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Spotlight

This roundtable series evaluates the use of therapies such as monoclonal antibodies in advanced non–small cell lung cancer with high PD-L1 expression, as discussed by participants at virtual live events.

Treating Patients With NSCLC and High PD-L1 Expression in the First Line

 [NCT03088540] demonstrate about the efficacy of cemiplimab [Libtayo] in key subgroups of the population of patients with non–small cell lung cancer?

The hazard ratio [HR] for death for patients with brain metastases at baseline is 0.17 [95% CI, 0.04-0.76], an 83% risk reduction in this subset.

 This is clear: immunotherapy has virtually no boundary through the blood-brain barrier, while the chemotherapy arm clearly underperforms. It’s a sicker population, so it’s not meant to compare one versus the other population, but only those 2 regimens. There is an improved benefit for older patients; I think the relative benefit was made in the underperformance of chemotherapy; it may not be as well tolerated.

Cemiplimab had the same benefit for locally advanced and metastatic disease. There was an [HR of 0.48] for squamous cell carcinomas, and that may not be as easy to treat in this setting, as well

How did patients with a greater than 50% PD-L1 expression respond to cemiplimab versus chemotherapy?

Looking at the disease response, there is about a 40% objective response rate for cemiplimab.

This is basically going back to the question, do we need chemotherapy? If you think about the 60% response rate that we would expect, here you have 40% for immunotherapy versus 20% for chemotherapy; I think they are additive in their respective value.

The median duration of response in this PD-L1–high subset is 6.0 months for chemotherapy—and this is the ECOG 1594 baseline—versus almost 17 months for the cemiplimab group. The time to response is really the time to first scan; there’s not a big difference [between the arms], but we know from our clinical assessments that chemotherapy works much faster between the 2 treatments.

What does this trial suggest about cemiplimab’s efficacy versus chemotherapy for different subsets of patients with high PD-L1 expression?

This brings us back to the case for PD-L1 levels. [Looking at the] depth and time of response there’s a clear correlation between the level of PD-L1 and the depth and length of response between the 2 responder populations. So, the closer we get to PD-L1 of 100%, the more impact we can expect, and the less likely we need chemotherapy. The way I do it in my clinic—aside from clinical assessment—is how favorable is the biomarker setup? If the patient has a PD-L1 level of less than 50%, I always add chemotherapy. If a patient has a PD-L1 level of greater than 50%, then it depends on the clinical assessment and how close the patient comes to a PD-L1 level of 100% between the 2 parts.

There are 3 subgroups of PD-L1 greater than 50%: 60% to 90%, 50% to 60%, and greater than 90%. There’s almost an exponential benefit increase as we move closer to 90% and greater. The response rate goes from 32% [for the 50% to 60% PD-L1 group] to 46% [for the greater than 90% PD-L1 group]. Median PFS [progression-free survival] goes from 4.3 months to 6.2 months to 15.3 months [in ascending order of PD-L1 expression]. And then, median OS [overall survival] goes from [21.9 months], to 22.1 months, to unreached, respectively. So, I think those would be a very interesting patient population for single agent PD-1 [inhibitor].

There is a risk of adverse events [AEs], and [concern for] how well the single agent PD-1 inhibitors are tolerated. We have these discussions with patients, what to expect, and I don’t want to undervalue the severity of AEs that can occur. But especially if you look at the higher grades, AEs are not common. There’s a high rate of continuation, and a high rate of tolerability. When we look at chemotherapy, the comparison is not quite fair; they’re such different [types] of AEs.

But 94% of patients were able to continue on cemiplimab. There was a surprisingly high number of AE-related discontinuations for chemotherapy, with 96%. The duration of therapy was much different.

What data support the use of cemiplimab plus a platinum doublet chemotherapy?

I do want to share [an important] point about the width of data that the EMPOWER-Lung 3 trial [NCT03409614] has reported. The approval for first-line cemiplimab and platinum doublet is currently in FDA review, and we have seen some of the data. This trial was for patients who are treatment-naive, with any PD-L1 expression. There was stratification by histology and PD-L1 levels for low, negative, and high—greater than 50%; with the primary end point being OS. 

The median OS was 22 months with cemiplimab and chemotherapy versus 13 months for chemotherapy alone.

 This seems very similar to what we’ve seen for the PD-L1 high groups, including those that are not immunotherapy responsive. Median PFS was 8.2 months versus 5.0 months, respectively. And the objective response rate was 43% for the cemiplimab group versus 22% for chemotherapy alone; the median DOR was also in a very similar level. So, it’s clearly [supporting] a notion that the chemotherapy will cover the PD-L1 less than 50% population quite well. With that width of data is coming, the FDA is reviewing the data, and hopefully by this summer there will be a decision on that, as well.

1. 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. 

. 2021;397(10274):592-604. doi:10.1016/S0140-6736(21)00228-2

2. Gogishvili M, Melkadze T, Makharadze T, et al. LBA51 - EMPOWER-Lung 3: Cemiplimab in combination with platinum doublet chemotherapy for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC). 

2021;32(suppl_5):S1283-S1346. doi:10.1016/annonc/annonc741

During a live virtual event, Martin F. Dietrich, MD, PhD, discussed the results of the EMPOWER-Lung 1 and EMPOWER-Lung 3 trials of cemiplimab for non–small cell lung cancer. 

Exploring Subset Analyses in the EMPOWER-Lung 1 Trial for NSCLC

A 72-year-old White man presents with chest discomfort, cough, and dyspnea ​

Medical history: mild chronic obstructive pulmonary disease​

Former smoker, 10 pack-years; quit 25 years ago​

CT of the chest and abdomen found a 9.0-cm spiculated mass in the left lower lobe, loculated pleural effusion in the left hemithorax​, right adrenal metastasis​

PET/CT: 18F-fluorodeoxyglucose uptake in the left lung mass, pleura and right adrenal gland​

Brain MRI: solitary brain lesion (1.5 cm)

Note: no central nervous system symptoms​

Physical exam: notable for decreased breath sounds in the left lung base; ECOG performance score of 1​

Laboratory work unremarkable with normal organ function and blood counts​

Image-guided biopsy of the lung mass shows a poorly differentiated adenocarcinoma of the lung​

Immunohistochemistry: PD-L1 tumor proportion score of 90% (22C3 pharmDx assay) ​

Tissue NGS (next-generation sequencing): negative for molecular aberrations in 

: What regimens are recommended for a patient with non–small cell lung cancer (NSCLC) with PD-L1 expression above 50%, who is negative for actionable biomarkers?

 Here we get very little guidance. The NCCN [National Comprehensive Cancer Network] guidelines have the full slew of opportunities between squamous and non-squamous histology…and I think the difference between single agent and combination is a mix of biomarker, PD-L1 assessment, maybe even some secondary markers like KEAP1, p53, and STK11 that may signify either a positive or negative response to immunotherapy, as well as the clinical assessment.

We looked at [my practice] and, overwhelmingly, we’re seeing the use of chemotherapy up front. So our patients, certainly during the pandemic, are coming in more symptomatic and requiring, in clinical judgement, the addition of chemotherapy. Otherwise, we don’t have any side-by-side comparison. So, those are all category 1 recommendation, based on phase 1 data, and so basically the selection is dependent on the clinician.

What data support the use of pembrolizumab (Keytruda) for patients with stage IV lung adenocarcinoma PD-L1 greater than 50%?

This is the KEYNOTE-024 phase 3 trial [NCT02142738]. [Patients enrolled on this trial] had untreated stage IV NSCLC, independent of histology. They had a total percentage score greater than 50%, no 

 mutations, no untreated brain metastases, and no active autoimmune disease requiring systemic therapy.

They were randomized [between] chemotherapy and pembrolizumab. There was a second course of pembrolizumab [for 1 year] versus crossover to pembrolizumab upon progression with chemotherapy. They allowed basically every conceivable platinum doublet for an international study. There was a steep drop-off of patients that didn’t receive subsequent second-line therapy, so choosing the right [first-line therapy] is important. The data are here very strong. The crossover has relatively small numbers.

The long-term follow-up [for overall survival (OS)] is important. The tail is at the beginning of the [Kaplan-Meier] curve. There’s [not much] crossover. So, the curves start to split within 3 to 6 months in favor of immunotherapy, and we maintain a relatively stable absolute OS benefit between the years to over 30% at 5 years for pembrolizumab in this subset. The hazard ratio [HR] is 0.62 [95% CI, 0.48-0.81], and the median OS is 26.3 months [95% CI, 18.3-40.4] for pembrolizumab versus 13.4 months [95% CI, 9.4-18.3] for chemotherapy. It’s a pretty good intrinsic marker, that is pretty consistent across the phase 3 trials to gauge how sick the individual patients are that were selected to participate.

Which trial demonstrated the efficacy of atezolizumab (Tecentriq) for this subset of patients with lung cancer?

So, looking at the IMpower110 study [NCT02409342], it has very similar trial design [to KEYNOTE 024]. It is a prospective evaluation for squamous or non-squamous stage IV NSCLC. This was a little bit less aggressive with PD-L1 levels in a hierarchical manner. This has only been approved for the first hierarchy of PD-L1 greater than 50%. Here, [patients received] atezolizumab versus chemotherapy with cisplatin or carboplatin plus pemetrexed versus cisplatin/carboplatin/gemcitabine for squamous cell carcinoma. Then there is a maintenance option for non-squamous disease, and a best supportive care for the squamous cell population. Patients received treatment until progression of disease.

In this study, there is crossing of the Kaplan-Meier curves for OS [due to more OS events in the first 4 months for patients receiving atezolizumab].

I am not quite sure why that is; the numbers look relatively alike. The median OS for chemotherapy was 13.1 months [95% CI, 7.4-16.5], so the comparator arm is certainly looking very similar [to that of the KEYNOTE 024 trial]. And then, the median OS for atezolizumab was 20.2 months [95% CI, 16.5-not estimable (NE)] in this subset.

We have a crossing of the curves [between 4 to 6 months]. So, this would be a trial where the chemotherapy upfront may have been a more reasonable option, based on the visuals. The HR [with 17 additional months of follow-up] is only 0.76 [95% CI, 0.54-1.09], which is not quite as impressive as we’ve seen with KEYNOTE-024. This is also a different [PD-L1 measurement] because it’s not the 22C3 Dako but the SP142 assay for assessment, in this trial.

Please describe the design of the cemiplimab (Libtayo) trial in this patient population.

The third registration trial in this setting is EMPOWER-Lung 1 [NCT03088540]. This patient population was all-treatment-naive NSCLC, with PD-L1 greater than 50%; 

 mutations were excluded. They allowed clinically stable central nervous system metastases that were treated, and then patients with hepatitis B or C and HIV were allowed. There is not a good reason not to include them, but they’ve never done it before in this larger setting.

The 1:1 randomization was to cemiplimab or chemotherapy of investigator’s choice; this was an international study, so there was more flexibility. Then, cemiplimab was given for 2 years, and there was a little bit of a different concept: not a second course of treatment, but an addition of chemotherapy. So basically, immunotherapy to chemoimmunotherapy augmentation upon progression versus crossover [from chemotherapy to cemiplimab monotherapy]. About three-quarters of patients took that crossover option, and there weren’t many patients that were able to continue treatment who didn’t choose that option. So this was very interesting, like a sequencing approach to those that were clinically able to.

When you look at the baseline characteristics, you see in both the intent-to-treat [ITT] population—there was a little bit of a difficulty confirming all the PL-L1 levels centrally for tissue availability, so that we have 2 sets of data: PD-L1 greater than 50% confirmed, and then the full ITT population. About 1 in 8 patients had brain metastases; and, as a particular area of interestwe see a little bit of an over-representation of [current] smokers [versus past smokers]. We don’t have any never-smokers in this trial, I think this was felt to be not necessarily helpful for non-smokers as much as it is for smokers. There is also a slightly over-representation of patients with squamous cell disease; obviously, when you exclude non-smokers or light smokers, you see that increase in patients with squamous histology. And, it’s also [related to] the way [cigarettes] are smoked internationally, filter-free, [which can lead to]a little bit of a different precipitation of carcinogens in the airway.

What was the response to therapy on the EMPOWER-Lung 1 study?

We see a picture that’s very similar to KEYNOTE-024. The Kaplan-Meier curves run in parallel for the first 3 to 6 months or so, and then start parting.

 In the ITT population, there was median OS of 22.1 months [95% CI, 17.7-NE] for cemiplimab, and 14.3 months [95% CI, 11.7-19.2] for chemotherapy [HR, 0.68; 95% CI, 0.53-0.87; 

 The median progression-free survival showed slight increase in the ITT population: 6.2 months for cemiplimab versus 5.5 months for chemotherapy. There is a much larger tail of the curve on an ongoing basis.

So, looking at OS in the confirmed PD-L1 greater than 50% population, it looks better.

There was certainly the suspicion that there were patients slipped in that didn’t have central confirmation of PD-L1 levels greater than 50%. The HR [of 0.57] is in the same ballpark, maybe even trending a little bit better than with KEYNOTE-024, with an unreached benefit here for OS [95% CI, 17.9-NE] versus 14.2 months [95% CI, 11.2-17.5] of median OS for the chemotherapy arm, and that’s within the same range that we’ve seen for IMpower110, and for KEYNOTE-024.

 There is almost a 3-month benefit in median PFS [8.2 months for cemiplimab versus 5.7 months for chemotherapy]. But the largest part of benefit here is not extending to the median number of population, but for the strong responder subset.

This was also a crossover study, so there was not necessarily a catching up [from the comparator arm]; I think that’s important for those trials in evaluation.

1. NCCN. Clinical Practice Guidelines for Oncology. Non–small cell lung cancer, version 3.2022. Accessed June 27, 2022. https://bit.ly/3xZFzJF

2. Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. LBA51 - KEYNOTE-024 5-year OS 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%. 

2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

3. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-Line treatment of PD-L1-selected patients with NSCLC.

2020;383(14):1328-1339. doi:10.1056/NEJMoa1917346

4. Jassem J, de Marinis F, Giaccone G, et al. Updated overall survival analysis from IMpower110: Atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC. 

 2021;16(11):1872-1882. doi:10.1016/j.jtho.2021.06.019

5. 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. 

6. Sezer A, Kilickap S, Gümüş M, et al. LBA52 - EMPOWER-Lung 1: Phase III first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. 

 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

During a Targeted Oncology live virtual event, Martin F. Dietrich, MD, PhD, discussed data from 3 trials of immunotherapy agents for patients with non–small cell lung cancer with high PD-L1 expression. 

Immunotherapies Offer Alternatives to Chemotherapy for PD-L1–High Lung Cancer

A 72-year-old White man presents with chest discomfort, cough, and dyspnea. He had a history of mild chronic obstructive pulmonary disorder and was a former smoker who quit 25 years ago and had 10 pack-years of exposure.​ A CT scan of the chest and abdomen revealed a 9.0-cm spiculated mass in the left lower lobe​, loculated pleural effusion in the left hemithorax​, and right adrenal metastasis. ​

PET/CT scan showed fluorine-18 fluorodeoxyglucose uptake in the left lung mass, pleura and right adrenal gland. A brain MRI showed a solitary brain lesion of 1.5 cm but no central nervous system (CNS) symptoms​.

Physical examination was notable for decreased breath sounds in the left lung base. His ECOG performance score was 1. Lab work was unremarkable with normal organ function and blood counts​.

An image-guided biopsy of the lung mass showed a poorly differentiated adenocarcinoma of the lung​. Immunohistochemistry showed PD-L1 tumor proportion score (TPS) of 95%.​ Tissue next-generation sequencing (NGS) was negative for molecular aberrations in 

G12C mutation​. The disease was microsatellite stable.

What are your thoughts on the EMPOWER-Lung 1 trial data (NCT03088540)?

​ How many of you only use National Comprehensive Cancer Network (NCCN) guidelines and how many use pathways?

 The question will still remain as cemiplimab [Libtayo] versus atezolizumab [Tecentriq] versus nivolumab [Opdivo] versus pembrolizumab [Keytruda]—which is better in terms of brain metastases? I don’t think they were going to compare them [head-to-head]. The cemiplimab study looked at brain metastases.

 That doesn’t mean that the others don’t work as well unless there are some other data that I’m not aware of.

 Exactly right. We’ve seen so many dramatic CNS regressions with pembrolizumab or combined immunotherapy or other drugs. Will somebody ever compare [efficacy with CNS between these drugs]? They are produced by different drug companies, so I’m not sure that will ever happen. We can do it retrospectively, but I don’t think that necessarily helps.

If we wait another month, we’re going to have another regimen. How you gauge in terms of your clinical practice is important. Does anybody want to talk about guidelines versus pathways?

 We’re a US Oncology practice in Las Vegas. We use the US Oncology pathways that help us. Whether you call them guidelines or pathways, we try to focus on those because we have to meet metrics on those as well.

During a live virtual event, Ravi Salgia, MD, PhD, discussed treatment considerations for a patient with non–small cell lung cancer with a brain metastasis. 