Targeting Beyond the Tumor: Radiation's Evolving Role in Oncogene-Driven Lung Cancer

Jonathan Sackett

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Meet the mutations

  Exon 19 deletions, L858R mutations, and T790M  

EGFR Mutations

1st & 2nd Generations of EGFR TKIs

• First-Generation
  • Examples: Erlotinib, Gefitinib
  • Mechanism: Reversible EGFR inhibitors
  • Key Points:
    • Effective for activating mutations (e.g., exon 19, L858R)
    • Limited against T790M mutation
    • Poor CNS penetration
  • Approval: Gefitinib (2003, IPASS), Erlotinib (2004, EURTAC)
• Second-Generation
  • Examples: Afatinib, Dacomitinib
  • Mechanism: Irreversible EGFR/HER inhibitors
  • Key Points:
    • Broader activity (e.g., G719X, S768I)
    • Limited T790M activity
    • Moderate CNS penetration
  • Approval: Afatinib (2013, LUX-Lung 3/6), Dacomitinib (2018, ARCHER 1050)

EURTAC

Erlotinib

median PFS 9.7 mos vs 5.2 months

• Erlotinib: Continuous daily dosing (150 mg/day) until disease progression or intolerable toxicity.
• Chemotherapy: Four cycles of platinum-based chemotherapy unless progression or toxicity occurred earlier.

3rd Generations of EGFR TKIs

• Third-Generation
  • Examples: Osimertinib
  • Mechanism: Irreversible, T790M-specific
  • Key Points:
    • Effective for T790M and CNS metastases
    • First-line for EGFR-mutated NSCLC
  • Approval: Osimertinib (2017, FLAURA/AURA3)
• Fourth-Generation
  • Examples: BLU-945, Lazertinib

FLAURA trial   

Osimertinib

First-Generation ALK Inhibitors

• Example: Crizotinib
• Mechanism: Inhibits ALK, ROS1, and MET.
• Key Points:
  • Effective against ALK rearrangements (e.g., EML4-ALK).
  • CNS Penetration: Limited, leading to high rates of CNS progression (PROFILE 1014 trial).
  • Radiation Sensitivity: Enhances radiosensitivity by suppressing DNA damage repair mechanisms.
  • Resistance: Mutations like L1196M limit long-term efficacy.
• Approval: 2011 (PROFILE trials).

Second-Generation ALK Inhibitors

• Examples: Ceritinib, Alectinib, Brigatinib
• Mechanism: Overcomes crizotinib resistance and achieves superior CNS penetration.
• Key Points:
  • Effective against ALK resistance mutations (e.g., L1196M, G1269A).
  • CNS Penetration: Significant improvements over crizotinib. Alectinib and Brigatinib achieve prolonged CNS control (ALEX and ALTA trials).
• Approval:
  • Ceritinib: 2014 (ASCEND trials).
  • Alectinib: 2015 (ALEX trial).
  • Brigatinib: 2017 (ALTA trial).

Third-Generation ALK Inhibitors

• Example: Lorlatinib
• Mechanism: Targets ALK resistance mutations (e.g., G1202R) and CNS metastases.
• Key Points:
  • CNS Penetration: High blood-brain barrier permeability; intracranial response rate of ~82% (CROWN trial).
  • Radiation Considerations:
    • Often delays need for SRS or WBRT.
  • Recommended after failure of second-generation inhibitors.
• Approval: 2018 (CROWN trial).

Drugs Targeting ROS1

• Examples: Crizotinib, Entrectinib, Lorlatinib, Repotrectinib.
• Mechanism: Inhibit ROS1 fusion-driven signaling to block tumor growth and progression.
• Key Points:
  • Crizotinib: First ROS1 inhibitor approved; limited CNS activity.
  • Entrectinib: Significant CNS penetration, durable intracranial responses (STARTRK trials).
  • Lorlatinib: Effective against crizotinib-resistant ROS1 mutations.
  • Repotrectinib: Promising in both ROS1 TKI-naïve and pretreated patients (TRIDENT-1 trial).
• Approval:
  • Crizotinib: 2016 (PROFILE trials).
  • Entrectinib: 2019 (STARTRK trials).

Drugs Targeting NTRK

• Examples: Larotrectinib, Entrectinib.
• Mechanism: Inhibit TRK fusions (NTRK1/2/3) to block tumor growth.
• Key Points:
  • Larotrectinib: High ORR (~75%) across multiple tumor types (NAVIGATE trial).
  • Entrectinib: Durable responses in CNS-positive disease (STARTRK trials).
  • Resistance: Secondary mutations (e.g., solvent front mutations) drive resistance to first-line TRK inhibitors.
• Approval:
  • Larotrectinib: 2018 (NAVIGATE, SCOUT trials).
  • Entrectinib: 2019 (STARTRK trials).

STARTRK Trials: Design and Patient Population

Study Overview:

• Combined analysis of three trials:
  • STARTRK-1 and ALKA-372-001: Phase I trials.
  • STARTRK-2: Phase II global basket trial.
• Target Population: Adults with ROS1 fusion-positive, locally advanced or metastatic NSCLC.

Inclusion Criteria:

• ROS1 fusion–positive NSCLC (confirmed by NGS or local testing).
• Measurable disease (RECIST v1.1).
• ECOG performance status 0–2.
• Asymptomatic or pretreated CNS metastases allowed.

Exclusion Criteria:

• Extracranial progression after prior ROS1 TKI (except CNS-only progression).
• Significant comorbidities or unresolved toxicities.

STARTRK Trials: Methods

• Intervention: Oral entrectinib 600 mg/day until progression, unacceptable toxicity, or withdrawal.
• Endpoints:
  • Primary: Objective response rate (ORR) and duration of response (DoR) (assessed by blinded independent central review [BICR]).
  • Secondary: Progression-free survival (PFS), overall survival (OS), and intracranial efficacy.
• Assessments: Imaging every 8 weeks and CNS-specific scans for patients with baseline CNS metastases.
• Safety Monitoring: Adverse events assessed per CTCAE v4.03.

STARTRK Trials: Key Results

• Overall Population (ROS1 TKI–Naïve):
  • ORR: 68% (95% CI: 60.2–74.8).
  • Median DoR: 20.5 months.
  • Median PFS: 15.7 months; median OS: 47.8 months.
• Patients with Baseline CNS Metastases:
  • Intracranial ORR: 80% (95% CI: 59.3–93.2).
  • Median intracranial DoR: 12.9 months.
  • Median intracranial PFS: 8.8 months.
• Post-Crizotinib Cohort:
  • ORR: 11%; Median PFS: 4.7 months.

Drugs Targeting RET Fusions

• Examples: Selpercatinib, Pralsetinib.
• Mechanism: Inhibit RET fusion-driven signaling to block tumor growth and progression.
• Key Points:
  • Selpercatinib: High ORR (~85%) with durable responses (LIBRETTO trials).
  • Pralsetinib: Efficacious in both RET fusion-positive NSCLC and thyroid cancers (ARROW trial).
  • Well-tolerated with manageable toxicities (e.g., hypertension).
• Approval:
  • Selpercatinib: 2020 (LIBRETTO trials).
  • Pralsetinib: 2020 (ARROW trial).

LIBRETTO trials

Selpercatinib

Drugs Targeting KRAS Mutations

• Examples: Sotorasib, Adagrasib.
• Mechanism: Inhibit KRAS G12C mutant protein, blocking downstream MAPK signaling.
• Key Points:
  • Sotorasib: First FDA-approved KRAS G12C inhibitor (CodeBreaK trials).
  • Adagrasib: High CNS activity; promising in pretreated patients (KRYSTAL-1 trial).
• Approval:
  • Sotorasib: 2021 (CodeBreaK trials).
  • Adagrasib: 2022 (KRYSTAL-1 trial).

Drugs Targeting MET Exon 14 Skipping

• Examples: Capmatinib, Tepotinib.
• Mechanism: Inhibit MET signaling to block tumor growth in MET exon 14 skipping mutations.
• Key Points:
  • Capmatinib: ORR ~40%, durable intracranial responses (GEOMETRY mono-1 trial).
  • Tepotinib: High CNS activity and sustained efficacy (VISION trial).
• Approval:
  • Capmatinib: 2020 (GEOMETRY mono-1 trial).
  • Tepotinib: 2021 (VISION trial).

ADAURA Trial:

Inclusion Criteria:

• Stage IB-IIIA NSCLC with EGFR mutations (Exon 19 deletions or Exon 21 L858R).
• Complete tumor resection with or without adjuvant chemotherapy.
• Age ≥18 years with ECOG performance status ≤1.

Exclusion Criteria:

• Presence of unresectable or metastatic disease.
• Patients with prior EGFR TKI therapy or incomplete recovery post-surgery.
• Active, uncontrolled systemic illnesses.

ADAURA Trial: Methods and Patient Flow

Methods:

• Study Design: Randomized, double-blind, placebo-controlled, phase III trial.
• Population: Stage IB-IIIA EGFR-mutated NSCLC (Exon 19 deletions or L858R mutations).
• Local Therapy Requirements:
  • Patients underwent **complete surgical resection** of their primary tumor prior to enrollment.
  • Adjuvant chemotherapy was allowed but not required, with regimens guided by institutional standards.
  • Radiation therapy was not mandated but could be utilized as part of the institutional post-surgical care plan before trial enrollment.
• Intervention: Adjuvant osimertinib (80 mg daily) vs. placebo for up to 3 years
• Monitoring: Imaging every 12 weeks for 2 years, then every 24 weeks thereafter.

Neoadjuvant TKIs: Reducing Tumor Burden

• Trial Design: Phase II trial evaluated neoadjuvant osimertinib in Stage II-IIIA EGFR-mutated NSCLC.

Inclusion Criteria:

• Stage IB-IIIA EGFR-mutated NSCLC.
• No prior systemic therapy or TKI use.
• Age ≥18 years with ECOG performance status ≤1.

Exclusion Criteria:

• Presence of unresectable or metastatic disease.
• Inability to tolerate TKIs or planned surgery.
• Active, uncontrolled systemic illnesses.

Blakely Trial: Methods and Patient Flow

Methods:

• Study Design: Phase II, single-arm trial evaluating neoadjuvant osimertinib for resectable EGFR-mutated NSCLC.
• Population: Stage II-IIIA EGFR-mutated NSCLC (Exon 19 deletions or L858R mutations).
• Local Therapy Requirements:
  • Patients must have resectable disease.
  • Definitive surgical resection planned following neoadjuvant therapy.
  • Adjuvant therapy was determined based on post-surgical outcomes.
• Intervention: Neoadjuvant osimertinib (80 mg daily) for 6-12 weeks prior to surgery.
• Endpoints:
  • Primary: Pathologic response rate, including complete and partial pathologic responses.
  • Secondary: Radiographic response, disease-free survival (DFS), and overall survival (OS).
• Monitoring: Imaging at baseline, during treatment, and before surgery. Pathologic assessment post-resection.

Peled Trial: Design and Patient Flow

Inclusion Criteria:

• Stage III EGFR-mutant NSCLC (Exon 19 deletion or L858R mutation).
• Performance status 0–1.
• Amenable to definitive chemoradiation or surgery.

Exclusion Criteria:

• EGFR TKI-resistant mutations (e.g., exon 20 insertion).
• Significant comorbidities (e.g., interstitial lung disease).
• Major surgery within 4 weeks before enrollment.

Timing of Radiation Therapy:

• Radiation therapy initiated after 12 weeks of neoadjuvant osimertinib for responders or stable disease.
• RT planning adapted to changes in tumor and nodal volume (based on GTV and PTV reduction).
• Patients with limited response received chemoradiation instead.

Peled Trial: Methods and Protocols

• Intervention: Osimertinib 80 mg daily for 12 weeks.
• Endpoints Primary: Objective response rate (ORR) via RECIST v1.1.
• Secondary: Gross tumor volume (GTV) reduction, circulating tumor DNA (ctDNA) dynamics, and safety.
• Definitive Therapy:
  • RT and/or surgery based on post-osimertinib response. (60Gy/30fx or 45Gy/15fx)
  • Patients with limited response received chemoradiation.
• Monitoring: PET-CT scans and ctDNA at baseline, 6 weeks, and 12 weeks.

Peled Trial: Key Results

• ORR: 95.2% (17 partial responses, 2 complete responses).
• Tumor Volume Reduction:
  • Median GTV reduction: 48% (P = 0.02).
  • Median PTV reduction: 31% (P = 0.01).
• Surgical Outcomes:
  • 3 patients underwent surgery; 1 achieved pathologic complete response.
• ctDNA:
  • Detected in 5 patients; 4 became negative during osimertinib therapy.

Critiques of the Peled Trial

• Strengths:
  • High ORR (95.2%) demonstrates osimertinib's efficacy as neoadjuvant therapy.
  • Significant reduction in tumor volumes improved RT planning.
• Limitations:
  • Small sample size (N=24).
  • No control arm to compare against standard chemoradiation or surgery outcomes.
• Unanswered Questions:
  • Long-term survival data are still limited.
  • How to integrate osimertinib with existing treatments (e.g., durvalumab).

LAURA Trial: Design and Enrollment

Inclusion Criteria:

• Unresectable stage III NSCLC with EGFR exon 19 deletions or exon 21 L858R mutation.
• Completed platinum-based chemoradiotherapy (concurrent or sequential).
• No progression during or after definitive chemoradiotherapy.
• WHO performance status 0-1.

Exclusion Criteria:

• History of interstitial lung disease or unresolved grade ≥2 adverse effects post-chemoradiotherapy.
• Symptomatic pneumonitis after chemoradiotherapy.
• Patients with mutations other than EGFR exon 19 or exon 21.

Patient Characteristics:

• Total patients: 216 randomized (143 osimertinib, 73 placebo).
• Most received **concurrent chemoradiotherapy**: 92% (osimertinib), 85% (placebo).
• Majority were Asian (81% osimertinib, 85% placebo).
• Performance status of 0: 56% (osimertinib) vs. 42% (placebo).

LAURA Trial: Design and Patient Flow

Timing of TKI Initiation in LAURA Trial

• Timing: TKI started within 6 weeks of completing chemoradiotherapy.
• Concurrent Chemoradiotherapy: 92% of osimertinib and 85% of placebo patients received concurrent therapy.
• Sequential Chemoradiotherapy: Smaller proportion: 8% (osimertinib) vs. 15% (placebo).
• Post-Treatment Monitoring: Regular imaging every 8 weeks (up to 48 weeks) and every 12 weeks thereafter.

Impact of Timing:

• Patients initiating osimertinib immediately after chemoradiotherapy achieved significant CNS progression-free survival benefits.
• No subgroup differences identified between concurrent and sequential chemoradiotherapy timing.

LAURA Trial: Key Results

• PFS: Median 39.1 months (osimertinib) vs. 5.6 months (placebo); HR 0.16 (P<0.001).
• CNS Progression: New brain metastases: 8% (osimertinib) vs. 29% (placebo).
• Safety: Grade ≥3 adverse events: 35% (osimertinib) vs. 12% (placebo).
• OS (Interim): 84% (osimertinib) vs. 74% (placebo) at 36 months (HR 0.81, P=0.53).

LAURA Trial: Key Results

• PFS: Median 39.1 months (osimertinib) vs. 5.6 months (placebo); HR 0.16 (P<0.001).
• CNS Progression: New brain metastases: 8% (osimertinib) vs. 29% (placebo).
• Safety: Grade ≥3 adverse events: 35% (osimertinib) vs. 12% (placebo).
• OS (Interim): 84% (osimertinib) vs. 74% (placebo) at 36 months (HR 0.81, P=0.53).

LAURA Trial: Key Results

• PFS: Median 39.1 months (osimertinib) vs. 5.6 months (placebo); HR 0.16 (P<0.001).
• CNS Progression: New brain metastases: 8% (osimertinib) vs. 29% (placebo).
• Safety: Grade ≥3 adverse events: 35% (osimertinib) vs. 12% (placebo).
• OS (Interim): 84% (osimertinib) vs. 74% (placebo) at 36 months (HR 0.81, P=0.53).

LAURA Trial: Toxicities

Radiation Pneumonitis

• Incidence:
  • Osimertinib: 48%
  • Placebo: 38%
• Severity:
  • Most cases were Grade 1–2.
  • Grade 3: 2% (osimertinib) vs. 0% (placebo).
  • No Grade 4 or 5 events were reported.
• Statistical Significance: Difference in incidence was not statistically significant.

Interstitial Lung Disease (ILD)

• Incidence:
  • Osimertinib: 8%
  • Placebo: 1%
• Severity:
  • Most cases were Grade 1–2.
  • Attributed primarily to pneumonitis.
• Statistical Significance: Not specified, but clinically relevant difference noted.

Management:

• Most radiation pneumonitis and ILD cases resolved with supportive care.
• Guidelines allowed continuation of osimertinib for mild to moderate symptoms.

Critiques of the LAURA Trial

• Unanswered Questions:
  • Is osimertinib superior to durvalumab for this population?
  • What is the optimal duration of osimertinib therapy?
• Applicability Concerns:
  • Heavy Asian patient representation; results may not generalize globally.
  • Exclusion of patients with unresolved post-chemoradiotherapy toxicities.
• Strengths:
  • Robust CNS control and extended PFS benefit.
  • Well-designed phase III trial with placebo control.

SINDAS Trial: Study Design and Patient Flow

Inclusion Criteria:

• EGFR-mutated NSCLC (Exon 19 deletions or L858R mutations).
• 1-5 synchronous oligometastases (confirmed by imaging).
• No prior therapy for metastatic disease.
• ECOG performance status ≤1.

Exclusion Criteria:

• Brain metastases.
• Concurrent severe illnesses or contraindications to radiotherapy.

Enrolled Population:

• 73% of metastases were bone lesions.
• Median age: 60 years; more patients in the RT+TKI arm had >2 metastases.

Timing of Radiation Therapy:

• Radiotherapy delivered upfront to primary tumor, involved nodes, and oligometastases (25-40 Gy in 1-5 fractions).
• Radiotherapy occurred **prior to TKI initiation** in patients with synchronous metastases.
• No radiotherapy was allowed in the TKI-alone arm until disease progression.

SINDAS Trial: Trial Design and Patient Flow

Methods:

• Radiotherapy: Delivered to all sites, including:
  • Primary tumor and involved mediastinal lymph nodes.
  • All oligometastatic sites (up to 5).
• Uniform Fractionation: 25-40 Gy in 5 fractions, including mediastinal nodes (unconventional for central structures).
• Techniques: SBRT, VMAT, or IMRT with constraints for adjacent organs (e.g., mean dose <16.5 Gy for trachea/bronchus).

SINDAS Trial: 5 Fx Dose Constraints

SINDAS Trial: Results

Key Results:

• TKIs Used: Gefitinib, Erlotinib, or Icotinib (Osimertinib not available).
• Median OS: 25.5 vs. 17.4 months (p < 0.001).
• Median PFS: 20.2 vs. 12.5 months (p < 0.001).
• Local Control (LC): 91% (RT+TKI) vs. 55% (TKI only).
• Toxicity: Grade 3-4 pneumonitis: 6% (RT+TKI), no grade 5 toxicity.

SINDAS Trial: Toxicities

Radiation Pneumonitis

• Incidence:
  • RT+TKI Group: 6% (Grade 3–4).
  • TKI-Only Group: 0% (Grade 3–4).
• Severity:
  • Most cases were mild (Grade 1–2).
  • No Grade 5 events were reported.
• Management:
  • Resolved with corticosteroids and supportive care.

Other Toxicities

• Fatigue:
  • Reported in both arms, with higher rates in RT+TKI group.
• Dermatologic and GI Toxicities:
  • Consistent with known profiles of first-generation TKIs (e.g., gefitinib, erlotinib).
  • Rash and diarrhea were the most common.
• Overall Safety:
  • No significant increase in Grade ≥3 toxicities between arms.
  • No treatment-related deaths reported.

Overall Toxicity Profile:

• Radiotherapy in combination with TKIs was generally well-tolerated.
• Low rates of severe toxicities suggest safety of this approach with appropriate management.

Critiques of the SINDAS Trial

• Outdated Systemic Therapy: Used first-generation TKIs (gefitinib, erlotinib, icotinib) instead of third-generation osimertinib, now the standard for EGFR-mutated NSCLC.
• Early Trial Closure: Lacked prespecified stopping criteria, raising concerns about long-term data robustness.
• Unconventional RT Protocol: Uniformly used 5-fraction RT for all sites, including mediastinal lymph nodes and primary tumor, which is not standard practice.
• Exclusion of Brain Metastases: Limited applicability in an era where CNS-penetrant TKIs (e.g., osimertinib) are standard.
• Inadequate Staging: PET imaging not uniformly used, potentially missing occult metastases.
• Timing of Radiotherapy: Optimal timing of RT (upfront vs. delayed) remains unanswered.

NORTHSTAR trial

NORTHSTAR Trial: Study Design and Patient Flow

Inclusion Criteria:

• Stage IIIB-IV EGFR-mutated NSCLC (Exon 19, L858R, or T790M mutations).
• Up to 3 metastases or TKI-naive/first-line osimertinib users.
• No progression after 6-12 weeks of induction osimertinib.
• ECOG performance status ≤1.

Exclusion Criteria:

• Prior osimertinib or third-generation EGFR TKIs.
• Symptomatic CNS metastases.
• Significant comorbidities (e.g., uncontrolled hypertension).

Enrolled Population:

• Induction osimertinib given to all patients for 6-12 weeks.
• Patients randomized to continue osimertinib alone or add consolidative RT (± surgery).

Timing of Radiation Therapy:

• RT delivered **after induction osimertinib** to target residual disease or consolidate response.
• Radiotherapy timing evaluated for toxicity and synergistic effects when combined with osimertinib.
• Designed for consolidative RT, not upfront therapy like in SINDAS.

Critiques of the NORTHSTAR Trial Design

Key Questions the Design Fails to Answer:

• Timing of Radiotherapy:
  • Does the benefit of consolidative RT differ from upfront RT as in the SINDAS trial?
  • Should RT be delivered only after achieving systemic control with osimertinib?
• Selection of Patients for RT:
  • How should patients with oligoprogressive disease be stratified?
  • Do patients with larger metastatic burdens benefit equally from consolidative RT?

Strengths and What It Solves:

• Inclusion of CNS Disease: The trial includes patients with limited brain metastases, addressing a key gap in prior studies like SINDAS.
• Modern Systemic Therapy: Incorporates osimertinib, a third-generation EGFR TKI with superior systemic and CNS efficacy.
• Focus on Consolidative RT: Evaluates RT in a setting that mirrors real-world practice, where systemic control is often achieved before considering RT.
• Improved RT Protocols: Standardizes RT techniques and fractionation schedules, improving reproducibility.

Best Practices for Oncogene-Driven NSCLC

• Comprehensive Molecular Testing:
  • Test for EGFR, ALK, ROS1, RET, MET, NTRK, KRAS mutations.
  • Incorporate liquid biopsies and ctDNA for real-time monitoring.
• Integrating Radiation and Systemic Therapy:
  • For oligometastatic disease, consider RT + TKIs (e.g., SINDAS trial).
  • In locally advanced settings, can use concurrent RT (e.g., LAURA trial).
• CNS Management:
  • Use CNS-penetrant therapies (e.g., osimertinib, lorlatinib).
  • Consider SRS over WBRT where appropriate.
• Toxicity Management:
  • Monitor and manage pneumonitis and ILD proactively.
  • Adapt treatment plans to minimize adverse events.

• Oligometastatic Disease:
  • Continued role for SBRT to enhance local control in patients responding to TKIs.
  • Potential synergy between RT and systemic therapies in CNS metastases management.
• Locally Advanced Disease:
  • Consolidative RT remains critical in patients with partial responses to systemic therapies.
  • Exploration of concurrent TKI and RT to minimize disease recurrence.
• Future Research Directions:
  • Defining the optimal timing and sequencing of local and systemic therapies.
  • Randomized trials to assess long-term survival benefits of RT in patients on modern TKIs.