Long-term Care for Patients with Lung Cancer: History and Update

Educational Objectives

The goal of this program is to improve the management of non-small cell lung cancer (NSCLC). After hearing and assimilating this program, the clinician will be better able to

1. Identify appropriate candidates for therapy with epidermal growth factor receptor inhibitors to treat NSCLC.
2. Select appropriate NSCLC patients for targeted immunotherapy.

Summary

Response rates for gefitinib in early trials: gefitinib is an epidermal growth factor receptor (EGFR) inhibitor; Kris et al (2003) demonstrated ≈10% response rate; Fukuoka et al (2003) demonstrated an ≈20% response rate; data reproducible in terms of racial difference; there was a higher response among Japanese people, east Asians, women, never smokers, or in individuals with adenocarcinoma histology

Genetic influence: Harvard research groups determined that the people who had the most significant responses to gefitinib had a somatic mutation in their EGFR, specifically a point mutation in the kinase domain of EGFR; mutations were more common in women, never smokers, people of East Asian origin, and individuals with adenocarcinoma; however, some people without the mutation responded, and some with the mutation did not respond; some of the inconsistency was related to the quality of molecular biology at the time

Bronchus 21 (BR.21) trial: second- or third-line Canadian cooperative group study; patients with non-small cell lung cancer (NSCLC) were randomized to a different EGFR inhibitor, erlotinib, or placebo; the primary endpoint was prolonged overall survival (OS); 29% reduction in the risk of death; median OS improved by ≈2 mo; resulted in erlotinib becoming licensed

Further analysis: identification of specific mutations was hampered by insufficient samples and the state of technology at the time; nonstatistically significant OS advantage in patients with proven EGFR mutations, in patients proven not to have mutations, and in patients with unknown mutation status; retrospective analysis failed to demonstrate that efficacy of EGFR inhibitors was limited to patients with EGFR mutations

Further gefitinib studies: the ISEL study failed to achieve statistical significance; gefitinib lost Food and Drug Administration approval as a result; in the INTEREST study, gefitinib was tested against a toxic second-line chemotherapy drug docetaxel; no difference in OS; erlotinib became the EGFR inhibitor of choice

IRESSA Pan-Asia Study (IPASS) trial: AstraZeneca's solution; the only pathway to first-line was to enrich for those people who were deriving more benefit; the IPASS study was designed around factors associated with benefit; study performed only in Asia in people who had never smoked and had adenocarcinoma; ≈60% of participants were women; patients with untreated advanced NSCLC were randomized to gefitinib or a platinum doublet; results were positive; gefitinib was always superior to chemotherapy for people with an EGFR mutation; despite clinical enrichment, gefitinib was not effective in the EGFR mutation-negative population

Response rate across various trials: in individuals with a proven EGFR mutation, response was 16% in the BR.21 trial; response increased slightly to 27% with a more sensitive assay; in a retrospective analysis of the INTEREST trial, response rate increased to 42%; response in the IPASS trial was 71%; in EGFR-negative individuals, response rates remained ≈7% in most studies but decreased to ≈1% in IPASS; the true positive predictive value of an EGFR mutation-positive test increased while the true negative predictive value of an EGFR mutation wild-type patient decreased; on the basis of the IPASS trial, the European Union approved gefitinib, but only for patients with an EGFR mutation; identification of EGFR mutations was difficult with the available technology and cost of testing at the time; turnaround time was also an issue for gefitinib as a first-line treatment

Targeting other molecular anomalies: the EGFR wild-type population was not homogeneous; while that population had no mutation, there were other molecular anomalies which could be acted on; data on anaplastic lymphoma kinase (ALK) gene rearrangement was presented in 2009; patients with ALK gene rearrangement were given ALK inhibitor therapy; most responded; 7 different molecular subtypes of lung cancer are currently identified

Role of technology: results from positron emission tomography allowed identification of clonal evolution and facilitated use of local ablative therapy for oligoprogressive disease to extend the duration of benefit

Changes in lung cancer biology: there are 2 primary ways in which biology transforms; signaling can be reactivated through the aberrant oncogene pathway, usually through a mutation in the same oncogene, or the pathway remains suppressed with activation of a second driver or some other pathway; this can result in EGFR patients progressing while on EGFR inhibitors; these are on target resistance mechanisms; the T790M mutation is the most common second driver pathway; increased understanding of the mechanisms of acquired resistance led to development of new medications; osimertinib, a third-generation EGFR inhibitor, worked on the original mutation and the T790M-acquired resistance mutation; growth within the body is not the only mechanism of acquired resistance; cancer can sometimes progress in the brain, where the medications would not penetrate; newer drugs are better at entering the brain; development turned toward suppressing resistance before it occurred

ALK inhibitors: crizotinib was the first ALK inhibitor; next-generation drugs include alectinib, ceritinib, and brigatinib; alectinib and brigatinib result in 50% reduction in progression-free survival; hazard ratio (the reduction of risk of progression or death) of lorlatinib is ≈80% compared with crizotinib

Side effects of ALK inhibitors: ≈80% of patients taking lorlatinib require a statin or triglyceride-lowering agent; can cause peripheral neuropathy and weight gain; causes cognitive side effects; alters mood, memory, and speech

Targeted therapy: pembrolizumab is a programmed death ligand 1 (PDL-1) inhibitor given to those with high expression of PDL-1; 70% chance of survival at 12 mo compared with 54% with chemotherapy alone; in individuals without elevated PDL-1 expression or driver oncogenes, immunotherapy added to chemotherapy provides benefit; 12-mo OS rate was 70% for individuals on chemoimmunotherapy compared with ≈50% for those who receive chemotherapy alone; patients with driver oncogenes tend not to benefit from immunotherapy

Readings

Bauer TM, Felip E, Solomon BJ, et al. Clinical management of adverse events associated with lorlatinib. Oncologist. 2019;24(8):1103-1110; Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866-74; Ha SY, Choi SJ, Cho JH, et al. Lung cancer in never-smoker Asian females is driven by oncogenic mutations, most often involving EGFR. Oncotarget. 2015; 6(7):5465-74; Jiang L, Su X, Zhang T, et al. PD-L1 expression and its relationship with oncogenic drivers in non-small cell lung cancer (NSCLC). Oncotarget. 2017; 8(16):26845-26857; Kuan FC, Kuo LT, Chen MC, et al. Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis. Br J Cancer. 2015;113(10):1519-28; Saijo N, Takeuchi M, Kunitoh H. Reasons for response differences seen in the V15-32, INTEREST and IPASS trials. Nat Rev Clin Oncol. 2009; 6(5):287-294; Takada M, Fukuoka M, Kawahara M, et al. (2002). Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002; 20(14):3054-3060.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Camidge is an advisor and Principal Investigator for Abbvie; an advisor for Achilles, Amgen, Anchiarno (SAB), Apollomics (SRC), and Archer; an advisor and Principal Investigator for AstraZeneca; an advisor for BeyondSpring, Bio-Thera (DSMB), and Blueprint; an advisor and Principal Investigator for BMS; an advisor for CBT Pharmaceuticals, Daiichi-Sankyo, Eisai, Elevation Oncology, Eli Lilly, and EMD Serono; an advisor and Principal Investigator for GSK; an advisor for Helssin, Janssen, Onkure, Medtronic, and Mersana; an advisor and Principal Investigator for Pfizer; an advisor for Qilu, and Ribon; an advisor and Principal Investigator for Roche; an advisor for Sanofi; an advisor and Principal Investigator for Seattle Genetics and Takeda; and as a Principal Investigator for Hansoh, Inhibrx, Karyopharm, Lycera, Medimmune, Merck, Phosplatin, Psioxus, and Rain Therapeutics. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Camidge was recorded at Advancing Knowledge in Multidisciplinary Lung Cancer Care, held May 22, 2021, and presented by University of Southern California, Keck School of Medicine, Department of CME. For information on future CME activities from this presenter, please visit: keck.usc.edu/cme/. Audio Digest thanks the speakers and University of Southern California, Keck School of Medicine for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

ON130101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.