A 59-year-old White man presented with chest pain, cough, and dyspnea. The patient was diagnosed with poorly differentiated adenocarcinoma of the lung.
During a Targeted Oncology Case-Based Roundtable event, Laura Q. M. Chow, MD, associate director, Clinical Research, director, Lung, Head, Neck & Clinical Immunotherapy Programs Livestrong Cancer Institutes, Professor, Department of Oncology, and associate chair of Education, Department of Oncology at Dell Medical School at the The University of Texas at Austin, discussed a 59-year-old patient with non–small cell lung cancer.
Targeted OncologyTM: How would you treat this patient in accordance with the National Comprehensive Cancer Network guidelines?
CHOW: For first-line therapy, the preferred regimen from the KEYNOTE-189 study [NCT02578680] is platinum, pemetrexed [Alimta], and pembrolizumab [Keytruda] as category 1.1 There’s good phase 3 evidence for the other recommendations of taxane and atezolizumab [Tecentriq], taxane/ atezolizumab or bevacizumab [Avastin], and then that of the recent trials with ipilimumab [Yervoy] and nivolumab [Opdivo]. Useful in certain circumstances would be a nonchemotherapy option of nivolumab and ipilimumab, or if the patient is not wanting or tolerating chemotherapy, pembrolizumab [monotherapy] could be considered, but this is a category 2B recommendation [from the NCCN guidelines].
What are the data for the carboplatin/pemetrexed/ pembrolizumab regimen that the participants selected for this patient?
The KEYNOTE-189 study was a large, randomized study that everybody has taken on as standard of care.2 This trial was presented a few years ago, was published, and has changed how we treat patients with non–small cell lung cancer [NSCLC] in the first line.
In the key eligibility criteria, there were no activating mutations of EGFR or ALK, and the reason for that is the fact that these patients tend not to respond as well to immunotherapy, so they were not included. Their PD-L1 status was assessed and [they had] good performance status with stable treated brain metastases and no signs of pneumonitis or interstitial lung disease. There were untreated patients with stage IIIb or IV nonsquamous disease either randomized to platinum/ pemetrexed/pembrolizumab or the platinum/pemetrexed combination with placebo instead for 4 cycles. They went on to receive pemetrexed/pembrolizumab or pemetrexed maintenance alone and then crossed over to pembrolizumab at progression. The crossover was optional. The randomization was stratified by PD-L1 tumor proportion score [TPS] less than 1%, or greater than or equal to 1%, and the primary end points were overall survival [OS] and progression-free survival [PFS].
Please discuss the efficacy of the KEYNOTE-189 trial.
The intention-to-treat population [data] were reported and published after almost 2 years of follow-up.3 The survival advantage for the group as a whole favored the combination of pembrolizumab with a very significant hazard ratio of 0.56 [95% CI, 0.45-0.70]. This was very significant and speaks very highly to this combination as being the acceptable standard of care for our patients.
We tend to think that patients with TPS scores that are higher respond better, but there was an OS advantage across most of the TPS scores. Our patient [would be in the] 1% to 49% group. There was still a good hazard ratio of 0.62 favoring survival for the pembrolizumab combination rather than that of placebo [95% CI, 0.42-0.92]. This is a reassuring choice in our patients who have low expression, 1% to 49%; they still benefit from chemotherapy and pembrolizumab.
How have other trials looked at pembrolizumab in NSCLC?
When we talked about single-agent immunotherapy, this was the KEYNOTE-042 study design [NCT02220894].4,5 Patients [had] PD-L1 TPS greater than or equal to 1%, did not have EGFR or ALK mutations, and [had] good performance status of 0 or 1 without brain metastases or pneumonitis. This was stratified into regions: east Asia vs rest of the world. Performance status, histology, squamous and nonsquamous were included, and then they stratified it by TPS score greater than or equal to 50% vs 1% to 49%.
This was a very controversial study when it was first presented at the American Society of Clinical Oncology Annual Meeting [in 2018]. Pembrolizumab was given every 3 weeks for up to 35 cycles, which is [approximately] 2 years, vs platinum-based chemotherapy for up to 6 cycles. Primary end point was OS and secondary end points were PFS, overall response rate, and safety.
There were OS [results] at various PD-L1 cutoff levels. I think the controversial part of this was the fact that there was an OS advantage across all PD-L1 cutoffs that were positive, but it was [mainly] pushed by the PD-L1 50% or greater group with the hazard ratio of 0.69 [95% CI, 0.56-0.85; P = .0003], and the Kaplan-Meier curves crossed. When you look at the PD-L1 greater than 20% group, the HR is still relatively good at 0.77 [95% CI, 0.64-0.92; P = .002], but the curves crossed and there’s less of a distinction. When you look at all the PD-L1 greater than or equal to 1% patients, it’s clear that the hazard ratio does support an improvement in survival with pembrolizumab; however, it’s a less robust hazard ratio of 0.81 [95% CI, 0.71-0.93; P = .0018], and these curves crossed.
What that tells us is...[that] if they’re not going to respond to the immunotherapy—unfortunately, this happens early on—we may want to consider chemotherapy for our patients who have more rapidly growing, heavy burden, or bulky disease. Eventually it evens out, but the patients do not do well initially because immunotherapy does take some time before it starts working. We would anticipate that [it will be] anywhere from 6 to 9 weeks before we get a decent response or stability.
When we look at patients who had a PD-L1 of 1% to 49% only, there was quite a lot of crossing of the curves. There was a benefit that still supports pembrolizumab, with a hazard ratio of 0.92 [95% CI, 0.77-1.11], but it’s a little less robust. It’s clear that most of the benefit was driven by the greater than or equal to 50% group and less so by the 1% to 49% group. We can still use pembrolizumab in this population and it would still be effective, but for very symptomatic patients with bulky disease, it may not be the best choice.
What results did the IMpower150 trial (NCT02366143) show in this space?
This was the atezolizumab study looking at the combination of paclitaxel/carboplatin plus or minus bevacizumab, then maintenance therapy without crossover of atezolizumab/ bevacizumab or bevacizumab alone as a control.6,7 They were treated with atezolizumab until progressive disease or loss of clinical benefit and/or treated with bevacizumab until progression of disease per RECIST criteria. This was a large study stratified by [sex], PD-L1, immunohistochemistry, and liver metastases for 1200 patients or more.
This was in intention-to-treat patients. The OS hazard ratio was 0.78 [95% CI, 0.64-0.96; P = .02], and still supported the addition of atezolizumab, bevacizumab, and chemotherapy vs bevacizumab and chemotherapy. This is what brought on the FDA approval of this regimen as standard of care and the standard option with improvement in survival that is still maintained quite far out.
What other therapies have been investigated for NSCLC?
As another option, CheckMate 227 [NCT02477826] is a very controversial study. When this was first designed, part of the issue was the fact that ipilimumab has quite a lot of toxicity and the dosing of ipilimumab was problematic.
I was involved in some of the early phase 1 studies of ipilimumab and nivolumab, and at full melanoma doses we had a lot of toxicity. When this study was initially designed, it was looking at the TMB population and they thought that they would have an OS advantage when they compared nivolumab and ipilimumab with chemotherapy.
Unfortunately, the OS advantage did not pan out, so they reconfigured the study and looked at it again, which was a little bit problematic. They were going to look at the less than 1%, but it did not meet its end point and instead they focused on the greater than or equal to 1% PD-L1 expression. It did not include any patients with EGFR/ALK mutations. For the main PD-L1 coprimary analysis, they were looking at nivolumab and ipilimumab vs chemotherapy.
Did the CheckMate 227 trial meet the necessary end points?
In terms of OS, it did meet its end point [HR, 0.79; 95% CI, 0.67-0.93], and it had a robust hazard ratio for PFS that was well maintained.8-10 There was a similar trend where the immunotherapy-only doublet arm did not do as well initially but the curves cross and the immunotherapy arms did have a maintained long-term survival advantage for those who responded well to immunotherapy. This is still a very well-maintained 3-year update that supports the improvement in survival of this combination.
When you look at it by PD-L1 score, the benefit was a little less robust for the 1% to 49% [HR, 0.94; 95% CI, 0.75-1.18], which we would not be surprised about, but for greater than or equal to 50%, it was quite clear that nivolumab and ipilimumab would be better than chemotherapy [HR, 0.70; 95% CI, 0.55-0.90].
What was the toxicity profile of ipilimumab/nivolumab?
This was a difficult regimen until they dropped the dose of ipilimumab plus nivolumab to make it palatable at 1 mg/kg every 6 weeks with the nivolumab at 3 mg/kg every 2 weeks.
If you look at all events, obviously chemotherapy has adverse events [AEs] that are not small; they were 36.0% grade 3 and 4, [and] with nivolumab/ipilimumab it was similar [32.8%]. The issue was that when you look at treatment-related severe AEs, they were higher in the nivolumab/ipilimumab group, which is not unexpected, as well as with AEs leading to discontinuation.
I believe most of the reason behind this is we know typical AEs of chemotherapy and cytopenias go away. Unfortunately, immune-related toxicities require that we have a low clinical suspicion for them and the incidences, when they do occur, become quite severe—up to grade 3 or 4. They often necessitate that they stop immunotherapy forever and initiate steroids. I think that’s part of the difficulty with nivolumab and ipilimumab vs chemotherapy when you’re considering this regimen up front.
I have heard, though, that for young, fit patients, it may not be an unreasonable choice because you still have the option of chemotherapy later on when they progress rather than considering second-line treatment.
Did this combination show efficacy in any other trials?
The CheckMate 9LA [NCT03215706] study design, which also did not have any EGFR mutations, was stratified by PD-L1, [sex], and histology.11 This was ipilimumab and nivolumab in combination with 2 cycles of chemotherapy vs 4 cycles of chemotherapy. This was until disease progression with a primary end point of OS.
The primary end point of OS was met [HR, 0.66; 95% CI, 0.55-0.80]. The overall response rate favored ipilimumab, nivolumab, and chemotherapy at 38% vs chemotherapy at 25%, which is what we would expect with chemotherapy. That serves as a reasonable end point and there was no crossing of the curves that we saw in the other immunotherapy-alone arms [of the previous studies], where those who had more rapid, bulky, progressive disease that did not respond to immunotherapy [had] a decrease in OS. This seemed to be a very reasonable study that led to OS and FDA approval.
For our patient who had PD-L1 1% to 49%, there was a clear survival advantage with the combination, although there was an advantage seen for most of the population.
When you’re using so many drugs, it’s not unreasonable that when you look at treatment-related AEs typically associated with chemotherapy there seems to be little bit more in terms of significant toxicities associated with the combination regimen.
As a result of both those studies...both regimens were approved [in May 2020] by the FDA as reasonable options: nivolumab and ipilimumab in first-line therapy for that of PD-L1 tumor expression greater than or equal to 1% and for first-line for all comers with chemotherapy.
1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 5.2021. Accessed September 27, 2021. https://bit.ly/31aF6nS
2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005
3. 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
4. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(suppl 18):LBA4. doi:10.1200/JCO.2018.36.18_suppl.LBA4
5. Mok TSK, Wu YL, Kudaba I, et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7
6. Socinski MA, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl 15):9002. doi:10.1200/JCO.2018.36.15_suppl.9002
7. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948
8. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
9. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
10. Ramalingam SS, Ciuleanu TE, Płużański A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-year update from CheckMate 227 part 1. J Clin Oncol. 2020;38(suppl 15):9500. doi:10.1200/JCO.2020.38.15_suppl.9500
11. Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501