment options, it has also complicated treatment decision-making at every stage of disease.

“In the EGFR Olympics, it’s nice to pick the best regimen up front, but this is ultimately now a triple jump with all the options we have for patients, so we have to be smart picking the right patient profile," Halmos explained. For patients with EGFR-mutated disease, the therapeutic pipeline may soon yield a new cohort of second-line treatment options, such as datopotamab deruxtecan and patritumab deruxtecan.

Halmos also listed the patient and disease characteristics that might be most helpful to consider when determining ideal personalized treatment strategies, including mutation type, CNS involvement, comutations, and circulating tumor DNA dynamics. “Shared decision-making is going to be more important than ever for patients with EGFR-mutated lung cancer,” Halmos concluded.

1. Halmos B. Management of advanced EGFR+ NSCLC. Presented at: 21st Annual Winter Lung Cancer Conference; February 2-4, 2023; Hollywood, FL. Accessed February 6, 2024.
2. Le X, Patel J, Shum E, et al. A multi-centre open-label randomized phase II study of osimertinib with and without ramucirumab in TKI-naïve EGFR-mutant metastatic NSCLC (RAMOSE trial interim analysis). Ann Oncol. 2023;34(suppl 2):S1313-S1314. doi:10.1016/j.annonc.2023.10.072
3. Nakahara Y, Kato T, Isomura R, et al. OSIRAM-1: a multicenter, open label, randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer (TORG1833). Ann Oncol.
2023;34(suppl 2):S1313. doi:10.1016/j.annonc.2023.10.071
4. Park S, Kim TM, Han JY. Phase III, randomized study of atezolizumab plus bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated non-small-cell lung cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol. Published online October 20, 2023. doi:10.1200/JCO.23.01891
5. Wang XS, Bai YF, Verma V, et al. Randomized trial of first-line tyrosine kinase inhibitor with or without radiotherapy for synchronous oligometastatic EGFR-mutated non-small cell lung cancer.
J Natl Cancer Inst. 2023;115(6):742-748. doi:10.1093/jnci/djac015
6. Planchard D, Jänne PA, Cheng Y, et al; FLAURA2 Investigators. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
7. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl
2):S1306. doi:10.1016/j.annonc.2023.10.062
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