Leal Discusses Therapy Selection in Oncogene-Driven Lung Cancer

Ticiana Leal, MD

During a Targeted Oncology Case Based Peer Perspective event, Ticiana Leal, MD, a team leader of the Thoracic Malignancies Disease Oriented Team at University of Wisconsin Carbone Cancer Center in Madison, WI, discussed the case of a 66-year-old patient with lung cancer and high PD-L1 expression.

Targeted Oncology™: Would you get molecular testing on this patient before starting treatment?

LEAL: The NCCN [National Comprehensive Cancer Network] guidelines say the minimum testing recommended is for EGFR, ALK, ROS1, BRAF, MET exon 14, RET, and PD-L1.¹ Although there is no recommendation for which panel we should use, the recommendation is for a broad molecular panel–based NGS [next-generation sequencing] approach. This minimizes tissue use and potential waste.

In addition, we also are looking for rare driver mutations because now we have therapy for NTRK [gene fusions]. We know that NTRK fusions can be seen in non–small cell lung cancer [NSCLC], even though it’s rare. For PD-L1 testing, the Dako 22C3 assay is preferred.

What are the potential treatment options for this patient with an EGFR mutation?

[Looking] at the NCCN guidelines, we’ve had multiple revisions—even as of 2020—given the multiple approvals in NSCLC. In the population with EGFR-mutant NSCLC, we have several different options that can be used in the frontline setting. Based on the NCCN guidelines for patients who have an EGFR mutation discovered prior to first-line systemic therapy, osimertinib [Tagrisso] is listed as a category 1 and a preferred agent.

We see other recommended category 1 agents based on the currently available data, including erlotinib [Tarceva], afatinib [Gilotrif], and gefitinib [Iressa]. Dacomitinib [Vizimpro] as well as erlotinib/ramucirumab [Cyramza] are now [recommended in the] NCCN guidelines.

Useful in certain circumstances is the combination of erlotinib plus bevacizumab [Avastin]. We don’t currently have EGFR TKI [tyrosine kinase inhibitor] plus chemotherapy, but we’ve seen results [from a study of] the combination of gefitinib plus chemotherapy based on 2 studies, including a study from India [CTRI/2016/08/007149] and a study from Japan [UMIN000006340].

The challenge with a patient [for whom] you discover an EGFR mutation is that after you start frontline therapy, there is the option to continue the current therapy versus switch to an EGFR TKI, with osimertinib as the preferred agent.

Which data support the use of osimertinib in the frontline setting for a patient like the one discussed in the case?

The FLAURA trial [NCT02296125] examined first-line osimertinib versus standard-of-care therapy for EGFR-mutant advanced NSCLC. We’ve seen these data presented and now published.

Patients who were treatment naïve with diagnoses of advanced NSCLC adenocarcinoma with either an EGFR exon 19 or 21 mutation with good performance status and stable CNS [central nervous system] metastases were randomized to osimertinib 80 mg daily versus erlotinib or gefitinib at standard-of-care doses. [There were] 279 patients on the osimertinib arm and 277 patients on the standard-of-care arm.²

Patients received the EGFR TKI until disease progression or unacceptable toxicity. The primary end point of the study was PFS [progression-free survival]. Secondary end points included overall response rate, duration of response, overall survival [OS], and safety. The median PFS with osimertinib was 18.9 months compared with standard of care at 10.2 months, with a hazard ratio of 0.46 [95% CI, 0.37-0.57] and a P value of less than .0001.

We’ve also seen the final OS results [that were presented at the European Society for Medical Oncology Congress 2019].³ The OS showed a median follow-up of 35.8 months in the osimertinib arm and 27.0 months with the standard-of-care arm. The median OS in the osimertinib arm was 38.6 months versus 31.8 months with a hazard ratio of 0.799 [95.05% CI, 0.641-0.997; P = .0462]. The 36-month OS rate was 54% versus 44%.³

In terms of crossover to osimertinib, 47% of the patients in the standard-of-care arm received subsequent treatment, which was 31% of all patients randomized from the standard-of-care arm. For our patient with CNS involvement, data show a 54% decrease in brain metastases when you use osimertinib versus the standard-of-care TKI.

How would you treat a patient with PD-L1–positive, EGFR-mutant NSCLC?

Per the NCCN guidelines for patients who have a presence of an oncogene, [data show that] use of a PD-1/PD-L1 inhibitor is not recommended because of lack of benefit with the presence of a driver oncogene.¹ A small study showed that the use of single-agent pembrolizumab [Keytruda] in the front line in patients with high expression of PD-L1 when they had EGFR-positive NSCLC was not effective. Another important society that we follow, SITC, or the Society of Immunotherapy for Cancer, also recommends [that] patients with nonsquamous advanced NSCLC with the presence of a driver oncogene, such as EGFR, ALK, or ROS1, [receive] frontline targeted therapy.⁴

A phase 2 study of pembrolizumab in the frontline setting for patients with positive EGFR status and positive PD-L1 expression status initially planned to enroll 25 patients who were TKI naïve.5 Patients were to receive the standard-of-care pembrolizumab at 200 mg intravenously every 3 weeks with a primary end point of overall response rate. The results showed that the study had to be halted because early on, there was a lack of any responses in patients. The majority of these patients had high PD-L1 expression of 50% or greater.

One of 11 patients was initially found to have a response, but after central review, they confirmed that this 1 responder did not have an EGFR mutation. There were 2 deaths within 6 months of enrollment, including 1 attributed to pneumonitis. This study showed that in patients with EGFR mutation, pembrolizumab monotherapy is the wrong thing to do, in my opinion. The current evidence does not support the use of a PD-1/PD-L1 inhibitor before a TKI, even for patients with a high PD-L1 expression. The toxicities that occurred during subsequent TKI also raised concerns about sequencing of PD-L1 inhibitors followed by TKI.⁵

In terms of sequencing, there have also been considerations that have been [looked at] in a retrospective fashion. Data published in the Annals of Oncology in 2019 show severe grade 3/4 toxicities documented for 126 patients with EGFR-mutant NSCLC who received both a PD-L1 inhibitor and an EGFR TKI.6 This sequence of PD-L1 blockade followed by an EGFR TKI, [such as] use of osimertinib, shows a higher rate than we usually see of severe immune-related adverse events [irAEs]. In the case of this retrospective review, 15% had a median onset of [severe irAEs] 20 days after osimertinib. All these patients required steroid, and most required hospitalization. Interestingly, in this retrospective review, this was not seen when you used PD-L1 blockade followed by erlotinib or when you reversed the sequence and you gave patients an EGFR TKI first, followed by PD-L1 blockade.⁶

What do you do, then, if you give somebody PD-L1 blockade with or without chemotherapy and testing comes back and they have an EGFR mutation? How long do you wait before you can switch them over to osimertinib?

I can tell you what I’ve done and what I’ve heard others in the thoracic oncology community have been doing. Realize that this is based on experience and not based on data at this point. I’ve seen a few times where patients had received a PD-L1 agent and then subsequently were found to have an EGFR mutation. They had been placed on osimertinib, and I specifically recall seeing a patient that was admitted with difficult-to-manage pneumonitis. It certainly seems to be a real phenomenon. What I’ve done in my own practice when I see this is if patients have received chemotherapy plus immunotherapy, I let them finish out the induction chemotherapy alone.

If they are benefiting from chemotherapy, I finish out the induction therapy and then switch them out after induction is done. Anecdotally, that has gone OK. The washout period is variable. It also depends on how your patient is doing on chemotherapy and whether you decide you’re going to give them osimertinib versus another EGFR TKI. This is a real problem because you might be compromising the ability for that patient to be able to continue on an EGFR TKI and whether they stay on osimertinib versus erlotinib.

There was another interesting case that I recall where a patient had gotten immunotherapy. They had received treatment with osimertinib and had severe pneumonitis and had trouble staying on an EGFR TKI. This patient then went on chemotherapy alone and stayed on maintenance pemetrexed [Alimta] for quite a while. After progression, they were able to get on an EGFR TKI with pemetrexed. I think it is something that we have to be cautious about.

Another study that looked at second-line data for patients with metastatic EGFR-mutated NSCLC. This meta-analysis included 3025 patients. [It] also showed that if patients had an EGFR mutation, they benefited more from docetaxel versus immunotherapy, which was not seen in the population that had wild-type EGFR. In that population, as expected, they benefited more from immunotherapy versus docetaxel chemotherapy. This meta-analysis is an important study that showed that compared with docetaxel, checkpoint inhibitors overall [induced] prolonged OS in the second-line NSCLC setting in patients with wild-type EGFR but not the EGFR-mutant tumors.⁷

This leads us to think about when to introduce immunotherapy for patients with EGFR mutations. The lack of benefit here suggests to me that we may need to consider combinations if we get to the point where patients have exhausted their EGFR TKI therapies.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 6.2020. Accessed September 11, 2020. https://bit.ly/2EAH60w}

_{2. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113- 125. doi:10.1056/NEJMoa1713137}

_{3. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 2019;30(suppl 5):567. doi:10.1093/annonc/mdz394}

_{4. Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6(1):75. doi:10.1186/s40425-018-0382-2}

_{5. Lisberg A, Cummings A, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J Thorac Oncol. 2018;13(8):1138-1145. doi:10.1016/j.jtho.2018.03.035}

_{6. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30(5):839- 844. doi:10.1093/annonc/mdz077}

_{7. Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):210- 216. doi:10.1001/jamaoncol.2017.4427}