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

Mary Jo Fidler, MD

During a Targeted Oncology^TM 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}