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Flora, Fauna, and Merryweather. Those were the fairies who bestowed their good graces on . For patients with non-small lung cancer (NSCLC), the ADAURA, FLAURA and MARIPOSA trials bestowed their munificence in terms of offering a better prognosis, the potential for improved overall survival (OS), and even the possibility of cure.

"The introduction of new agents with novel mechanisms of action, including bispecific monoclonal antibodies and antibody-drug conjugates (ADCs), along with the development of novel tyrosine kinase inhibitors (TKIs), has expanded the proportion of tumors with an oncogene-driven alteration that can be targeted with specific agents," explained Jordi Remon, MD, PhD, of the National Cancer Centre Singapore/Duke-NUS Oncology Academic Clinical Programme, and colleagues in an review. "Understanding mechanisms of resistance may enable the personalization of sequential treatment approaches at the time of disease progression."

The team pointed out that the primary treatment goal for early-stage NSCLC is cure, and that extended OS has been achieved in the metastatic setting with TKIs for patients with certain oncogene-driven NSCLC, and that the ADAURA trial is the first biomarker-selected adjuvant study, where the addition of adjuvant TKI to the standard of care in resected lung cancer subsequently resulted in an improved OS.

As for unresectable NSCLC, the trial established a year of consolidation durvalumab (Imfinzi) after completion of definitive chemoradiotherapy (CRT) as the standard of care, Remon's group stated. One ongoing trial -- osimertinib (Tagrisso) versus placebo until progression after completion of definitive CRT in LAURA -- has already shown that the agent achieved the study's primary progression-free survival (PFS) endpoint, they added. Updated LAURA findings were presented at the 2024 ASCO meeting, and experts called them "practice changing."

In the metastatic setting, FLAURA findings "led to the adoption of first-line osimertinib for patients with advanced EGFR-mutated NSCLC," the authors said, while MARIPOSA pitted amivantamab (Rybrevant), an EGFR-MET bispecific antibody, plus lazertinib (Leclaza) against osimertinib monotherapy. The study, along with , was able to "demonstrate superiority of a combination therapy over osimertinib alone," they said.

But Remon and colleagues cautioned that acquired resistance (AR) remains a major obstacle. "The mechanisms of AR on osimertinib remain unknown in up to half of patients ... while real-world data and certain clinical trials suggest that subsequent tailored therapy on osimertinib progression may improve the outcome, obtaining a genomic profile at progression is not always feasible in daily practice," the team wrote. "The integration of genomic, proteomic, and phenotypic analyses shows promise in identifying actionable targets and designing innovative therapeutic interventions tailored to the dynamic evolution of resistance in this clinical context."

In related news, in a 2024 , Deepa Rangachari, MD, of Beth Israel Deaconess Medical Center in Boston, and colleagues, agreed that "acquired treatment resistance and cancer progression within the CNS [central nervous system] are inevitable during the disease course and present a challenging transition in the care continuum." They discussed a case of a patient with a 20-year pack history who was diagnosed with lung adenocarcinoma with the EGFR exon 19 mutation and co-alteration in TP53.

Rangachari's group also highlighted findings from the phase III trial, which evaluated atezolizumab (Tecentriq) plus bevacizumab, paclitaxel, and carboplatin (ABCP) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. In an accompanying , host Rohit Singh, MD, of the University of Vermont Medical Center in Burlington, offered his take on the ATTLAS data and the case presented by Rangachari and colleagues.

What treatment did this case patient receive?

Rangachari et al: The patient undergoes palliative radiotherapy to brain and symptomatic skeletal metastases. The patient begins first-line palliative osimertinib with tumor response, but 17 months later, the patient has symptomatic progression. Rebiopsy confirms adenocarcinoma of the lung; tumor molecular reprofiling yields identical results as before. The patient is here [as of April 2024] to discuss ongoing treatment options, including chemotherapy, immunotherapy, targeted therapy, or symptom-focused care.

In our own practice, decisions regarding continuation of osimertinib involve a detailed discussion of relative risks/benefits and shared decision-making with the patient. Key considerations include the presence of previous/current brain metastases, drug tolerability, and patient preference. In our case, given the history of previous brain metastases and sustained intracranial control noted at the time of disease progression, we elected to continue osimertinib along with platinum-doublet chemotherapy and deferred the addition of the ICI [immune checkpoint inhibitor] and VEGFi [vascular endothelial growth factor inhibitors] to the chemotherapy backbone. The patient remains on treatment with clinical and radiographic improvement to date.

What is a "patient-centered care continuum after cancer progression" in EGFR-mutated advanced NSCLC?

Rangachari et al: For patients with asymptomatic and/or limited progression, it is important to consider options for local interventions (i.e., radiation, surgery, or ablation) that may safely extend EGFR TKI treatment. By contrast, patients with multifocal cancer progression who desire and are eligible for treatment should be offered next-line systemic therapy. Options include platinum-doublet chemotherapy with/without ICI and VEGFi.

Given uncertain benefits with many of these combinations, we strongly recommend consideration of a clinical trial if available and aligned with the patient's wishes. In an occasional patient with an identifiable and/or actionable mechanism of treatment resistance, we favor exhausting all targeted therapy strategies before moving onto chemotherapy.

How do findings from the ATTLAS trial fit into that care continuum?

Rangachari et al: Conducted in Korea, the ATTLAS trial provides further experience with the combination of chemoimmunotherapy and VEGFi in TKI-resistant advanced EGFRm [EGFR-mutated] NSCLC. Importantly, more than 50% of patients had received only a first- or second-generation EGFR TKI at study enrollment. Median PFS was significantly improved in the ABCP group [8.48 vs 5.62 months], without a difference in OS.

ATTLAS thus offers a biologically rational way to combine and modulate systemic therapy after progression on an EGFR TKI although many questions remain unanswered regarding optimal patient selection and sequencing/combining of agents.

What are some take-home messages from ATTLAS?

Singh: Patients with EGFR-mutated or translocated NSCLC for whom prior TKI ABCP regimen failed showed a statistically significant prolongation of PFS and response rate compared with chemotherapy alone. Patients in the subgroup with EGFR L858R, without acquired T790M mutation, and presence of brain metastases showed more benefit. In the exploratory biomarker analysis, interestingly, the impact on PFS was correlated with PD-L1 expression.

In terms of PFS, the study found that the higher the PD-L1 expression, the better the need to take into consideration that all the patients were from a single country with Asian ethnicity. And most importantly, the majority of patients were treated with first- and second-generation TKIs, whereas third-generation TKIs are the standard of care in the United States.

And what about the Grand Rounds case?

Singh: The decision to continue or change therapy at cancer progression is based on factors like drug tolerability, patient preferences, and specific subgroups with different outcomes, such as those with brain metastasis or specific EGFR-mutation subtypes. Choosing between combination therapy strategies the concept of progression involves personalized decision-making to optimize treatment outcomes. Ultimately, the approach to management should be tailored to individual patient needs, preferences, and eligibility for different treatment modalities.

Read the review here.