Roundtable Discussion: Fidler Breaks Down the Steps for Targeted Treatments in Metastatic NSCLC

Case-Based Roundtable Meetings Spotlight, Case-Based Roundtable Meetings Spotlight December 1, 2021,

Oncologists discuss a 59-year-old man with poorly differentiated adenocarcinoma of the lung.

During a Targeted OncologyTM Case-Based Roundtable event, Mary Jo Fidler, MD, associate professor, Division of Hematology, Oncology, and Cell Therapy, Rush Medical College, discussed a 59-year-old man with non–small cell lung cancer.

SHAH: I do next-generation sequencing [NGS] with FoundationOne CDx, as well as a Guardant [Health] liquid biopsy prior to initiating treatment.

FIDLER: [Does] anyone else use both liquid biopsy and tissue biopsy at the same time?

KAPLAN: Yes, I also do both at the same time, [using] Guardant liquid biopsy and then usually Caris [Life Sciences], unless an in-house [biopsy is] done. We’ll do them simultaneously and usually get the [results of the] liquid biopsy first so we can see if there’s an actionable mutation within a shorter period.

KOKO: Usually, if the tissue is available, I will do FoundationOne testing with the tissue. I will only do the liquid biopsy if there is no tissue available. If I’m thinking of the second line, then [I am more likely to] do liquid [testing]. But I don’t do [both] combined.

FIDLER: The National Comprehensive Cancer Network [NCCN] guidelines recommend broad-based testing like everyone [here] is doing. I feel like these guidelines are evolving; [they now include molecular testing for] KRAS, EGFR, ALK, ROS1, BRAF, RET, and NTRK1/2/3 mutations and MET exon 14 skipping. The recommendation is that testing should be [conducted as part of] a broad molecular panel and also include PD-L1 plasma testing.1

In this case, we already have [immunohistochemical] PD-L1 testing, but we know that plasma testing can [also] be done. We learned [from data presented] 2 years ago that whether the driver [mutation] was found in the plasma or in the tissue, it was equally actionable. [For a significant] percentage of the time, it was found only in the blood and not in the tissue, and vice versa.2 Especially for [patients for whom] I have high suspicion, I do both tests.

It sounds like most of us are using the next-generation panel; FoundationOne has this capability and we use Tempus quite a bit. However, to capture as many fusions as possible, [using an] RNA sequencing platform as part of the test is a little better. RNA sequencing can test for large fusions that can be missed by DNA sequencing; [in particular,] NTRK2 and NTRK3 [fusions] and some ALK and ROS1 fusions can be missed by DNA [sequencing]. I’ve had times where I’ve had to order repeat biopsies, especially in patients with no nicotine dependence.

There was a presentation at [the] American Society of Clinical Oncology [(ASCO) Annual Meeting] this year, showing that testing for all these markers isn’t [very] common; there’s room for improvement. In a large community network [study, supported by electronic medical record] data, only about 50% of people with a diagnosis of stage IV nonsquamous cell carcinoma had [testing] for all 5 markers recommended at the time.3 There were also data at ASCO suggesting that if patients had NGS, they were more likely to enroll in clinical trials,4 and also data showing that African American patients were less likely to have NGS testing.5

RAMADAS: Did Oncotype develop an NGS [test] for lung or only for breast [cancer]?

FIDLER: There is a similar test that Medicare is paying for now, but it’s not called Oncotype. I think it’s called Oncocyte. It’s an Oncotype-like [test] for lung [cancer], looking at early-stage tumors. The [number] of patients used to create and validate the test wasn’t large; I don’t know if it’s quite ready for [mainstream use].6

KAPLAN: Also, they don’t test [for] EGFR in the early stage [in which there might be] benefit from the osimertinib mesylate [Tagrisso] adjuvant.

FIDLER: Yes. It’s a good point that we should probably be testing in the [neo]adjuvant setting [for] EGFR, but I’m recommending that for all patients [with disease stage] IB and above. We may have immunotherapy approved too; the benefit for atezolizumab [Tecentriq] post operation seemed more focused on patients with PD-L1 expression.7 More data are coming out [regarding] the combination of chemotherapy plus immunotherapy, [suggesting that PD-L1 expression could be] useful in identifying 25% of pathological complete responses. We don’t yet know about overall survival and progression-free survival [PFS] results.8

FIDLER: The combination of carboplatin, nab-paclitaxel [Abraxane], and atezolizumab is FDA approved. Interestingly, the regimen did not meet the end point in [patients with squamous non–small cell lung cancer (NSCLC) in IMpower130 (NCT02367781)], but it is an FDA-approved choice [for patients with nonsquamous NSCLC].9,10 I use quite a bit of the carboplatin, pemetrexed [Alimta], plus pembrolizumab [Keytruda] combination. I think what’s left for us to figure out is how to incorporate nivolumab [Opdivo] and ipilimumab [Yervoy]. That [combination is] FDA approved for PD-L1–positive NSCLC.11 I would not start with single-agent pembrolizumab.

[According to the NCCN guidelines], there are quite a few treatment options for NSCLC with PD-L1 expression that ranges from at least 1% to 49%. The preferred regimen is pemetrexed and pembrolizumab plus either carboplatin or cisplatin. Another category 1 regimen is the quadruplet with carboplatin, paclitaxel, bevacizumab [Avastin], and atezolizumab. The combination of carboplatin, nab-paclitaxel, and atezolizumab [is also recommended].1 The [regimen studied in] CheckMate 9LA [(NCT03215706), nivolumab, ipilimumab, plus platinum chemotherapy and pemetrexed,] is also listed. Additionally, nivolumab and ipilimumab [used as a stand-alone combination] is listed as “useful in certain circumstances” and is supported by category 1 data.1

TAJUDDIN: Could you describe how you pick 1 option over the other?

FIDLER: [In my] experience, the carboplatin, pemetrexed, and pembrolizumab combination is very well tolerated. I used nivolumab plus ipilimumab when the approval came out [for that combination]11 for people who really didn’t want to have chemotherapy [and who] also weren’t necessarily the best chemotherapy candidates. I did not [find] that the nivolumab and ipilimumab combination was any easier [on patients] than was the carboplatin, pemetrexed, and pembrolizumab combination. I do like the choice of the nab-paclitaxel [combination], because patients who are fit for chemotherapy but have renal dysfunction cannot get the pemetrexed, so it’s still less than the platinum doublet plus an immune checkpoint inhibitor.12 I, ultimately, base [my choice] on the adverse event [AE] profile.

TAJUDDIN: Usually, I pick the carboplatin, pemetrexed, and pembrolizumab combination because we have been [using] it longer and have more experience [with it].

RICH: Do you think there’s a role for bevacizumab if [a patient is] immunotherapy eligible?

FIDLER: I do. The IMpower150 study [NCT02366143]13,14 was the only large phase 3 trial that included patients with a history of driver mutations. There are good preclinical data to suggest synergy [between] antiangiogenic drugs (like bevacizumab) and immune checkpoint inhibitors, so I think there is a rationale to combine [bevacizumab with immunotherapy]. Paclitaxel is usually not as palatable as carbo[platin] plus [pembrolizumab because of accompanying] neuropathy and hair loss, but I do [discuss] it with patients who have driver mutations and need to switch from their tyrosine kinase inhibitors.

FIDLER: I have [used a single-agent immune checkpoint inhibitor], rarely, for [patients with] low PD-L1 expression.

The NCCN guidelines, [as mentioned, recommend several different regimens] for patients with PD-L1 expression that ranges from at least 1% to 49% [in the context of] nonsquamous [disease].1 [These include] single-agent pembrolizumab, which was based on category 2B data from the KEYNOTE-042 study [NCT02220894]. This was a randomized 1:1 trial in patients who had a TPS [tumor proportion score] of greater than or equal to 1%, and the [treatments were] pembrolizumab vs carboplatin plus paclitaxel or carboplatin plus pemetrexed for [patients with nonsquamous disease].11,12

The primary end point was overall survival [OS] in cohorts [defined by TPS] as greater than or equal to 50%, greater than or equal to 20%, and greater than or equal to 1%.

The cohort defined by a TPS of greater than or equal to 1% and the whole trial population [showed that], technically, this was a positive trial with respect to median OS in the experimental arm vs the control arm at 16.7 months vs 12.1 months, respectively [HR, 0.81; 95% CI, 0.71-0.93; P = .0018]. However, it appears that most of the benefit was in the cohort with [the highest] PD-L1 expression and OS at 20 months vs 12.22 months, respectively [HR, 0.69; 95% CI, 0.56-0.85; P = .0003].

In an analysis of patients similar to the one we are discussing here [with a TPS of 1% to 49%], there was not a great difference between the arms. One could argue that the benefit of pembrolizumab may be like that of chemotherapy alone for patients with low PD-L1 expression, [so it is] probably not the best treatment. The [survival] curves do cross, suggesting that some patients may get sicker more quickly [when treated with] single-agent pembrolizumab vs chemotherapy.

FIDLER: For the patients in the KEYNOTE-189 study [NCT02578680], if you’re doing maintenance with pembrolizumab plus pemetrexed and somebody is having an AE, which [drug] ends up getting pulled off first?

KAPLAN: It depends on the [AEs]. If it’s an immune [-related AE, I stop] the immuno-oncology agent [IO]. But usually [I need to stop] the chemotherapy [pemetrexed].15,16 I think I would stop the chemo before the IO unless it was an IO-related toxicity.

KAPLAN: We’ve had patients [who have been] on pembrolizumab and other IOs for months or even years and who are doing incredibly well. When to stop, I think, is more difficult [to determine] than how long to [continue]. If the patient is doing well and is tolerating [the regimen], you keep going.

Some of the [regimens] that [have to be discontinued because of] toxicity tend to [still] add benefit for a while [after they have been discontinued] because the patient just had a better immune response. I do know of patients who had to be put on steroids and who continued on low-dose steroids but who then went back to the IO, and some of them are still doing well. Every person is individual.

STANKIEWICZ: I try to keep [patients on maintenance] until it works, basically, unless there are toxicities. I have a patient [with] squamous [disease] who has been [on] single-agent nivolumab for the past 3 to 4 years and is doing very well.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 7.2021. Accessed November 3, 2021. https://bit.ly/3HjNx4f

2. FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression. FDA. May 18, 2020. Accessed November 7, 2021. https://bit. ly/3CbRVhC

3. FDA approves atezolizumab with nab-paclitaxel and carboplatin for metastatic NSCLC without EGFR/ALK aberrations. FDA. Updated December 5, 2019. Accessed November 4, 2021. https://bit.ly/3c5C5KS

4. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):924-937. doi:10.1016/S1470-2045(19)30167-6

5. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. May 15, 2020. Accessed November 8, 2021. https://bit.ly/30flYb6

6. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. Updated May 27, 2020. Accessed November 4, 2021. https:// bit.ly/3osxmZP

7. 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

8. 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

9. 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

10. 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

11. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) vs 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

12. 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

13. Akinboro O, Vallejo JJ, Mishra-Kalyani PS, et al. Outcomes of anti-PD-(L1) therapy in combination with chemotherapy versus immunotherapy (IO) alone for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 score 1-49%: FDA pooled analysis. J Clin Oncol. 2021;39(suppl 15):9001.

14. 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

15. 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

16. 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