Late-Stage Therapeutic Options in Lung Cancer
During a live virtual event, Benjamin P. Levy, MD, discussed the case of a patient with non–small cell lung cancer and an EGFR exon 19 deletion. This is the second of two articles based on this event.
Targeted OncologyTM: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for molecular testing of a patient with nonsquamous non–small cell lung cancer (NSCLC)?
BENJAMIN P. LEVY, MD: [According to] NCCN recommendations, molecular testing should include [EGFR, ALK, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping, RET, KRAS], and PD-L1 testing should be done, too.1 We should be doing broad molecular testing. Broad panels and NGS [next-generation sequencing] panels are nice because they minimize tissue use. You can identify some rare drivers, and you have about a 50% to 60% chance of identifying a driver mutation. Caris Life Sciences’s [molecular profiling] is nice because it does both DNA and RNA. RNA is the best way to detect ALK, ROS, RET, and NTRK. Fusions are best identified by RNA-based panels.
At Johns Hopkins Medicine, we didn’t have an RNA-based panel, and as of a year ago, we were about to send everything to Caris, but we now have a DNA- and RNA-based panel. I think where you send the test to is very important.
What does the NCCN recommend concerning frontline testing and decision-making?
Clinicians should obtain molecular testing for actionable biomarkers before administering immunotherapy, if possible. PD-L1 expression can be elevated in patients with oncogenic drivers. But, despite that, targeted therapy is what is best, and should take precedence over treatment with immune checkpoint inhibitors. In a very famous phase 2 study, roughly 20 patients with EGFR-mutant lung cancer and high PD-L1 received pembrolizumab [Keytruda] instead of osimertinib [Tagrisso] because they had a high PD-L1, and no one responded to pembrolizumab, even though they had a high PD-L1.2 So, that will tell you the chance of responding to immunotherapy—at least single-agent immunotherapy as a first-line agent, if the patient is EGFR-mutated—is 0. That’s why we try to get the molecular profile beforehand.
What are the recommended therapies for a patient with confirmed EGFR exon 19 deletion or L858R mutations?
In the NCCN guidelines, osimertinib is a category 1 recommendation [and is the preferred regimen].1 Interestingly, erlotinib [Tarceva] is still a category 1, as is gefitinib [Iressa]. Osimertinib is the preferred based on an overall survival advantage from FLAURA [NCT02296125].3 It’s very rare that we don’t use osimertinib.
I think there has been a lot of confusion about this, but there are contraindications to patients treated with a PD-1 drug in the presence of an oncogene. There has been a lack of data of efficacy….One of the challenges is that the data would suggest, at least for first-line therapy, that single-agent immunotherapy doesn’t have a lot of [efficacy] in EGFR-mutant lung cancer or other drivers. So, I think that’s important to note.
There are data in the second line that monotherapy is less effective in patients with EGFR exon 19 deletions, L858R mutations, and ALK mutations.1 And then, the data from the small study showed that single-agent pembrolizumab was not effective.2 It had no response rate in patients who are EGFR positive, even when their PD-L1 was high. So, don’t be fooled by the PD-L1.
If you start with immunotherapy, then you find out they have an [EGFR driver mutation], and [consider] giving them osimertinib, there may be toxicity with sequencing immunotherapy followed by targeted therapy. So, if you start with immunotherapy, and then you have to give targeted therapy, there can be an overlapping in toxicity, and this can lead to problems with pneumonitis and other toxicities. So, you have to be careful.
The reverse is not true. If you start with targeted therapy, you can sequence to immunotherapy. But when you start with immunotherapy, you need to wait probably 8 to 12 weeks before starting targeted therapy. That is very important as we look at sequencing strategies.
What are the Society for Immunotherapy of Cancer recommendations?
Essentially, patients with nonsquamous advanced NSCLC and an actionable mutation should be started with targeted therapy first, probably get chemotherapy, and then probably get a checkpoint inhibitor after that.4
There is a study that everyone should be mindful of: it’s KEYNOTE-789 [NCT03515837]. This is a study of patients with EGFR-mutated lung cancer who’ve received a TKI [tyrosine kinase inhibitor], most receiving osimertinib, who were then randomly assigned upon progression to either chemotherapy or chemotherapy plus immunotherapy. This study was asking the question, “Does adding immunotherapy to chemotherapy at the time of progression on osimertinib do anything versus chemotherapy alone?” That will answer a lot of questions. Is there a role to adding immunotherapy to chemotherapy post-osimertinib when patients have progressed? Keep your eyes out for it because it will come out soon.
What evidence is there for immune-related AEs occurring when immunotherapy is followed by a TKI?
This is [supported by] Adam J. Schoenfeld, MD’s study looking at PD-L1 blockade followed by osimertinib, and the development of severe immune-related adverse events [AEs]. Six out of 41 patients had severe immune-related AEs, 15% of patients.5 You must be careful if you are going to start immunotherapy, and then sequence to targeted therapy like osimertinib, as you may cause real harm.
This study [provided data concerning]severe immune-related AEs. If you have a patient who has a high PD-L1 expression and put them on immunotherapy…then you find out they have an EGFR mutation, and then you give them targeted therapy like osimertinib, there is a real problem with toxicity there. That overlapping toxicity can be a problem for patients; it can [lead to] grade 3 and 4 AEs. [Five out of those 6] patients had to be hospitalized because of the toxicity.5
There was a meta-analysis showing that checkpoint inhibitors are no better than docetaxel in the second line for patients who have EGFR-positive disease.6 The meta-analysis showed all of the phase 3 studies comparing immunotherapy with docetaxel, back when docetaxel was the standard; if you looked at the subset of patients who were EGFR-mutated, patients did not do better with immunotherapy than with docetaxel.
The bottom line is that immunotherapy doesn’t work [in this population]. The meta-analysis specifically for EGFR-mutated patients favors docetaxel. I know there are one-offs…but most of the time, patients who are EGFR-positive don’t do well with at least single-agent immunotherapy. KEYNOTE-789 will answer the question about adding immunotherapy to chemotherapy versus chemotherapy alone post-osimertinib.
1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 3.2022. Accessed September 6, 2022. https://bit.ly/3OIkqtA
2. Lisberg A, Cummings A, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J Thorac Oncol. 2018;13(8):1138-1145. doi:10.1016/j.jtho.2018.03.035
3. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
4. Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6(1):75. Published 2018 Jul 17. doi:10.1186/s40425-018-0382-2
5. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30(5):839-844. doi:10.1093/annonc/mdz077
6. Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):210-216. doi:10.1001/jamaoncol.2017.4427