Timely update. MRD monitoring post-surgery will likely change this paradigm in the next few years. In the meantime, this is a good summary and in-depth discussion. Follow-up is necessary to understand impact on overall survival.
ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.
In 2017, ASCO with Ontario Health—Cancer Care Ontario published a guideline on adjuvant therapy in resected stage I-III non–small-cell lung cancers (NSCLCs).1 Two randomized control trials (RCTs)2,3 were published in 20202 and 20213 and prompted this amendment to the 2017 guideline.
A targeted electronic literature search to identify RCTs of osimertinib and atezolizumab in this patient population was conducted. No additional randomized trials were uncovered. Members from the original Expert Panel reconvened to assess key evidence from the Wu and Felip trials and to create and approve the revision to the recommendations.
In the Wu et al2 targeted therapy trial, patients with completely resected EGFR (Ex19 del or L858R) mutation–positive stage IB-IIIA (7th edition, AJCC Cancer Staging Manual),4 NSCLC were randomly assigned to receive either osimertinib (80 mg once daily) or placebo for 3 years or until disease recurrence or fulfillment of a criterion for discontinuation. Administration of postoperative chemotherapy before random assignment was allowed but not mandatory (given in 26% and 75% of stage IB and II-IIIA patients, respectively). The benefit of postoperative osimertinib was not affected by the use of postoperative chemotherapy. The primary end point was disease-free survival (DFS) according to investigator assessment among patients with stage II-IIIA disease. A total of 682 patients were randomly assigned; 60% received adjuvant chemotherapy. At 24 months, 90% of stage II-IIIA patients receiving osimertinib (95% CI, 84 to 93) versus 44% receiving placebo (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio [HR] for primary study end point 0.17; 99.06% CI, 0.11 to 0.26; P < .001). In the stage IB-IIIA population, 89% of the patients receiving osimertinib versus 52% receiving placebo were alive and disease-free at 24 months (95% CI, 85 to 92 v 95% CI, 46 to 58; overall HR 0.20; 99.12% CI, 0.14 to 0.30; P < .001). Overall survival data, a secondary end point, are immature, and it is unknown whether there is an overall survival benefit.
In the Felip et al3 immunotherapy trial, patients with completely resected stage IB (≥ 4 cm)-IIIA (7th edition, AJCC Cancer Staging Manual)4 NSCLC were randomly assigned to receive adjuvant atezolizumab (1,200 mg every 21 days for 16 cycles or 1 year) or best supportive care (BSC) after adjuvant cisplatin-based chemotherapy. The primary end point was investigator-assessed DFS in patients with stage II-IIIA NSCLC with at least 1% programmed death-ligand 1 (PD-L1) expression. A total of 1,005 patients were randomly assigned and included in the intent-to-treat population. At 32 months median follow-up, DFS was greater for patients with stage II-IIIA, PD-L1–positive with atezolizumab versus BSC (HR, 0.66; 95% CI, 0.50 to 0.88; P = .0039) and also for all patients with stage II-IIIA with atezolizumab versus BSC (HR, 0.79; 95% CI, 0.64 to 0.96; P = .020).
The quality of the evidence of these studies was assessed using the GRADE tool. Wu et al had a high certainty of evidence, whereas Felip et al had a moderate certainty of evidence.
Stage IB (3 < T ≤ 4 cm, N0M0): Adjuvant osimertinib is recommended for patients with sensitizing EGFR (Ex19del or L858R) mutations (Type: evidence based; Evidence quality: high; Strength of recommendation: strong).
Adjuvant cisplatin-based chemotherapy and/or atezolizumab are not recommended for routine use in this patient group. A postoperative multimodality evaluation, including a consultation with a medical oncologist, is recommended to assess benefits and risks of adjuvant therapies for each patient. Factors to consider other than tumor stage when making a recommendation for adjuvant therapy are outlined after the adjuvant systemic therapy section of the 2017 guideline (Type: evidence based and panel consensus, benefits outweigh harms, especially in patients with larger tumors; Evidence quality: intermediate; Strength of recommendation: moderate).
Stages IIA, IIB, and IIIA: Adjuvant cisplatin-based chemotherapy is recommended for all patients. Adjuvant osimertinib is recommended after chemotherapy for patients with tumors with sensitizing EGFR mutations, regardless of the PD-L1 status. Adjuvant atezolizumab is recommended for all patients with PD-L1 ≥ 1% after cisplatin-based chemotherapy except for patients with sensitizing EGFR mutations (Type: evidence based and panel consensus; Evidence quality: high; Strength of recommendation: strong).
Note: the guideline recommendations are based on the 7th edition staging system used in the studies as opposed to the current 8th edition staging system for lung cancer.5
Another possible option for first line NSCLC EGFR mutated (non-exon 20) is Osimertinib (osi). Osi and chemotherapy had less brain metastases. And with Amivantamab and Lazertinib (EGFR inhibitor), the combination had better PFS and OS (HR0.8). Higher toxicity though with 10% discontinuation vs 3% for Osimertinib. This is interim analysis, toxicity was EGFR related mostly.
Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo in the EGFR mutated patients. Osmiertinib shows efficacy in patients with EGFR mutation who underwent curative surgery or chemoradiotherapy.
Perioperative nivolumab (Nivo) showed a 20% 18-month EFPS improvement. This is another option to consider for your patients with stage IIA-IIIB NSCLC. Of note, the study arm received chemo + Nivo x 4 cycles preoperatively, then 12 months of Nivo therapy, and toxicities were as expected.
FCS medical oncologist and hematologist Ernesto Bustinza-Linares, MD has co-authored an abstract published in the American Society of Clinical Oncology Journal, JCO Precision Oncology, that uncovers a new testing method to determine personalized care options for patients with metastatic non-small cell lung cancer (NSCLC). The abstract’s authors address the limitations of existing guidelines that recommend checkpoint immunotherapy, sometimes in combination with chemotherapy, for treating NSCLC, which often discounts patient variability and immune factors. The findings from the study show that by incorporating additional plasma proteome-based testing, combined with the standard protein inhibitor testing, clear differences in patient outcomes were observed after applying targeted treatments based on the testing results.
This is the same issue as the 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) article, this one was negative though. A question for the previous trial would be: do we need PDL-1 inhibitor, or just VEGF inhibitor, recall the pts with tumors with high PDL-1 expression did better though, so most likely we need both with chemotherapy.
FCS Hematology Oncology Review creates a platform for our physician network to observe the most recent articles and studies available in the oncology and hematology world. By sharing these articles we are building our wealth of knowledge of new observations and treatments as they come available.
