During a Targeted Oncology case-based roundtable event, Roy S. Herbst, MD, PhD, and Joshua K. Sabari, MD, discussed molecular testing and the use of immune checkpoint inhibitors with participants.
STRAUSS: I’d probably check next-generation sequencing [NGS] on tumor tissue, and then I might do it on blood as well. I’ve been doing blood and tumor tissue together.
GILLANI: We do the same thing now, and we have moved away from à la carte testing and try to do up-front tissue-based NGS as well as liquid DNA-based [testing].
NEWSOME: I would generally start with tissue testing first; if that gave me the information I needed, I wouldn’t necessarily do a liquid biopsy up front. If [the tissue testing] didn’t give me the information I needed or if there were not enough tissue, then I would typically use a liquid biopsy.
VIVEKANANDARAJAH: I typically do NGS on the tissue, and I send for the liquid biopsy at the same time.
SABARI: In all patients, even patients with squamous cell carcinoma, I obtain tissue-based NGS up front. We do have an RNA-based assay, as well as a DNA-based assay.
I know that’s something that most folks are moving to now. And I do send [for] liquid biopsy up front at the same time. I think they’re complementary of each other.
HERBST: I would do an NGS profile [as well]. There are 7 or 8 different actionable mutations that you wouldn’t want to miss here, and [to] give them the best care, you would want to get them all. Liquid biopsy can also help, if you can add that, but [whether you do] it up front or not it depends [on if] it’s paid for or not. If you can get it paid for, it doesn’t hurt. But you can also wait.
For nonsquamous non–small cell lung cancer [NSCLC], the National Comprehensive Care Network [NCCN] recommends frontline molecular testing for MET exon 14 skipping and for mutations in EGFR, ALK, ROS1, BRAF, NTRK1/2/3, RET, and now KRAS.1 This is hot off the NCCN press because of the new Amgen drug, sotorasib [Lumakras].2
This testing should be conducted as part of a broader molecular testing regimen and [should include] PD-L1 testing, of course. A broad molecular panel–based NGS approach is recommended because it minimizes tissue use and potential wastage, identifies rare driver mutations, and it’s the way to improve patient care.
If there is insufficient tissue to allow for all this testing, [such as with a] repeat biopsy, plasma testing, or both should be done. Although PD-L1 expression can be elevated in patients with an oncogenic driver, the targeted therapy for the oncogenic driver should take precedence over treatment with an immune checkpoint inhibitor [ICI], [according to these NCCN guidelines].1
What that’s saying is that if PD-L1 expression is high and there is an EGFR, ALK, or ROS1 [mutation in the tumor], it’s probably the mutational status that’s driving PD-L1 expression. The recommendation, and I would agree, would be to use the targeted therapy first.
SABARI: Back in 2016 and 2017 when we were really excited about immunotherapy, we used to try to use it in the frontline setting. However, I think the rate of immune-related adverse events is quite high in patients who receive up-front PD-L1 inhibitors followed by tyrosine kinase inhibitors.
We know from retrospective studies,3 as well as some prospective studies,4 that the response rates and the durability of response [are] low. So I would really avoid using a PD-1 or PD-L1 inhibitor in the driver-mutant population.
GILLANI: Is this [testing] stage dependent, or does it happen automatically? [That is], do you have to tell your pathologist that [a given patient] is stage IV or has unresectable stage III disease? Or are you doing it in all patients, including earlier-stage patients?
NEWSOME: [Given] the data on adjuvant EGFR inhibitors,5 I’m generally doing it up front, no matter what stage the [patient is], as opposed to waiting until [the patient] develops metastatic disease. We usually have to tell our pathologists what we want, and that’s how we’re doing it.
VIVEKANANDARAJAH: I agree, especially in patients who are nonsmokers, I’m doing the EGFR testing up front but just in the adjuvant setting.
SABARI: I’m in the minority here. Given the PD-L1 expression of 95%, I would spare this gentleman chemotherapy in the front line. I would give a single-agent PD-1 inhibitor, and this is based on the KEYNOTE-024 data [NCT02142738] from 2016.6 I’m curious [about] why others would do platinum-doublet chemotherapy plus therapy that targets [either PD-1 or PD-L1]. Is it the bulk of disease? The symptoms?
VIVEKANANDARAJAH: I [would use] the platinum doublet with anti–PD-L1 therapy because of the bulky disease. Also, I am not sure about the patient’s age, but I thought it was relatively young, and with the amount of disease burden that was there, I thought it [would be] better to use the chemotherapy option with the anti–PD-L1 therapy.
ASIK: I [would use] single-agent PD-L1 therapy (pembrolizumab [Keytruda]), based on the 95% PD-L1 [expression].
HUANG: I also [would use] single-agent pembrolizumab.
NEWSOME: I have to say that I [am] torn between using a single-agent PD-1– or PD-L1–targeted therapy versus combining that with platinum-doublet chemotherapy. This is a situation where you need to see the patient. You have to have a conversation with the patient. These decisions are not always made in isolation. I think [for this patient] I [would use] chemotherapy with PD-L1–targeted therapy because he did have a fair bulk of disease, he was relatively young, and there was a 2-cm brain metastasis.
I guess the question is, what do we do with the brain metastasis? I know that immunotherapy does achieve central nervous system penetration, but pemetrexed [Alimta], which presumably is what people would use [in the chemotherapy option], gets decent penetration as well.
That is what pushed me [toward adding] the chemotherapy doublet. But again, I was torn between the single-agent [immunotherapy] and the chemoimmunotherapy.
HERBST: A 2-cm metastasis is a little bit bigger than I’d be comfortable with just watching. I probably would have used a gamma knife or something, but [you make a] good point there.
The NCCN guidelines offer several first-line therapy choices for patients with adenocarcinoma and PD-L1 expression of at least 50%. There’s pembrolizumab, pembrolizumab plus chemotherapy; atezolizumab [Tecentriq], now licensed in this setting based on [data from the] IMpower110 trial [NCT02409342]7; and cemiplimab-rwlc [Libtayo], [a new drug8 supported by category 1 data9].1
We also have the quadruplet regimen that consists of carboplatin, paclitaxel, bevacizumab [Avastin], and atezolizumab; the combination of carboplatin, albumin-bound paclitaxel [Abraxane], and atezolizumab; and the combination of ipilimumab [Yervoy], nivolumab [Opdivo], pemetrexed, [and either carboplatin or cisplatin].1 There’s a lot of choices here. I think that I would probably go with a single-agent drug, and atezolizumab, cemiplimab, or pembrolizumab are all reasonable.
SABARI: I would do single-agent pembrolizumab here, but is there any rationale behind using one PD-1 or PD-L1 inhibitor versus another in the single-agent setting and with PD-L1 expression greater than 50%? [These inhibitors] all have NCCN category 1 data.1
HERBST: No, I think it’s a matter of choice. These drugs have not been compared head-to-head; they’ve all been compared with chemotherapy, but I think these drugs are all quite equivalent.
SABARI: One thing I have found is that the quadruplet regimen of carboplatin, paclitaxel, bevacizumab, and atezolizumab is a lot tougher to tolerate than single-agent therapy. And the CheckMate 9LA regimen [NCT03215706], ipilimumab, nivolumab, and chemotherapy, is a lot harder to tolerate than single-agent PD-1–targeted therapy.10
I do think there is a role for those combinations if you have a younger patient with bulky disease if you want to [treat aggressively], but I agree with using single-agent pembrolizumab in the front line most of the time.
GILLANI: How much more response do you [achieve with] chemoimmunotherapy versus with immunotherapy alone in a patient like this with high PD-L1 expression?
This is a 70-year-old man, [so] we might have one shot at the goal, and if we don’t get a response out of single-agent immunotherapy, we could be in trouble.
HERBST: The response with a PD-1– or PD-L1–targeting agent used alone is upward of 40%.11 The chemotherapy probably increases that a little bit but with much more [adverse] effects. The question of what [happens] if you add the chemotherapy if you don’t have response [to the single agent] is being studied right now in a trial that’s being done [by] the SWOG [Southwest Oncology Group] Cancer Research Network.12
ASIK: I would use a single-agent PD-L1 inhibitor because of the high PD-L1 expression, 95%. And again, pembrolizumab covers the brain metastasis too. That’s my reasoning.
BRAUNSTEIN: I [would choose] the platinum doublet with the PD-L1 inhibitor. In the KEYNOTE-189 trial [NCT02578680], I think that there was no real survival benefit as the responses looked better [in patients like this one who had a] higher [PD-L1] TPS [tumor proportion score].13 Just given the extent of this patient’s disease I think adding chemotherapy would be a benefit.
MALIK: I [would choose] the combination because there are widespread metastases, including in the brain. [I also agree] that I may have one shot at this in the beginning, and if the performance status decreases, I may not be able to introduce chemotherapy in a reasonable fashion later.
STRAUSS: I’ve been burned a couple times when giving immuno-oncology monotherapy to patients with high PD-L1 expression, so I feel like it protects you to give something with a little bit of a higher response rate, [which acts] as a backup in case the PD-L1 agent doesn’t work.
HERBST: I think that I would try the single agent and then add chemotherapy if [the single agent] didn’t work, but again, you really need to see the patient.
HERBST: These drugs are probably equivalent, but most of the data [support] pembrolizumab; that’s why the market is pretty much cornered by pembrolizumab, as I think it should be. The 5-year data from the KEYNOTE-024 trial showed 35% survival.14 When I was doing this in 1993, in frontline lung cancer, [survival at] 5 years was 0%, and [survival at even] 2 years was almost 0% in the metastatic setting.
Has anyone here had their pharmacy suggest that they use something else for cost reasons? Has anyone ever tried anything else in the frontline setting? Or is pembrolizumab just a reflexive choice?
BRAUNSTEIN: Yes, [it is] somewhat reflexive, just based on the KEYNOTE[-024] study. To some extent, I feel like [these drugs are] interchangeable, but I typically use pembrolizumab.
MODI: We typically use pembrolizumab. It’s [the] way to go if the TPS for PD-L1 is more than 50%.
GILLANI: Yes, I use pembrolizumab too, but we have got a very aggressive cemiplimab pharmaceutical representative who reminds me almost every week to consider using this drug and who sends me the information from the NCCN guidelines and The Lancet paper.15
HUANG: Yes, we have long-term data for pembrolizumab14; [we have] been using this [drug] for a long time. You can use it every 3 weeks or every 6 weeks. I don’t know why we’d change to something else. I use this a lot already. I’m very familiar with this drug.
NEWSOME: I use pembrolizumab mostly for [the reason that was just mentioned]—the option to go every 6 weeks. I don’t usually start giving it every 6 weeks; I start giving it every 3 weeks, but [later] you have the option to [space the doses] every 6 weeks, and the patients are having good response and tolerating it.
ASIK: Efficacy [is one of the main factors for me]. The approximately 40% response rate for pembrolizumab is good, and it’s safe.14 The higher the PD-L1 [TPS], the better the response rate. I do use it in squamous and nonsquamous disease. [In regard to] logistics, I use it every 6 weeks.
NEWSOME: [I have] pretty much the same thoughts. I don’t think any of us can say whether there’s [different] effectiveness, safety, or tolerability among the different immunotherapies, so I think it’s dealer’s choice. Probably the [most important] thing for me is the fact that we can give pembrolizumab every 3 weeks or every 6 weeks.
BRAUNSTEIN: I [agree with] what everybody has said so far: the dosing schedule and the efficacy. I tend to use pembrolizumab more in the nonsquamous NSCLC.
SABARI: So site, burden of disease, and burden of metastasis [are common reasons for] adding chemotherapy.
Does the burden of metastasis or site of disease help guide the [choice of a] PD-1 or PD-L1 inhibitor?
HUANG: Yes, if patient has a lot of tumor burden and is symptomatic, I will look for whatever combnation will produce the highest response rate.
[For example], atezolizumab, bevacizumab, pemetrexed, and carboplatin together produced an approximately 60% response rate.16
MODI: Usually I prefer the schedule of every 3 or 4 weeks, and we continue until disease progression.
TANG: I have a patient on single-agent pembrolizumab, and the patient now shows no disease. I will continue the single agent until the disease progresses. She [is now] 2 years out. I guess if she hits 5 years, [I might have] a discussion [with her about discontinuation], but for now I will continue to give her the single-agent treatment.
ASIK: I continue for 2 years if there’s no progression. I prefer pembrolizumab administered every 6 weeks.
ZHU: I would continue until disease progression if the patient can tolerate it.
HUANG: I usually do it for 2 years, but I will do a PET [positron emission tomography] scan. If there is still residual disease, I continue. If the PET scan is negative, I stop there.
STRAUSS: I think that the patient preference comes into play here. Some patients are very against stopping it; it’s kept them alive beyond [what they expected], so they’re hesitant to stop. But then again, some patients are happy to stop and be free of it. So I think patient preference is important in this discussion.
HUANG: [I would] change to chemotherapy. If a patient does not have much response [and has] progression with initial treatment, I would not continue. I would stop [the ICI] and just switch to chemotherapy. If a patient has a very good response for a while and then progresses, I might add chemotherapy [to the ICI].
MALIK: If there is disease progression, I would change the treatment. I don’t have your kind of experience with pembrolizumab or the other agents, so I’m not aware of [any] benefit of continued treatment during disease progression.
HERBST: This patient never really benefited that much to begin with, correct?
SABARI: Yes. I would stop the immunotherapy here, in this setting, and I would generally transition to chemotherapy. To Dr Huang’s point, though, if a patient has benefited on [ICI] therapy for a prolonged period (12 months or so), I generally do add chemotherapy [to the ICI]. I think there is an ECOG [Eastern Cooperative Oncology Group] study looking at this question.
HERBST: Right, the INSIGNA trial [NCT03793179]. [In this trial, patients] start with single-agent [pembrolizumab] and then switch to chemotherapy alone or to chemotherapy plus pembrolizumab17 because we don’t know if you should keep [the pembrolizumab] going.
1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 1.2022. Accessed January 12, 2022. https://bit.ly/3LE0ury
2. Lumakras. Prescribing information. Amgen Inc; 2021. Accessed January 15, 2022. https://bit.ly/3rSgnCW
3. Huang Q, Zhang H, Hai J, et al. Impact of PD-L1 expression, driver mutations and clinical characteristics on survival after anti-PD-1/PD-L1 immunotherapy versus chemotherapy in non-small-cell lung cancer: a meta-analysis of randomized trials. Oncoimmunology. 2018;7(12):e1396403. doi:10.1080/2162402X.2017.1396403
4. Tanaka I, Morise M. Current immunotherapeutic strategies targeting the PD-1/PD-L1 axis in non-small cell lung cancer with oncogenic driver mutations. Int J Mol Sci. 2021;23(1):245. doi:10.3390/ijms23010245
5. Dang A, Dang S, Vallish BN. Efficacy and safety of EGFR inhibitors in the treatment of EGFRpositive NSCLC patients: a meta-analysis. Rev Recent Clin Trials. 2021;16(2):193-201. doi:10.2174/1574887115999201103200248
6. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi:10.1056/NEJMoa1606774
7. Tecentriq. Prescribing information. Genentech Inc; 2021. Accessed January 13, 2022. https://bit.ly/3uT2iXW
8. FDA approves cemiplimab-rwlc for non-small cell lung cancer with high PD-L1 expression. FDA. Updated February 22, 2021. Accessed January 16, 2022. https://bit.ly/3HS7q1T
9. Libtayo. Prescribing information. Regeneron Pharmaceuticals Inc; 2021. Accessed January 13, 2022. https://bit.ly/3sIWFZz
10. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211. Published correction appears in Lancet Oncol. 2021;22(3):e92.
11. Scheff RJ, Schneider BJ. Non-small-cell lung cancer: treatment of late stage disease: chemotherapeutics and new frontiers. Semin Intervent Radiol. 2013 Jun;30(2):191-8. doi: 10.1055/s-0033-1342961
12. Lara PN Jr, Moon J, Hesketh PJ, et al. SWOG S0709: randomized phase II trial of erlotinib versus erlotinib plus carboplatin/paclitaxel in patients with advanced non-small cell lung cancer and impaired performance status as selected by a serum proteomics assay. J Thorac Oncol. 2016;11(3):420-425. doi:10.1016/j.jtho.2015.11.003
13. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-1517. doi:10.1200/JCO.19.03136
14. Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. LBA51 KEYNOTE-024 5-year update: first-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. Ann Oncol. 2020;31(suppl 4):S1181-S1182.doi:10.1016/j.annonc.2020.08.2284
15. Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;397(10274):592-604. doi:10.1016/S0140-6736(21)00228-2
16. Lam TC, Tsang KC, Choi HC, et al. Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure. Lung Cancer. 2021;159:18-26. doi:10.1016/j.lungcan.2021.07.004
17. Testing the timing of pembrolizumab alone or with chemotherapy as first line treatment and maintenance in non-small cell lung cancer. ClinicalTrials.gov. Updated January 12, 2022. Accessed January 15, 2022. https://bit.ly/3GRv90Y