A 59-year-old White male presented with chest pain, cough, and dyspnea and an image-guided biopsy revealed poorly differentiated adenocarcinoma of the lung.
During a Targeted OncologyTM Case-Based Roundtable event, D. Ross Camidge, MD, PhD, professor, Medicine–Medical Oncology, Joyce Zeff Chair in Lung Cancer Research, University of Colorado Denver School of Medicine, discussed a 59-yea-old patient with non–small cell lung cancer (NSCLC).
Targeted OncologyTM: What data do you consider when choosing a regimen to treat a patient like this?
CAMIDGE: The NCCN [National Comprehensive Cancer Network] guidelines [list chemotherapy with carboplatin or cisplatin plus pemetrexed (Alimta) plus pembrolizumab (Keytruda) as the preferred first-line therapy for NSCLC (non–small cell lung cancer)].1 But the other regimen that has category 1 data is the IMpower150 [NCT02366143] regimen [carboplatin plus atezolizumab (Tecentriq) plus bevacizumab (Avastin)].2,3 NCCN also lists carboplatin plus nab-paclitaxel plus atezolizumab.1 I don’t quite know why you would use that in an adenocarcinoma. Then there’s the 2 ipilimumab [Yervoy]/nivolumab [Opdivo] regimens.4,5 There’s ipilimumab plus nivolumab alone, [which the NCCN lists as a category 1 regimen that is useful in certain circumstances].1 And then there’s ipilimumab plus nivolumab and 2 cycles of platinum plus pemetrexed, that’s the CheckMate 9LA [NCT03215706] regimen, which NCCN considers as one of the other recommended category 1 regimens.4,5 Finally, you have pembrolizumab monotherapy, [which is a category 2B regimen that the NCCN lists as useful in certain circumstances].1 But the pembrolizumab data for those that have PD-L1 less than 50% hardly blows you away.6,7
[Let’s go through] everybody’s favorite, the KEYNOTE-189 trial [NCT02578680] that compared platinum chemotherapy plus pemetrexed plus pembrolizumab with platinum chemotherapy plus pemetrexed plus placebo.6,7 Eligibility criteria were as follows: untreated stage IIIb or IV nonsquamous NSCLC, no activating EGFR [mutation] or ALK [translocation], [PD-L1 sample, ECOG performance status 0 or 1, no interstitial lung disease or pneumonitis requiring systemic steroids], and brain metastases had to be treated to get [into the study]. One of the things about all immunotherapy is that the data set in brain metastases is pretty slim. The data for pembrolizumab monotherapy are what you might expect with any immune monotherapy, you have about a 20% response rate. For me, that is not high enough that I would feel comfortable allowing a patient with brain metastases a 20% chance of response. I’d still irradiate.
Patients received the treatment regimen or the control regimen every 3 weeks for 4 cycles [followed by] pemetrexed plus pembrolizumab maintenance, or just pemetrexed maintenance.6,7 The primary end points were OS [overall survival] and progression-free survival [PFS]. The OS at 12 months was 70% [in the treatment arm], and 48% in the control arm [HR, 0.56; 95% CI, 0.45-0.70].7 The 24-month OS, and these patients received subsequent therapies, was 45% [in the treatment arm] and 30% [in the control arm]. Now, the PFS showed a significant advantage for [those with a] PD-L1 TPS [tumor proportion score] of 1% to 49% [HR, 0.62; 95% CI, 0.42-0.92], greater than or equal to 50% [HR, 0.59; 95% CI, 0.39-0.88], but not for less than 1% [HR, 0.52; 95% CI, 0.36-0.74]. But the OS was positive in all three subgroups.
If you had a patient who had TPS greater than or equal to 50%, who gives pembrolizumab monotherapy and who gives the carboplatin, pemetrexed, pembrolizumab [regimen]?
FAHED: I gave chemotherapy once [when the] patient was very symptomatic.
CAMIDGE: You would prioritize the chemotherapy/IO [immunotherapy] based on symptoms?
FAHED: Yes, my go-to is single-agent IO, except when I had 1 patient who was really symptomatic and on oxygen. I didn’t want to take a chance on that; I wanted to increase response rates as much as possible.
CAMIDGE: I think that’s fair. Dr Rana, what do you do?
RANA: I would say a similar practice as Dr Fahed. Most of the time, if a patient is not that symptomatic, I prefer using IO alone. But, if the disease burden is quite high and we need response quickly, then I would add chemotherapy. But that would be a small subset of population, young patient with heavy disease burden.
CAMIDGE: Given that even with high PD-L1, the response rate is running only about 50%. When do you scan, given there’s a 50:50 chance that they could derive no benefit if you just gave pembrolizumab monotherapy? Do [you] scan early or scan late?
RANA: I prefer to wait for at least 4 cycles, until the patient is clinically deteriorating in front of my eyes.
SORIANO: I usually do it after 3 [cycles], because I think 6 weeks is just a little too early to see a response.
IRUKU: I wait around 3 cycles because the median time to response is around 1 to 1.5 months. So, 3 cycles, approximately.
CAMIDGE: I’ll tell you what I do, which doesn’t make it right, it’s just what I do. I go into it with the idea that there’s about a 50% chance that they won’t respond. The responses I’ve seen, at least most of the responses, happened on the first assessment, which in the study was done at 6 weeks. So, I scan after 2 cycles, like every other chemotherapy [regimen], and with the goal that if the [tumor is] not shrinking, I am bailing out and adding in chemotherapy.
What are the data for other regimens in patients with different levels of PD-L1 expression?
CAMIDGE: In KEYNOTE-042 [NCT02220894] they allowed in people [with a PD-L1 expression] greater than or equal to 1%, as opposed to greater than or equal to 50%.8,9 The OS was presented as greater than or equal to 50%, greater than or equal to 20%, and greater than or equal to 1%. So, they were [likely thinking], “We’re going to get something that’s positive one way or another.” But, greater than or equal to 1% contains greater than or equal to 20% and contains greater than or equal to 50%. They had a survival advantage that was statistically significant in everything from 1% and above. But in those that were in the 1%-49% [group], it was not significant [HR, 0.92; 95% CI, 0.77- 1.77]. Most of that benefit [they presented] was being driven by those with a high PD-L1. This comes back to the idea [that] you have to look at the data, and not just the headline. I think [the regimen in] KEYNOTE-042 is for when you have no other option.
In the IMpower150 study they [compared 3 different regimens].2,3 Arm A was atezolizumab plus carboplatin plus paclitaxel [ACP], arm B was atezolizumab plus bevacizumab plus carboplatin plus paclitaxel [ABCP] and arm C was the control arm with BCP only]. Most of the focus was on arm B vs arm C. It was a positive study. At 12 months [the OS for the ABCP regimen was] 67.3% and it was 60.6% for BCP; at 24 months it was 43.4% and 33. 7% [stratified HR for death, 0.78; 95% CI, 0.64-0.96; P = .02]. Very similar to what we saw with KEYNOTE-189 and nothing to suggest it’s better. It certainly brings more cost and more toxicity.
[The IMpower150 study] included people with EGFR and ALK abnormalities.2,3 There weren’t many, but that became more of its dominant story, although it [has] nothing to do with its [approval] by the FDA.2,3,10,11 There were 700-odd patients in this study; the EGFR and ALK [subgroup was] about 60 or 80 patients across [arms B and C]. Once you get down to subgroups, you don’t know that they’re balanced in terms of other things; they’re not stratified, at that level. The EGFR data appeared to show an improvement, enough that it was included in the EMA [European Medicines Agency] label, but not in the FDA label.11,12 The ALK data [have] only ever appeared in oral presentations, it has never appeared in print. My guess is it never got past the reviewers in a journal. So, I think it’s provocative, I think one really wants to wait and see whether that’s going to be confirmed in later studies.
FAHED: In the EGFR [population], you think the benefit is mainly driven by bevacizumab?
CAMIDGE: Well, bevacizumab was in both arms, so I don’t know. My impression is that there is a subgroup of patients with EGFR [mutations] who respond to immunotherapy, but it is by no means all. Back in the days when we had immune monotherapy, it was easier to pull apart. But you would get patients who had a smoking history and had an EGFR mutation or had an EGFR mutation and had huge levels of PD-L1. There was a suggestion that those were the ones who were responding. So, I wouldn’t rule it out, but I don’t know that we can take that benefit as uniform in all patients with EGFR [mutations].
The issue for me is when I get to the chemotherapy aspect, if I have a patient with an EGFR [mutation] and I’ve run out of TKI [tyrosine kinase inhibitor] options, I have to [use] chemotherapy. For me the big question is: Do I give any kind of chemoimmunotherapy and stop the TKI? You have to stop the TKI because it doesn’t interact well with the immunotherapy. Or do I not give the immunotherapy because the benefit’s not that great, and I keep the TKI going, for example, to continue central nervous system protection. Those studies are going to go on and we’ll be able to answer that. In my own practice here, I would say we were split 50:50. So, I tended to not give immunotherapy and keep the TKI going. Other colleagues would give the IMpower150 [regimen] and stop the TKI. I don’t know which is the right answer.
FAHED: The answer is to get a good EGFR inhibitor, like a newer generation.
CAMIDGE: Yes. So, [let’s discuss] CheckMate 227 [NCT02477826].13-15 They got rid of EGFR and ALK to go in, they subdivided [based on] PD-L1 expression, and with 3 arms in each 1. In those who had [greater than or equal to 1%] PD-L1 expression, investigators gave nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy alone. In those with PD-L1 [expression less than 1%, the arms were nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone.] So, they didn’t do a nivolumab alone arm if there was less than 1% PD-L1.
The OS benefit of nivolumab plus ipilimumab was much more marked than with chemotherapy in those who had high PD-L1 [HR, 0.79; 95% CI 0.67-0.93].14,15 And technically, it wasn’t statistically significant in those with [PD-L1 expression of] 1% to 49%. So, I don’t think nivolumab plus ipilimumab is a game changer as an immune [monotherapy] option, other than the [in the patients that] I’d be giving chemoimmunotherapy to.
What are the adverse events (AEs) most associated with nivolumab plus ipilimumab, and how does this affect your choice of treatment?
CAMIDGE: [They compared AEs with nivolumab plus ipilimumab] vs chemotherapy.14 It was a range of different histology-specific chemotherapies. [There were] 76% to 77% on ipilimumab having any treatment-related toxicities, and 33% having grade 3 or 4. It’s not a walk in the park. Treatment-related AEs [at grade 3 or 4] leading to discontinuation were higher with nivolumab plus ipilimumab at 12% than with chemotherapy at [4.9%]. The more ipilimumab you give, the more the toxicity. But they had different [ipilimumab dosing] regimes for small cell lung cancer, NSCLC, and other [cancers]. So, it really was a bit of a messaging problem.
In terms of messaging by a company, it was a complex study that drip-fed information [over time] and they had different dosing regimens for different tumor types. And then, they added insult to injury by saying “I know we told you [to] use an immunotherapy alone regimen, and that was our market. But, by the way, here it is with chemotherapy.” So the left hand and the right hand were saying different things. CheckMate 9LA was essentially chemotherapy-lite, with zero evidence.16,17 They just said, “Well, we’re just going to give 2 cycles of chemotherapy.” But we’re talking platinum plus pemetrexed, and so it’s not that toxic. Would anyone use the [CheckMate] 9LA regimen?
FAHED: This has a benefit of only 2 cycles of chemotherapy.
CAMIDGE: But is that a benefit?
FAHED: If you have similar numbers at 12 months, really hard to compare those cross-studies, but let’s assume we have the same benefit. Which one is a better regimen?
CAMIDGE: Yes. I guess you could say you save the cost of 2 cycles of chemotherapy, and the toxicity, maybe. Is that your argument?
FAHED: That’s one argument.
CAMIDGE: Would that sway you, in the community, to do that?
FAHED: Well, it didn’t yet, but I’m open to the idea.
CAMIDGE: Yes. It’s like if the patient is usually either fit enough or [they are not fit enough] when they walk through the door. It’s not that it changes during but that would be an example.
FAHED: Honestly, theoretically, what matters more than anything else to me is that plateau. Does ipilimumab add to the plateau?
CAMIDGE: We don’t know. One of the things that they’ve tended to show, which I think is a little misleading, is they show a curve which is duration of response. Of course, any pure immune response tends to be very long-lived. So they show this thing with a fantastically high duration of response for nivolumab plus ipilimumab, which is much lower for a nivolumab plus chemotherapy combination. That’s partly because some of the nivolumab/ chemotherapy responses are chemotherapy responses. But then, you have to look down in the footnote, and you go, “Well, what’s the response rate?” It’s 20-30% with nivolumab plus ipilimumab, and it’s 60% with nivolumab plus chemotherapy.16,17
One of the things they really pushed was the PD-L1 less than 1%, and they also pushed that for the nivolumab plus ipilimumab, which was not part of the [FDA approval].16-18 Certainly, you have some people who’d say, “Well, if you have PD-L1 less than 1%, I’m going to use nivolumab plus ipilimumab or 9LA.” But show me the data. Show me the head-to-head against KEYNOTE-189 in that population, and we just don’t have that.
The toxicity of nivolumab plus ipilimumab plus chemotherapy it’s more than with carboplatin plus pemetrexed plus pembrolizumab in KEYNOTE-189 because it’s got ipilimumab in there.7,16,17 It’s slightly less, I guess, because you only have 2 cycles of chemotherapy, not 3 cycles. The things that are mostly different are the myelosuppression. But when you get down to the AEs that are more immune, then obviously they’re much more with the nivolumab plus ipilimumab.17
1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2021. Accessed July 30, 2021.https://bit.ly/3fCWQjp
2. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. Accessed July 30, 2021. doi:10.1056/NEJMoa1716948
3. 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. Accessed July 30, 2021. doi:10.1200/JCO.2018.36.15_suppl.9002
3. 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. Accessed August 3, 2021. doi:10.1200/JCO.2020.38.15_suppl.9501
4. 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. doi:10.1016/S1470-2045(20)30641-0
5. 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. Accessed August 3, 2021. doi:10.1056/NEJMoa1801005
6. 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. Accessed August 3, 2021. J Clin Oncol. 2020;38(14):1505-1517. doi:10.1200/JCO.19.03136
7. 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). Accessed August 4, 2021. doi:10.1200/JCO.2018.36.18_suppl.LBA4
8. 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. Accessed August 4, 2021. doi:10.1016/S0140-6736(18)32409-7
9. FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression. FDA. News release. FDA Drug Approvals and Databases. May 18, 2020. Accessed August 4, 2021. https://bit.ly/2HNJx1U
10. Tecentriq. Prescribing information. Genentech, Inc; 2021. Accessed August 4, 2021. https://bit.ly/2TZFHZJ
11. Tecentriq. Product information. Roche Pharma AG; 2021. Accessed August 4, 2021. https://www.ema.europa.eu/en/documents/product-information/tecentriq-epar-product-information_en.pdf
12. 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. Accessed August 4, 2021. doi:10.1056/NEJMoa1801946
13. 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. Accessed August 4, 2021. doi:10.1056/NEJMoa1910231
14. Ramalingam SS, Ciuleanu TE, Pluzanski 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. Accessed August 4, 2021. doi:10.1200/JCO.2020.38.15_suppl.9500
15. 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. Accessed August 4, 2021. doi:10.1016/S1470-2045(20)30641-0
16. Reck M, Ciuleanu TE, Dols MC, 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. Abstract presented at: the 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-31, 2020. Accessed August 4, 2021. doi:10.1200/JCO.2020.38.15_suppl.9501
17. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. News release. FDA Drug Approvals and Databases. May 27, 2020. Accessed August 4, 2021. https://bit.ly/35tnarl