During a Targeted Oncology Case-Based Roundtable event, Mark A. Socinski, MD, discussed the case of a 59-year-old patients with non–small cell lung cancer.
During a Targeted Oncology Case-Based Roundtable event, Mark A. Socinski, MD, the executive medical director, AdventHealth Cancer Institute member, Thoracic Oncology Program in Orlando, FL, discussed the case of a 59-year-old patients with non–small cell lung cancer (NSCLC).
Targeted OncologyTM: What type of molecular testing would you obtain in a patient such as this?
SOCINSKI: A review of the NCCN [National Comprehensive Cancer Network]1 recommendations shows a…list of molecular alterations. There are 7 of them to date that have an FDA-approved drug. It’s hard to think of doing one-off testing for all of these even though some of them may have an FDA-approved companion diagnostic. The NCCN recommends broad molecular testing, which is essentially NGS [next-generation sequencing]. Whoever you’re using for broad molecular testing is doing both DNA- and RNA-based testing because you can miss some of the fusions with just DNA testing. PD-L1 testing also is part of it and because it’s a single slide and it’s IHC, it shouldn’t be a big deal. The broad-spectrum NGS approach is recommended as it minimizes tissue use and identifies the rare drivers. What our hope as oncologists is [is to get] the right treatment to the right patient at the right time.
I believe the NCCN is a little soft on the repeat biopsy or plasma testing. I haven’t [often] run into the reimbursement issues and if I have, it’s been solved relatively quickly with no disadvantage to my patients, and that’s happened on a couple of occasions. I do both of them because I think it’s clear that we find some things in blood we don’t find in tissue and we find some things in tissue we don’t find in blood. They suggest [repeat biopsy testing] if you have insufficient tissue, but you may wait 3 weeks. So this is one of my rationales for using blood[-based testing].
What would be your preferred regimen recommendation for this patient?
The NCCN guidelines recommend the preferred first-line therapy as carboplatin, pemetrexed [Alimta], and pembrolizumab [Keytruda]. Other recommended [regimens] include carboplatin/nab-paclitaxel [Abraxane] and regimens with bevacizumab [Avastin]. One regimen they didn’t include is the nivolumab/ipilimumab [Opdivo/Yervoy] plus 2 cycles of chemotherapy. In this setting, pembrolizumab is a category 2B recommendation and all the others are category 1 recommendations.1
KEYNOTE-189 [NCT02578680] is a [phase 3 study of platinum therapy plus pemetrexed chemotherapy with or without pembrolizumab in patients with first-line metastatic nonsquamous non–small cell lung cancer (NSCLC). Key eligibility criteria were] first-line treatment of [stage] IIIB to IV [nonsquamous NSCLC], no activating EGFR or ALK translocation, PD-L1 status, good ECOG performance status, no untreated brain metastases, and no interstitial lung disease or pneumonitis requiring steroids. The trial simply added pembrolizumab to carboplatin/pemetrexed, including during the maintenance phase.2
The population had a median follow-up of about 2 years. The median overall survival [OS] was [22.0 months in the pembrolizumab-combination arm versus 10.7 months in the placebo-combination arm; HR, 0.56; 95% CI, 0.45-0.70]. Of note in this trial, in my opinion, the control arm did relatively less well than expected. For carboplatin/pemetrexed, 10.7 months is low in this population. The addition of pembrolizumab makes it 22 months, with a hazard ratio of 0.56, so [there is] almost a 50% risk reduction in death with pembrolizumab.3
Regardless of PD-L1 status, the hazard ratios are pretty similar across the 3 subgroups [TPS < 1%, TPS 1%-49%, TPS ≥ 50%]. So PD-L1 expression really doesn’t differentiate the treatment in this setting.3
What other regimens can be used and in which patient populations?
The other regimens are in the NCCN guidelines [and various clinical trials]. For IMpower150 [NCT02366143], you had to be bevacizumab eligible. That is a different population than was included in the KEYNOTE-189 trial.
Pemetrexed may not be ideal for certain patients such as those with borderline creatinine clearances. Carboplatin/nab-paclitaxel does have a role here based on IMpower130 [NCT02367781]. Nivolumab/ipilimumab plus chemotherapy [carboplatin or cisplatin, pemetrexed] is the CheckMate 9LA trial [NCT03215706] regimen, and then nivolumab/ipilimumab by itself was investigated in the CheckMate 227 trial [NCT02477826]. The NCCN guidelines regimens are useful in certain circumstances. Pembrolizumab alone in KEYNOTE-042 [NCT02220894] is useful in certain circumstances.1
KEYNOTE-042 is a follow-up study of KEYNOTE-024 [NCT02142738], which was done in the high expressors [of a PD-L1 TPS] greater than 50%. It showed an advantage to pembrolizumab in the population [with a PD-L1 TPS] greater than 1%. Pembrolizumab was compared head-to-head with carboplatin and then paclitaxel. Almost 50% of the patients in this trial had a PD-L1 [expression] greater than 50%.4,5
[In KEYNOTE-042], the OS of the various PD-L1 cutoff points of greater than 50%, greater than 20%, and greater than 1% [showed an advantage with pembrolizumab], but this might have been driven more by the high expressors that were nearly 50% of this population. [However, the pembrolizumab arm] doesn’t do as well for the first 6 months as the [chemotherapy arm (carboplatin, paclitaxel, pemetrexed)].
There’s an early disadvantage for immunotherapy, and then there’s a late advantage. The issue I have in my clinic is people that are getting immunotherapy by itself without chemotherapy are dying sooner than [those receiving] chemotherapy alone. With the chemotherapy plus immunotherapy population, we don’t see that early disadvantage.4,5
How did PD-L1 status and mutational status play a role in these trials?
One of the questions we had from KEYNOTE-042 was about the [OS of the population with a PD-L1 TPS of 1%-49%]. This was negative when an exploratory analysis was done, which was not part of the original statistical plan. In the 1%-49% [population, there was an] early disadvantage for the immunotherapy group for almost a year. So there are some issues here regarding immunotherapy alone.4,5
For IMpower150, there are preclinical data suggesting that heightened states of VEGF are very immunosuppressive. That was part of the rationale for looking at adding immunotherapy to bevacizumab. The control arm was the winner of the ECOG 4599 [trial]—carboplatin, paclitaxel, bevacizumab, an FDA-approved regimen. IMpower150 either added atezolizumab to the 3-drug regimen or substituted atezolizumab for bevacizumab in [experimental] arm A. The primary analysis, which was the first statistical plan, was to compare [experimental] arm B with [comparator] arm C.6 The IMpower150 trial did meet its primary end point in OS, with a hazard ratio of 0.78 [95% CI, 0.64-0.96; P = .02], for arm B versus arm C.6,7
CheckMate 227 looked at the nivolumab/ipilimumab combination. Again, this was a large trial. It divided patients into 2 subsets based on PD-L1 expression, PD-L1 positive and PD-L1 negative. The primary end point was OS in the PD-L1–positive population [≥ 1% expression]. The comparison was of histology-based chemotherapy, whether one had squamous or nonsquamous [NSCLC], chemotherapy was dictated by that—nivolumab alone versus nivolumab/ipilimumab, using 1 mg/kg every 6 weeks for ipilimumab. For the comparison in the PD-L1– negative [group (< 1% expression)], it was histology-based chemotherapy versus adding nivolumab to chemotherapy, or the nivolumab/ipilimumab combination.8,9
In the PD-L1–positive population, [investigators compared OS for nivolumab/ipilimumab versus chemotherapy alone]. By the time we heard about this trial, no one was using chemotherapy alone as the standard of care. The nivolumab/ipilimumab group had an early disadvantage compared with the chemotherapy-only group of around 6 months [HR, 0.79; 95% CI, 0.67-0.93].9,10
In the randomized groups with the PD-L1–negative and the PD-L1–positive [population,] there’s a suggestion that maybe the nivolumab/ipilimumab performed a little bit better in the PD-L1–negative population.…Additional exploratory subgroup analyses looked at the population with a TPS of 1% to 49% and those with greater than or equal to 50%; the hazard ratio wasn’t very impressive in those with a TPS of 1% to 49% [HR, 0.94; 95% CI, 0.75-1.18]. Nivolumab/ipilimumab works better in the patients [with negative PD-L1 expression], but also it works better in the highly positive patients, so I’m not quite sure how to interpret these subset analyses.9
For toxicity, we have a fair amount of experience with nivolumab/ipilimumab. There were no surprises in this trial, although treatment-related serious adverse events [AEs] and treatment-related AEs that led to drug discontinuation were higher in the nivolumab/ipilimumab arm compared with the chemotherapy alone arm.9
What other trials looked at nivolumab/ipilimumab in this setting?
CheckMate 9LA took a slightly different approach. They again had the chemotherapy alone as the control arm, which is not the standard of care. They had 2 cycles of chemotherapy with the nivolumab/ipilimumab in a similar population to [CheckMate 227].11,12
OS was the [primary] end point. Compared with chemotherapy alone and chemotherapy with nivolumab/ipilimumab, we don’t see an early disadvantage with the nivolumab/ipilimumab like we saw with CheckMate 227. The hazard ratio here was a bit better [HR, 0.66; 95% CI, 0.55-0.88].11,12
Regardless of PD-L1 status, whether it was negative, positive, 1% to 49%, or greater than 50%, all the hazard ratios seem to be about the same.11,12
For safety, it was [similar to] CheckMate 227 regarding nivolumab/ipilimumab plus the chemotherapy. One of the things we’ve learned about immunotherapy is that you don’t change the toxicity of chemotherapy by adding immunotherapy to it and you don’t change the toxicity of immunotherapy by adding chemotherapy to it. Because you’re using more drugs, you’re at risk of having more toxicity. But there were no surprises. The majority of treatment-related select AEs were probably immune\ related—skin, endocrine, gastrointestinal, hepatic, nephritis, pneumonitis, and some hypersensitivity reactions—so no big surprises from a safety point of view.11,12
[The FDA approved nivolumab/ipilimumab for use] in the PD-L1–positive population based on the CheckMate 227 data in the first-line setting and then nivolumab/ipilimumab with chemotherapy in all [regardless of PD-L1 status].13,14
Would you change treatment in this patient, and, if so, what second-line therapy would you use?
The REVEL trial [NCT01168973] took patients who needed second-line therapy, [including those with] prior use of bevacizumab, then simply grafted ramucirumab on to docetaxel at the standard FDA dose of 75 mg every 3 weeks.
The [ramucirumab/docetaxel experimental arm] showed a modest benefit in median OS [HR, 0.86; 95% CI, 0.75- 0.98; P = .02] and median progression-free survival [PFS; HR, 0.76; 95 % CI, 0.68-0.86; P < .0001] and also in not quite a doubling of the [overall] response rate [ORR; odds ratio, 1.89; 95% CI, 1.41-2.54; P < .0001]. This trial met the triple end points of OS, PFS, and ORR. There is a relatively modest benefit from the addition of ramucirumab to docetaxel.15
Reck et al led an analysis looking at various subgroups [including] patients with aggressive or rapidly progressing disease.16 They divided patients into those who remained on first-line therapy for 4 weeks or less, 8 weeks or less, and 12 weeks or less. This [did not include those with prior] immunotherapy.
The whole point of the analyses was that whether you progressed earlier or later, the benefit of docetaxel seemed to be about the same in all the subsets. Maybe in the true progressors the benefit was a little better in those patients who progressed early in this setting, but certainly there is no reason not to use docetaxel in patients with rapid progression on their first-line regimen.
Safety outcomes were not different between the 2 arms of the trial with regard to treatment-related dose adjustment or treatment-related AEs leading to death. Serious AEs were roughly similar between the 2 arms.15,16
1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 4.2021. Accessed May 20, 2021. https://bit.ly/3f3DJ28
2. Gandhi L, Rodr guez-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, Rodr guez-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/NEJMoa17169488
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, 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. 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
12. 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
13. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. Updated May 27, 2020. Accessed December 21, 2020. https://bit.ly/35tnarl
14. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥ 1%). FDA. May 5, 2020. Accessed May 20, 2021. https://bit.ly/33YFhUR
15. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. doi:10.1016/S0140-6736(14)60845-X
16. Reck M, Paz-Ares L, Bidoli P, et al. Outcomes in patients with aggressive or refractory disease from REVEL: a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV nonsmall- cell lung cancer. Lung Cancer. 2017;112:181-187. doi:10.1016/j.lungcan.2017.07.038