Debate: Osimertinib Alone as Front-Line Therapy for a Patient with Metastatic EGFR NSCLC

Speaker: Dr. Julia Rotow

Core Argument

Osimertinib monotherapy remains a highly effective and better-tolerated frontline option for many patients with EGFR-mutated NSCLC, especially those with lower-risk features. Universal adoption of combination therapy risks overtreatment and unnecessary toxicity.

Supporting Points

1. Real-World Feasibility Is Limited

• Clinical trial populations are highly selected; >50% of real-world patients wouldn’t qualify for trials like FLORA2 or MARIPOSA.
• Comorbidities, CNS involvement, and performance status exclude many from combination regimens.

2. Benefit of Combination Therapy Is Modest for Some

• For lower-risk patients (exon 19 deletions, TP53 wild-type, no liver/CNS metastases), combination therapy adds only 3–5 mo of PFS.
• In the MARIPOSA study, 11% of patients with no high-risk features saw no PFS gain with combination.

3. Monotherapy Still Offers Durable Outcomes

• Case example: A 66-year-old woman on monotherapy since 2019 showed long-term control and excellent quality of life.
• Consolidative radiotherapy at progression can extend benefits further.

4. Post-Progression Strategies Can Compensate

• Patients often receive platinum-based chemotherapy or amivantamab in second-line settings.
• Mariposa-2 shows PFS improvement when amivantamab is used post-osimertinib.

5. Combination Therapy Carries Significant Toxicity

• Increased Grade 2–3 skin, infusion, hematologic, and MET-related toxicities.
• "Time toxicity": More frequent hospital visits, IV infusions, and at-home care burden.

6. Patients Prefer Monotherapy

• Surveys show ~75% of patients and caregivers prefer monotherapy over combination regimens.
• Patients value preserving quality of life, especially during first-line treatment.

7. Cost and Long-Term Planning

• Combination therapy is costlier and may limit future well-tolerated oral options.
• For some patients, the first-line setting may be their only chance at oral-only, low-toxicity therapy.

Conclusion

While combination therapy can benefit some, particularly those with high-risk features, it should not be universally applied. For selected patients, monotherapy offers a balance of efficacy, tolerability, and quality of life. Treatment decisions must be individualized, weighing clinical risk factors and patient preferences.

Striking the Balance: Optimizing Amivantamab Use and Handling Its Adverse Effects in Patients with Lung Cancer

Speaker: Jennifer Carlisle

Introduction

The session focused on optimizing amivantamab, a bispecific antibody targeting MET and EGFR, in the treatment of non-small cell lung cancer (NSCLC), particularly in EGFR-mutated subtypes. Emphasis was placed on managing its toxicities through evidence-based supportive care and prophylactic strategies.

Mechanism and Indications

Amivantamab is a bispecific antibody with MET and EGFR binding domains that blocks signaling, induces receptor degradation, and triggers ADCC and trogocytosis.

FDA approvals:

• CRYSTALIS trial → Exon 20 insertion mutations (accelerated).
• PAPILLON trial → Amivantamab + chemotherapy for Exon 20 insertions.
• MARIPOSA & MARIPOSA-2 trials → Use in classical EGFR-mutated NSCLC.

Adverse Effects and Management Strategies

1. Dermatologic Toxicities

• Common Issues: Scalp and skin eruptions, paronychia.
• Prophylactic Strategy (COCOON trial):
  • Oral doxycycline/minocycline for 12 weeks.
  • Topical clindamycin on scalp.
  • Chlorhexidine on nails.
  • Ceramide-based moisturizers twice daily.
• Outcome: Reduced Grade ≥2 dermatologic AEs (7% vs. 34.3%), decreased dose modifications and discontinuations.
• Persistent Cases: Early dermatology referral; consider isotretinoin, dapsone, or propranolol in refractory cases.
• Specific Condition: Erosive pustular dermatosis of the scalp, presenting with crusts, ulceration, and potential scarring alopecia.

2. Venous Thromboembolism (VTE)

• Incidence: Up to 37% with amivantamab + lazertinib.
• Risk Factors: Age >60, treatment response.
• Timing: Majority of events occur within 4 months.
• Recommendation: Prophylactic anticoagulation for ≥4 months.

3. Infusion-Related Reactions (IRRs)

• Incidence: 66% with IV formulation vs 13% with SC formulation (PALOMA 3 trial).
• Management:
• SKIPPirr Ph 2 Trial: Dexamethasone 8 mg BID for 2 days prior + standard IV premeds → IRR reduced to 22%.
• Awaiting wider approval of subcutaneous formulation.

Ongoing Trials:

1. LungMAP S1900J: Amivantamab in MET-amplified NSCLC.
2. NEOPREDICT-EGF: Neoadjuvant setting.
3. COPERNICUS: Comprehensive supportive care + SC amivantamab + lazertinib or chemo.

Patient-Centered Perspective

Advocacy from patient emphasized informed decision-making. With multiple frontline EGFR-targeted options now available, treatment should align with patients' life context and values.

Final Takeaways

• Implement COCOON regimen for skin toxicities.
• Ensure 4-month anticoagulation with amivantamab + lazertinib.
• Use dexamethasone pre-treatment to reduce IRRs.
• SC amivantamab may offer improved safety and tolerability in the near future.

A Phase 3, Randomized Study of Adjuvant Acituzumab Tirumotecan plus Pembrolizumab vs Treatment of Physician’s Choice in Participants with Triple-negative Breast Cancer who Received Neoadjuvant Therapy and did not Achieve a Pathologic Complete Response at Surgery.

Speaker: Heather McArthur

Background

Trop-2 is a transmembrane glycoprotein that is broadly expressed and often upregulated in multiple cancers, including triple-negative breast cancer (TNBC). Its expression is particularly significant in TNBC, with approximately 80% of TNBC tumors demonstrating high Trop-2 levels. This overexpression is associated with poor prognosis, making Trop-2 a rational therapeutic target in this aggressive breast cancer subtype.

About Sacituzumab tirumotecan (Sac-TMT)

Sac-TMT is an antibody-drug conjugate (ADC) specifically engineered to target Trop-2. It consists of:

• A humanized anti-Trop-2 monoclonal antibody
• A hydrolytically cleavable linker
• A potent cytotoxic payload KL610023

Notably, Sac-TMT is designed with an average drug-to-antibody ratio (DAR) of 7.4, which enhances drug delivery to Trop-2–expressing tumor cells. The ADC is optimized for enhanced linker stability in serum, potentially improving its therapeutic index by minimizing premature drug release and maximizing tumor-targeted cytotoxicity.

The TroFuse-012 phase 3, open-label, randomized study is comparing the effects of Sac-TMT plus pembrolizumab versus treatment of physician's choice on invasive disease-free survival (iDFS) in participants with triple-negative breast cancer (TNBC) who received neoadjuvant therapy with the KEYNOTE-522 regimen and did not achieve pCR at surgery.

Study Population

Inclusion Criteria: Participants must meet all of the following

• Age ≥18 years
• Centrally confirmed TNBC (per ASCO/CAP guidelines)
• No evidence of locoregional or distant relapse, as assessed by the physician
• Received ≥5 doses of neoadjuvant pembrolizumab with carboplatin/taxane and ≥1 dose of anthracycline, followed by surgery
• Non-pCR at surgery
• Eligible to continue adjuvant pembrolizumab
• Tumor sample available for Trop2 testing (central)
• Adequate organ function
• ECOG performance status 0 or 1
• Controlled HIV on ART
• Undetectable HBV or HCV viral load at screening

Exclusion Criteria: Participants will be excluded if they have

• Known germline BRCA mutation and are eligible for adjuvant olaparib
• Grade ≥2 peripheral neuropathy
• Clinically significant cardiovascular or cerebrovascular disease within 6 months
• Prior treatment with a Trop2-targeted or topo-isomerase-I–containing ADC
• Prior use of anti–PD-(L)1 therapy or similar immune agents (except in KEYNOTE-522)
• Radiation therapy ≤3 weeks prior to enrolment or unresolved radiation-related toxicity
• Active autoimmune disease requiring systemic therapy in the last 2 years (except replacement therapy)
• History of non-infectious pneumonitis/interstitial lung disease requiring steroids

Treatment Arms

• Arm A (Investigational arm)
  • Pembrolizumab: 400 mg IV every 6 weeks (Q6W) × 5 doses
  • Sac-TMT: 4 mg/kg IV every 2 weeks (Q2W) × 12 doses
• Arm B (Control arm – Physician's choice)
  • Pembrolizumab: 400 mg IV Q6W × 5 doses
  • Or Pembrolizumab (same dose) + Capecitabine: 1000–1250 mg/m² orally BID
• Administered on Days 1–14 and 22–35 (2 weeks on, 1 week off) per 6-week cycle × 4 cycles

Primary Objective

To compare invasive disease-free survival (iDFS) between arms:

• iDFS is defined as the time from randomization to:
  • Invasive local, regional, or distant recurrence
  • Invasive contralateral breast cancer
  • Death due to any cause
• Determined by investigator assessment

Assessments

 

 

 

 

 

 

 

Enrollment began Q2 2024. Clinical trial information: NCT06393374.

Optimizing Neoadjuvant Therapy in Locally Advanced NSCLC: Current and Emerging Strategies

Speaker: Dr. Benjamin Besse

This session provides an update on optimizing neoadjuvant therapy for locally advanced NSCLC, focusing on current standards and emerging strategies.

Rationale for Neoadjuvant Treatment

Neoadjuvant treatment aims to:

• Eradicate micro-metastatic disease not visible on scans.
• Potentially downstage the tumor, although formal proof of avoiding procedures like pulmonectomy in lung cancer is not yet available.
• Improve patient compliance, as nearly all patients can receive neoadjuvant treatment compared to about 70% for adjuvant therapy due to post-surgical complications.
• Allow for assessment of pathological response.

However, risks include disease progression and complications.

Comparison of Chemotherapy Strategies

Historically, the overall survival hazard ratio (HR) for neoadjuvant versus adjuvant chemotherapy has been consistently around 0.87, suggesting no overall survival (OS) advantage for giving chemotherapy before surgery compared to after.

Immunotherapy in the Neoadjuvant Setting

• It is generally agreed that exposing the immune system to immunotherapy while the tumor is present (displaying neoantigens) is beneficial.
• Single-agent neoadjuvant immunotherapy shows a pathological complete response (pCR) rate up to 13%.
• Combinations of immunotherapies, or immunotherapy plus a VEGF blocker, show better pCR rates (up to 29%).
• Six Phase III studies are ongoing or have reported, primarily perioperative studies (neoadjuvant chemo-immunotherapy followed by an adjuvant component for up to one year). Only one study (CheckMate 816) was purely neoadjuvant (3 cycles of chemo-IO followed by surgery).

Challenges and Open Questions

• Patients not proceeding to surgery: Approximately 20% of patients in chemo-IO-surgery strategies may not reach surgery, potentially being "undertreated" if upfront radiotherapy was the better option. This highlights the importance of upfront treatment decision-making.
• Pathological Response Assessment: While a pCR is a good prognostic factor indicating a lower relapse risk, patients can still relapse. Assessment of pCR with immunotherapy is complex due to the presence of fibrosis, not just necrosis.
• Role of ctDNA Clearance: Clearance of circulating tumor DNA (ctDNA) after one cycle of chemo-IO may identify patients with good prognosis, but it's not a perfect predictor of no relapse.
• PD-L1 Negative Patients: Data suggests a benefit of neoadjuvant chemo-immunotherapy across all PD-L1 expression levels, including negative.
• Adjuvant Component: The necessity of an adjuvant immunotherapy component after neoadjuvant chemo-IO is debated. Comparisons between trials (e.g., CheckMate 816 vs. CheckMate 770) suggest that including adjuvant immunotherapy in analyses might bias results by selecting patients with better prognoses. Proper randomized trials are needed to clarify this.
• Targeted Therapies (TKIs): Limited data exist for TKIs in the neoadjuvant setting. Short courses of osimertinib show low pCR rates (0-4%), while alectinib appears slightly higher (12-17%). Emerging data for osimertinib alone or in combination with chemotherapy suggest increased pCR compared to chemotherapy alone, but efficacy outcomes (like EFS) may differ.
• Antibody-Drug Conjugates (ADCs): ADCs are being explored to improve pCR rates. Initial data from the Neocoast 2 study (datopotamab deruxtecan + durvalumab + chemo) show an encouraging 34% pCR, including 25% in PD-L1 negative patients (though based on a small sample size of 12 patients).
• Sample Size Discrepancies: Small sample sizes in early immunotherapy trials have led to vastly different pCR rates, highlighting the need for caution in interpreting results from smaller studies.
• Immune System Considerations: Factors like T-cell senescence (observed in 25% of metastatic patients, independent of age) may influence immunotherapy benefit, but data are lacking in neoadjuvant trials.
• Chronotherapy: Intriguing retrospective data from meta-analyses (13 studies, 1600 patients) suggest that immunotherapy given in the morning might significantly improve OS (HR:0.5), a finding replicated in other recent abstracts. This suggests that the timing of immunotherapy administration might be crucial and warrants further investigation.
• Cost and Dose Optimization: An Indian study (retrospective) suggests a very positive signal for low dose nivolumab combined with chemotherapy. A forthcoming Phase III trial with 8% of the standard nivolumab dose in metastatic patients is anticipated to show impressive results, suggesting potential for dose optimization and cost reduction.

Conclusion

Neoadjuvant chemo-immunotherapy is the standard of care for patients with resectable Stage II and III NSCLC who do not have actionable genomic alterations. The role of targeted therapy as induction treatment in patients with resectable NSCLC and actionable genomic alterations is not yet established. The decision for local treatment (radiotherapy vs. surgery) should be made upfront, not after chemoimmunotherapy.

ALPHA3: A Pivotal Phase 2 Study of First-line (1L) Consolidation with Cemacabtagene Ansegedleucel (cema-cel) in Patients (pts) with Large B-cell Lymphoma (LBCL) and Minimal Residual Disease (MRD) after Response to Standard Therapy

Speaker: Jason Westin

Introduction

This session details the ALPHA3 study, a pivotal Phase 2 trial investigating cemacabtagene ansegedleucel (cema-cel) as a first-line consolidation therapy for patients with large B-cell lymphoma (LBCL) who have minimal residual disease (MRD) after standard treatment.

Unmet Medical Need in LBCL

Approximately 60% of LBCL patients are cured with first-line immunochemotherapy. However, about 30% of patients who achieve remission will relapse within two years, in addition to 10% with refractory disease. This highlights a significant unmet need for better identification and treatment of high-risk patients.

Role of MRD and Cema-cel

A highly sensitive and specific MRD test, "Phase Seek," can identify patients at the highest risk of relapse. MRD-positive patients historically relapse within a median of less than six months post-treatment.

Cema-cel is an off-the-shelf allogeneic CD19 CAR T-cell product. It has demonstrated comparable safety and efficacy to autologous CD19 CAR T-cell therapies in relapsed/refractory LBCL in Phase 1 studies.

The immediate availability of cema-cel makes it suitable for consolidation of remissions in MRD-positive patients, aiming to prevent future relapse.

ALPHA3 Study Design

• Type: Pivotal Phase 2, first randomized trial to assess CAR T-cell therapy as a consolidation strategy in MRD-positive LBCL after standard first-line immunochemotherapy.
• Seamless Design (Part A & B):
  • Part A: Patients are randomized 1:1:1 to standard of care observation or cema-cel (120 million CAR T-cells) following a 3-day fludarabine/cyclophosphamide lymphodepletion, either with or without ALLO-647 (anti-CD52 monoclonal antibody). The preferred lymphodepletion regimen will be chosen after an early interim analysis.
  • Part B: Patients will be randomized 1:1 to receive treatment with the selected lymphodepletion regimen and cema-cel, or to the observation arm.
• Administration: Treatment can be given in outpatient or inpatient settings.
• Primary Endpoint: Event-free survival (EFS) per independent review committee (IRC).
• Key Secondary Endpoints (Hierarchical Testing): Progression-free survival (PFS) per IRC and overall survival (OS).
• Other Secondary Endpoints: Rate of MRD clearance and safety.

Patient Eligibility and Enrollment

• Prescreening for MRD: Required before main study consent.
• Eligibility for MRD testing: Histologically confirmed DLBCL, high-grade B-cell lymphoma, or primary mediastinal B-cell lymphoma; IPI score 2-5, or ANN ARBOR stage III/IV, or equivocal interim/end-of-treatment PET-CT response; completion of full first-line therapy; achieved complete or partial response.
• MRD Testing: Requires a tumor sample from initial diagnosis and a blood sample 3-8 weeks after end of treatment.
• Only MRD-positive patients can proceed to main study enrollment.
• Main Study Enrollment Criteria: Successful prescreening, ECOG performance status 0-1, no progression since MRD testing, and adequate organ function.
• Exclusion Criteria: Prior CD19-targeted agent, history of CNS involvement, LBCL transformed from other malignancy, or need for systemic immunosuppressive agents.
• Recruitment: Actively recruiting across academic and community cancer centers, with an expected enrollment of approximately 240 patients. Site activation in the US is near completion, with international sites opening in summer 2025.

Prediction of Survival After De-escalated Neoadjuvant Therapy in HER2+ Early Breast Cancer: A Pooled Analysis of Three WSG Trials

Speaker: Monika Graeser

Introduction

This presentation shares findings from a pooled analysis of three West German Study Group (WSG) trials, focusing on the prediction of survival after de-escalated neoadjuvant therapy in HER2-positive early breast cancer. The aim is to reduce treatment toxicities by minimizing or omitting chemotherapy.

WSG Strategy for De-escalation

The WSG strategy uses a short 12-week de-escalated neoadjuvant treatment instead of the standard 18-24 week chemotherapy and anti-HER2 therapy. This approach tests chemo-free combinations or ADC-based regimens, reflecting the heterogeneity of HER2-positive disease. Patient selection is based on hormone receptor status and molecular subtype, with a comprehensive translational research program embedded to identify prognostic and predictive biomarkers.

Study Design

• The pooled analysis included data from three completed WSG de-escalation trials (out of four completed and one ongoing), involving over 700 randomized patients. PCR was the primary endpoint for each trial, with survival as a secondary endpoint.
  • In patients without PCR, adjuvant chemotherapy was mandatory.
  • In patients with PCR, the omission of adjuvant chemotherapy was permitted.
• The trials compared different regimens based on hormone receptor status:
  • Hormone Receptor-Negative Trial: Twelve weeks of dual HER2 blockade with or without paclitaxel.
  • Two Hormone Receptor-Positive Trials: Twelve weeks of T-DM1, trastuzumab, or dual blockade (with or without endocrine treatment or paclitaxel).
  • Key Aspect: A significant portion of patients in these trials received completely chemo-free treatment.

Survival Outcomes

• Patient Numbers: Survival data was available for 713 patients; 564 received chemo-free or ADC-containing neoadjuvant treatment, and 149 received short 12-week taxane-based chemotherapy.
• Tumor Characteristics: Over 50% of tumors were larger than 2 cm, and one-third were node-positive.
• PCR Rates: Approximately one-third of patients achieved PCR after chemo-free or ADC neoadjuvant treatment, while about two-thirds achieved PCR after chemo-containing neoadjuvant treatment.
• Adjuvant Chemotherapy: 137 PCR patients opted for no adjuvant chemotherapy, with 63 being completely chemo-free (neither neoadjuvant nor adjuvant chemotherapy).
• Overall Survival: After more than five years of follow-up, an excellent overall survival was observed across all groups. There were no significant differences in invasive disease-free survival (IDFS), distant disease-free survival, or overall survival between the chemo-containing and chemo-free/ADC neoadjuvant cohorts. For instance, the five-year overall survival was 98% for the chemo-containing cohort and 97% for the chemo-free or ADC-containing cohort.
• Non-PCR Patients: Patients with non-PCR had a significantly lower IDFS (86% vs. 95% for PCR patients), indicating PCR is prognostic for IDFS. OS showed a numerically lower survival for non-PCR but was not statistically significant.

Factors Associated with IDFS

• Chemo-Containing Cohort: PCR was the only factor significantly associated with IDFS in both univariable and multivariable analysis.
• Chemo-Free/ADC Cohort: In univariable analysis, larger tumor size, positive nodal status, and higher stage were unfavorably associated with IDFS, while PCR was favorably associated. In multivariable analysis, only nodal status and PCR were significant.

Impact of Adjuvant Chemotherapy and Molecular Score

• Adjuvant Chemotherapy in PCR Patients (Chemo-Free/ADC Neoadjuvant): No significant benefit was observed for adding adjuvant chemotherapy in patients who achieved PCR after chemo-free or ADC neoadjuvant treatment. This finding persisted even after propensity scoring analysis.
• Molecular Score for Treatment Guidance: Clinical factors alone are insufficient to predict who benefits from chemotherapy versus chemo-free neoadjuvant therapy. A newly developed and validated molecular score (including baseline gene expression data and clinical markers) can predict PCR in chemo-free/ADC neoadjuvant treatment recipients and may help guide future de-escalation strategies. This score suggests that neoadjuvant chemotherapy might benefit patients in the "low prognostic score" group, but not the "high prognostic score" group.

Conclusion

• De-escalation strategies in this patient group are both feasible and, importantly, safe.
• A 12-week regimen of paclitaxel plus HER2 blockade in the neoadjuvant setting demonstrated excellent five-year survival, highlighting its efficacy.
• For selected Stage I-II HER2-positive early breast cancer patients, neoadjuvant treatment solely with anti-HER2 therapies or Antibody-Drug Conjugates (ADCs) can be considered.
• Patients who achieve a pathological complete response (PCR) after chemo-free or ADC neoadjuvant treatment show no additional benefit from subsequent adjuvant chemotherapy. This suggests that for these responders, further chemotherapy can be safely omitted.
• Clinical factors alone are insufficient to perfectly predict which patients will benefit most from chemo-free approaches. The development of a molecular score, incorporating baseline gene expression data and clinical markers, shows promise in guiding treatment selection and could support future de-escalation strategies by identifying patients who might or might not benefit from chemotherapy.

Let's Talk Toxicity: The Role of Shared Decision-Making in Front-Line Treatment Selection for Patients with Metastatic EGFR + NSCLC

Speaker: Dr. Jessica Bauman

Introduction

The session focused on how shared decision-making (SDM) plays a central role in choosing first-line (1L) therapy for patients with metastatic EGFR-mutant NSCLC. With the growing complexity of treatment options, the aim was to highlight how patient-centered care—including preferences, toxicity tolerance, and goals—should guide therapy selection.

Evolving Treatment Landscape

Treatment for advanced EGFR+ NSCLC has evolved from osimertinib monotherapy (FLAURA) to newer combination regimens:

• Osimertinib + Chemotherapy (FLAURA2)
• Amivantamab + Lazertinib (MARIPOSA)
• These combinations have demonstrated improved progression-free survival (PFS), but with trade-offs in toxicity, cost, and convenience.

Case-Based Discussion

A hypothetical 51/F with metastatic EGFR L858R-mutant NSCLC (plus TP53 co-mutation and asymptomatic brain metastases) was discussed to frame real-world decision dilemmas:

• Should treatment be different for limited disease?
• How do co-mutations and toxicity preferences impact choice?
• What supportive services should be considered?

Comparative Evaluation of 1LOptions

 

 

What Patients Value Most

Insights from qualitative studies and preference-based experiments reveal that:

• Top Priorities: Extending life, maintaining quality of life, functional independence.
• Key Concerns: Side effects (fatigue, nausea, cognitive issues), uncertainty of benefit, and loss of control.
• Patients expressed strong desire to be involved in decision-making; most wanted shared or autonomous choice.

Discrete Choice Experiments

• Patients were willing to accept increased toxicity or inconvenient regimens for even small OS gains (1–6 mo).
• About 50% would decline treatment if it only improved PFS without an OS benefit.
• Cost, administration mode, and adverse events also influenced preferences.

Role of Palliative Care

• Early integration of palliative care was advocated
• Helps with symptom management, coping, and decision support.
• Proven to improve quality of life, prognostic understanding, and caregiver outcomes (e.g., reduced distress).
• Recommended even at diagnosis, especially when complex treatment trade-offs are involved.

Key Takeaways

• Frontline therapy decisions in EGFR+ NSCLC are increasingly complex, and one size does not fit all.
• Incorporating patient goals, values, and toxicity preferences is essential.
• Shared decision-making improves patient satisfaction and outcomes.
• Palliative care should be considered a standard adjunct to enhance holistic care from diagnosis.

Debate: Combination Approaches as Front-Line Therapy for a Patient with Metastatic EGFR Non–Small Cell Lung Cancer

Speaker: Dr. Alessio Cortellini

Introduction

The role of EGFR-targeted combination therapy in the first-line treatment of EGFR-mutated mNSCLC has been debated as emerging clinical trial data have suggested potential benefits over standard osimertinib monotherapy. The possibility of replacing monotherapy with combination regimens has been explored in light of recent advancements in survival outcomes, resistance mechanisms, and treatment tolerability. Perspectives were presented by expert clinicians to evaluate whether front-line standards should be redefined.

Rationale for Combination Approaches in First-Line Therapy

The aggressive nature of lung cancer, particularly in EGFR-positive disease, is highlighted, where patients are frequently lost across treatment lines. Data from clinical trials (MARIPOSA, FLAURA2) demonstrate that 12-54% of patients do not receive second-line therapy, suggesting that upfront combination treatment may prevent missed opportunities for effective therapy.

Should Combination Therapy Be Used for Selected Patients?

Prognostic factors such as TP53 mutations, ctDNA status, CNS, and liver metastases are examined. However, subgroup analyses lack formal interaction tests, making clinical interpretation uncertain. Even in patients without high-risk features, combination therapy shows benefits, implying that restricting combos to high-risk groups may lead to under-treatment. Given the prevalence of these factors (e.g., TP53 co-mutations in 40-70% of patients), most patients may benefit from up-front intensification.

CNS Disease and Long-Term Control

CNS metastases are common in EGFR-mutant lung cancer, and while osimertinib provides strong short-term control, combination therapies may offer delayed intracranial benefits, as seen in progression-free survival trends (though not statistically significant).

Safety and Toxicity Management

Toxicity with combination therapies is front-loaded but decreases over time due to dose adjustments and prophylactic measures (e.g., skin regimens, steroids, anticoagulation). Subcutaneous amivantamab may further improve tolerability and long-term drug delivery.

Re-evaluating Survival Metrics

In trials like MARIPOSA and FLAURA2, delayed survival curve separation suggests non-proportional hazards. Restricted Mean Survival Time (RMST) analysis reveals increasing survival benefits over time, supporting long-term efficacy. Combination therapies also lead to less complex resistance mechanisms, reinforcing their durability.

Conclusion

Combination therapy in first-line EGFR-positive lung cancer is justified to maximize efficacy and prevent patient loss across treatment lines. Prognostic factors should not limit its use, as benefits extend beyond high-risk groups. Toxicity is manageable with adaptive strategies, and long-term survival gains become more apparent over time. Thus, upfront combination treatment represents a long-term investment in patient outcomes.

ASCO 2025, May 30 – June 3, Chicago