Treatment for a patient with poorly differentiated adenocarcinoma of the lung was the topic of discussion between Joshua K. Sabari, MD and peers during a Case-Based Roundtable.
During a Targeted Oncology Case-Based Roundtable event, Joshua K. Sabari, MD, assistant Professor, Department of Medicine , NYU Langone’s Perlmutter Cancer Center in Ne York, NY, discussed the case of a 59-year-old patient with non–small cell lung cancer.
Targeted OncologyTM: If the patient had NTRK fusion– positive disease, what would have been your choice of regimen?
SABARI: There are 2 therapies that are FDA approved for NTRK fusion in non–small cell lung cancer [NSCLC]: entrectinib [Rozlytrek] and larotrectinib [Vitrakvi]. Both are appropriate and have robust activity. They were approved after small, single-arm studies. There are [ongoing] confirmatory studies, but either entrectinib or larotrectinib would be an option here.
If somebody had a driver mutation—which is the key here of why molecular sequencing patients is so important—there’s an FDA-approved matched targeted therapy.
It would be crazy to give that patient immunotherapy, but it’s not crazy to give them chemotherapy because it still has activity. With immunotherapy, the response rate in a driver mutation–positive population is very low. The risk of having toxicities down the road, particularly when subjected to other tyrosine kinase inhibitor small molecules, is relatively high for immune-related adverse events [irAEs].
If you identified an EGFR mutation, ALK, or NTRK fusion up front, I would forgo immunotherapy and chemotherapy in the frontline setting and treat with the targeted therapy alone. These patients are fragile and may only see 1 regimen of therapy. You’d want to give them the best possible regimen up front.
What would be your preferred regimen recommendation for this patient?
In the NCCN guidelines, if PD-L1 expression is positive greater than or equal to 1%, or low, meaning less than 50%, and if their ECOG performance status is 0 to 2, or if they have an adenocarcinoma, the category 1 recommendation is carboplatin or cisplatin, which is not commonly used in the United States in patients with metastatic disease. [The usual regimen is] carboplatin, pemetrexed [Alimta], and pembrolizumab [Keytruda].1 There are many other recommended [treatment] strategies. It’s just a question of how to interpret the data [to determine] what the best possible regimen for the patient is.
The KEYNOTE-189 study [NCT02578680] was an interesting and practice-changing study that was published in 2018 in the New England Journal of Medicine by Leena Gandhi, MD, PhD.2
In 2015 and 2016, pembrolizumab moved to the frontline setting after the KEYNOTE-024 study [NCT02142738].3 Prior to that, we only had chemotherapy in the frontline setting. The randomized study comparing chemotherapy [with] immunotherapy was positive, and it specifically looked at patients with PD-L1 expression greater than or equal to 50%.
Why is single-agent nivolumab (Opdivo) not approved in the frontline setting?
The nivolumab studies compared nivolumab with chemotherapy and looked at all PD-L1 expression for all-comers. They did not select for high PD-L1 expression. That’s why that was a negative study.
Chemotherapy was better than nivolumab in all-comers. But pembrolizumab was approved in the PD-L1–high patient population. The KEYNOTE-189 study bore out in about all the other patients, PD-L1 negative or those with PD-L1 less than 50%.
How do the KEYNOTE-189 study data support the preferred recommendation in this patient?
The KEYNOTE-189 study was a randomized phase 3 study. Patients were randomized 2:1. They received carboplatin or cisplatin plus pemetrexed and pembrolizumab followed by pemetrexed and pembrolizumab maintenance [for the treatment arm] vs carboplatin or cisplatin and pemetrexed [plus placebo] followed by maintenance [with pemetrexed plus placebo for the control arm].
Interestingly, this study did allow for crossover. At the time of progression, patients were allowed to get pembrolizumab.2 In the intention-to-treat population, the overall survival [OS] rate at 12 months and at 24 months is far better in the chemotherapy plus immunotherapy arm vs the chemotherapy-alone arm.
The median OS [mOS] was 22 months in patients treated with pembrolizumab in combination with chemotherapy vs 10.7 months in patients treated with chemotherapy alone.4 I remember [initially] seeing these data in an era when we didn’t have great therapeutics and chemotherapy was our only option. Patients with low PD-L1 did not do well with single-agent chemotherapy. This study was practice-changing.
A lot of people said the patients with high PD-L1 might just do better than those with low PD-L1. Those with a TPS [tumor proportion score] between 1% and 49% have an HR of 0.62 [95% CI, 0.42-0.92].
At 12 months and at 24 months, the OS rate persists [for the pembrolizumab arm], and the mOS is about 22 [months for the pembrolizumab arm] vs 12.1 months [for the chemotherapy-alone arm].4
It’s not just pembrolizumab [or high PD-L1] driving this. The chemotherapy, and particularly the pemetrexed, potentially has a clinical and biologic rationale. Interestingly, in those with TPS of less than 1%, there was still a significant difference in mOS of 17.2 months in the pembrolizumab arm vs 10.2 months in the chemotherapy-alone arm.
Again, not as great of a difference as in those with TPS of greater than 50% or those with positive TPS between 1% [and] 49%.4
These results led to the FDA approval of this regimen across the board. But in clinical practice, we [commonly] use it in patients who have PD-L1 expression between 0% [and] 49%.
Please discuss your thoughts on these poll results.
When you’re thinking about this question, it’s not a trick question. There are circumstances when we don’t want to give chemotherapy to patients, and there are patients who we can see in the clinic who may be older and have other comorbidities, which prevent them from receiving chemotherapy.
Interestingly, 0 people said “Sometimes” and 1 voter said “Often,” which is probably more common in clinical practice than we think. It’s very interesting to hear and see what actually happens in clinical practice. I would say I rarely use a single-agent PD-1 or PD-L1 inhibitor in someone with PD-L1–low or –negative NSCLC.
What are the data on use of a single-agent immune checkpoint inhibitor for patients with low–PD-L1 NSCLC?
KEYNOTE-042 [NCT02220894] is another interesting study that looked at pembrolizumab vs chemotherapy, not only in the population with PD-L1 expression of greater than 50%, but also in those with greater than or equal to 1%. This was presented [in 2018] by Gilberto Lopes, MD, at [the American Society of Clinical Oncology meeting] and later published in the Journal of Clinical Oncology.5 The data were somewhat controversial because it was compared with KEYNOTE-024, which was the initial study published in 2016 that led to the FDA approval of pembrolizumab alone in high PD-L1–expressing patients, and KEYNOTE- 189 had already been presented in all-comers on pembrolizumab plus chemotherapy.3
This study looks at patients with stage III and IV unresectable metastatic NSCLC, which is different from some of the other studies. Patients had to have PD-L1 expression of greater than or equal to 1%. They excluded patients with EGFR and ALK alterations, which was different from the IMpower150 [NCT02366143] study and other studies. Patients had to have an ECOG performance status of 0 or 1 with no unstable or untreated central nervous system metastases. This study randomized patients 1:1 to pembrolizumab vs chemotherapy.5,6 They looked at OS in those with a TPS of greater than or equal to 50%, 20%, and 1% as the primary end point.5,6
Those with PD-L1 TPS greater than 50% did the best in terms of OS, and those greater than 20% still did OK, but less well than the greater than 50% [group].5,6 Those with greater than or equal to 1% had some benefit, but again, less than in the prior groups.
This study was very controversial and had a lot of press. It led to the FDA approval in stage III unresectable disease with positive PD-L1 expression. Still, I take these data with a grain of salt. The population with TPS greater than 50% had a mOS of 20 months in the pembrolizumab arm vs 12.2 months for the chemotherapy. This is what we saw in the KEYNOTE-024 initial study. But when you look at the population with TPS greater than or equal to 1%, the mOS is 16.7 months for pembrolizumab vs 12 months for chemotherapy, with an HR that is still respectable at 0.81 [95% CI, 0.71-0.93], but nowhere near 0.69 [95% CI, 0.56-0.85] in the population with PD-L1 expression of greater than 50%.5,6
Again, a very strategic study allowing the FDA approval of this agent across the board. With this study, Merck & Co, Inc, had approval in the population with PD-L1 expression greater than 50%. They already had the approval of pembrolizumab plus chemotherapy in all-comers, and now they have the approval of pembrolizumab alone in the population with PD-L1 greater than or equal to 1%. But [in clinical practice], I still think we add chemotherapy [consisting of] the pemetrexed-based platinum doublet in patients who have TPS lower than 50%.
It’s interesting that immunotherapy takes some time to work, and you do have a drop-off of patients who clearly don’t do well with immunotherapy alone, but chemotherapy works in that population.
Past the 6-month mark is when the patient population separates. [Unfortunately], you see this in clinical practice and even in patients with high PD-L1 expression. The response rate is still only about 50% to 55%. Half of our patients are not having a clinical response to these therapies. You have a significant drop-off in the beginning.
Is the argument, then, that you should add chemotherapy to the immunotherapy?
The argument is that you should add chemotherapy, particularly in patients who have low PD-L1 expression. There are purists who give everybody chemotherapy and immunotherapy. I think you have increased toxicity in that population if you’re looking at all-comers and just giving chemotherapy, but there are people who really believe that—especially in the squamous [cell lung cancer] population.
Even with the KEYNOTE-407 study [NCT02775435], the chemotherapy plus immunotherapy arm looked far better than the immunotherapy alone, [similar to] what we saw from KEYNOTE-024. There are some people that give everybody a taxane-based regimen with immunotherapy in the [squamous] population.
The exploratory analysis in KEYNOTE-042 in the population with PD-L1 expression between 1% [and] 49% had an OS rate of 34.6% for pembrolizumab vs 26.5% for chemotherapy at 24 months.5,6 Again, the HR here is not that great. This is not something I commonly use in this patient population. I prefer to use chemotherapy plus immunotherapy. I reserve immunotherapy alone for patients with high PD-L1 expression, outside some of those circumstances we talked about, such as poor ECOG performance status, etc.
What other regimens can be used for patients with low–PD-L1 NSCLC?
The next studies are relatively complicated in the sense that they have multiple arms. The IMpower150 study compared a 4-drug regimen [vs a couple of control arms], when there was nothing approved except for chemotherapy [at the time]. This was a massive study of 1200 patients randomized 1:1:1.7
Arm B was the experimental arm, and if patients met the criteria for 1 arm, they could then continue to the second part of the study, so a relatively complex design. Arm B was atezolizumab [Tecentriq], carboplatin, paclitaxel, and bevacizumab [Avastin], followed by atezolizumab and bevacizumab maintenance.7
The OS rate for the intention-to-treat arm B with atezolizumab, bevacizumab, carboplatin, and paclitaxel [ABCP] and the bevacizumab, carboplatin, and paclitaxel [BCP] alone arm [was 67.3% vs 60.6% at 12 months and 43.4% vs 33.7% at 24 months, respectively (stratified HR, 0.78; 95% CI, 0.64-0.96; P = .02)].7,8
These data are not as robust as the KEYNOTE-189 regimen, as mOS was 19.2 months vs 14.7 months, whereas KEYNOTE-189 was 22 months vs 10 months.8 It’s tough to compare data across trials, but clearly there was a benefit for getting ABCP, which led to an FDA approval of this regimen. The major problem in clinical practice is the toxicity of getting this 3-chemotherapy regimen or 2 chemotherapies and the VEGF inhibitor.
Why do the tails of both the ABCP and BCP Kaplan- Meier curves meet at the end?
It’s probably [because of] drop-off and not having information on those patients. Most likely, those are censored patients or those lost to follow-up, but I’d love to have all the data and see the difference between the curves throughout.
If the ABCP arm was flat at 30% to 40% range of survival long term and the BCP arm kept going down and no patients were alive, that would be what we would hope to see. I think the curves meet [because of] censoring.
I don’t think there are many patients alive at 33 months on chemotherapy alone. In your own clinical practice, look at driver-negative patients who never receive immunotherapy and what their duration of response and survival is. It’s not as good as the BCP curve suggests.
How does immunotherapy compare with chemotherapy based on the CheckMate 227 study data?
About 2000 patients were enrolled in the CheckMate 227 study [NCT02477826], which was like 3 phase 3 clinical trials in one. The first clinical trial was in PD-L1–positive patients with TPS greater than or equal to 1%, with about 1200 patients enrolled. The second part was in PD-L1– negative patients with TPS less than 1%, where they basically recapitulated the same study.
The third study part enrolled another 500 patients, which was basically nivolumab vs chemotherapy.9 That’s equivalent to KEYNOTE-024, the initial study published back in 2016 of pembrolizumab vs chemotherapy. This was a very controversial trial. First off, the chemotherapy alone vs chemotherapy plus nivolumab arms were negative. Chemotherapy performed better than chemotherapy plus nivolumab, which doesn’t make a lot of sense. In 1189 patients, PD-L1 expression was greater than or equal to 1%. This is where they studied ipilimumab [Yervoy] plus nivolumab vs chemotherapy vs nivolumab alone. The goal was to look at OS in the PD-L1–selected population, and they added a second primary end point later of PFS [progression-free survival] in TMB.9
The study was recapitulated in patients who have PD-L1 expression less than 1% with ipilimumab plus nivolumab vs chemotherapy vs nivolumab alone. One of the major controversies with the study was initially presented at the [American Association for Cancer Research meeting] by Matthew Hellmann, MD, where a subset analysis that was not prespecified, looking at TMB, was shown. It looked like across the high– and low–PD-L1 groups, a TMB greater than or equal to 15 mutations per megabase led to a better response and PFS.10 Unfortunately, that did not pan out when we look at OS. It seems like TMB selected for both chemotherapy and immunotherapy, and patients did better overall than those with low TMB. They went back to the drawing board, took out the subset analysis, and presented the updated data, including the 4-year OS rate. This regimen has had FDA approval for about a year now. The mOS of patients with PD-L1 [expression greater than 1% was 17.1 months in ipilimumab plus nivolumab vs 14.9 months in chemotherapy alone (HR, 0.76; 95% CI, 0.65-0.90)].10 There’s a crossover for the ipilimumab plus nivolumab and the chemotherapy arms. At 36 months, there is some separation in the 2 curves.
If you compare these data [with] the other studies, it didn’t look as good at months 36 and 48. Some people argue that, for the ipilimumab plus nivolumab arm, the duration of response and the PFS benefit is maintained at 4 years. Maybe there’s going to be a prolonged tail to this curve, but it’s yet to be seen. Clearly those patients who received ipilimumab plus nivolumab did better than those on chemotherapy alone, but the arm we don’t have is nivolumab plus chemotherapy, which is equivalent to the standard of care we currently have of pembrolizumab plus chemotherapy.
The mOS [rates] were quite high in the control arms. It is unclear whether this is [because of] other immunotherapies being used in the crossover setting. In the populations with PD-L1 greater than 50% or less than 1%, you tend to see a little more of a difference. In those with PD-L1 expression of greater than or equal to 50%, the HR is 0.66 [95% CI, 0.52-0.84]. If you look at nivolumab plus ipilimumab, 37% of patients are alive at 48 months or 4 years vs chemotherapy alone at 20%. In those with low PD-L1 expression, it was 24% with nivolumab-ipilimumab vs 10% with chemotherapy after 4 years. Across all studies, it [now] looks like patients with high PD-L1 expression tend to do better.10
Where this study got a lot of press was looking at some of the other studies, such as the 5-year OS rate for KEYNOTE-024. For those with PD-L1 expression greater than 50%, OS was about 30% to 35%, so 30% to 35% of patients are alive at 5 years. [At 4 years] in the PD-L1–negative population, it was 24%, which was quite high. It’s remarkable that even in a PD-L1–negative population—which we think is oftentimes refractory to immunotherapy—24% of patients are alive at 4 years.10 The HRs here are both relatively high, but it’s not comparing apples to apples; it’s comparing the high and low PD-L1 expression groups.
What are some of the AEs you’ve seen with immunotherapy, particularly ipilimumab and nivolumab?
I remember the early phase 1 studies where they were using 10 mg/kg of ipilimumab, and we were seeing very high rates of irAEs. With the current regimen of 1 mg/kg every 6 weeks, the irAEs are far lower. It is also approved in melanoma and renal cell cancers.
The fact that it’s now moving into lung cancer should make us more vigilant about these irAEs. The results published in the New England Journal of Medicine paper on grade 3 and 4 AEs showed 33% in the nivolumab plus ipilimumab arm vs 36% in the chemotherapy arm.11
If you look at what they were, there is somewhat of a difference. So 1.7% diarrhea in the nivolumab plus ipilimumab arm, which is likely immune-related diarrhea, vs the 0.7% in the chemotherapy arm. No grade 3 or 4 rash was seen with the chemotherapy-treated arm, but it was about 1.6% in the nivolumab plus ipilimumab arm. Grades 3 and 4 are significant AEs. Patients are hospitalized and have discontinued or reduced dose in their therapy.11
Grade 3 and 4 fatigue is similar in both arms at 1.7% for nivolumab plus ipilimumab vs 1.4% for chemotherapy. For grade 3 and 4 neutropenia, which is one of the major AEs of chemotherapy, there was none in the ipilimumab plus nivolumab arm vs about 9.5% in the chemotherapy arm.11
What I always think is important and interesting is when they look at what is treatment related or treatment emergent, what leads to treatment discontinuation? Always take this with a grain of salt because this is up to the investigator to decide what is treatment-related AEs [TRAEs] vs what is disease related per se.
The grade 3 and 4 TRAEs were 18% for ipilimumab plus nivolumab vs 10.7% for chemotherapy. The discontinuation rate was almost triple or double in the ipilimumab-nivolumab arm vs in the chemotherapy arm. It’s important to think about this when prescribing patients these medications.11
[For example], in someone [who] has an underlying immune history of rheumatoid arthritis, lupus, or multiple sclerosis, I would be very wary about using double immunotherapy, such as in this case, the CTLA-4 inhibitor and the PD-L1 inhibitor.
I would be wary of using a PD-L1 inhibitor alone as well, but I think there are some more data to support that and to manage our patients. Overall, it looks like the irAEs are slightly higher in the ipilimumab plus nivolumab arm vs in the chemotherapy arm.11
1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 6. Accessed October 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. Reck M, Rodríguez-Abreu D, Robinson AG, et al. 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
4. 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
5. 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). doi:10.1200/JCO.2018.36.18_suppl.LBA4
6. 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
7. Socinski MA, Jotte R, 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
8. 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
9. 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
10. Paz-Ares LG, Ciuleanu TE, Lee JS, et al. Nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (NSCLC): 4-year update from CheckMate 227. J Clin Oncol. 2021;39(suppl 15):9016. doi:10.1200/JCO.2021.39.15_suppl.9016
11. 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