Dual VEGFR/EGFR Targeting Strategies Gain Prominence in NSCLC

Mary Jo J. Fidler, MD

During a Targeted Oncology Case-Based Peer Perspective Roundtable, Mary Jo J. Fidler, MD, associate professor, Division of Hematology, Oncology, and Cell Therapy, Department of Internal Medicine, Rush Medical College, Rush University Medical Center discussed targeting VEGFR and EGFR in patients with non–small cell lung cancer (NSCLC).

Targeted Oncology™: What would be your next therapeutic step for this patient with stage IV NSCLC?

FIDLER: The patient is anxious to start therapy. This is a never-smoking Asian man with adenocarcinoma with high PD-L1 expression of 100%.

You could argue that the patient may want treatment sooner [than waiting for molecular panel test results]. If that [were] the case, then I would recommend either a cycle of platinum doublet chemotherapy without immunotherapy or waiting before doing palliative radiation, something that wouldn’t delay systemic therapy down the road.

In this case, I would [wait] for the molecular panel testing results, hoping that we could control the patient’s pain until these came back. Starting with immunotherapy runs the risk of increased toxicity if this patient were to have a driver mutation. Schoenfeld and colleagues [published a study] showing high rates, close to 30%, of grade 3 to 4 toxicities in various organs, not just pneumonitis, when starting with immunotherapy and switching to an EGFR tyrosine kinase inhibitor [TKI].¹

This phenomenon also has been reported with ALK agents and ROS1 agents, so my choice would be to wait for molecular panel test results. If [the patient] needed treatment, then starting with 1 cycle of chemotherapy or potentially with palliative radiation could also make sense.

What are the National Comprehensive Cancer Network (NCCN) recommendations for molecular testing for patients with nonsquamous NSCLC?

The NCCN recommendations suggest using a molecular panel. This is thought to be cost-effective and also maximizes tissue use and avoids waste of tissue.² It also allows for identification of rare driver mutations such as the NTRK mutation. I’ve had a few patients with lung cancer with NTRK, RET, or MET exon 14 mutations and these [mutations] are standard drivers now. We saw some encouraging data at ASCO [the American Society of Clinical Oncology 2020 Virtual Scientific Program] looking at an antibody-drug conjugate with results in HER2-mutated lung cancer [NCT03505710].³

It’s important to do a broad panel, and it is [more] cost-effective than testing for 1 gene at a time. PD-L1 testing up front is also recommended.

Are molecular testing results for liquid biopsies (blood samples) concordant with results for tissue biopsies? We have some information on this. A study looking at the Guardant360 assay was published in JAMA Oncology by [Charu] Aggarwal, MD, PhD, and colleagues. That study compared the Guardant360 assay with next-generation sequence testing on tissue in the frontline setting for NSCLC. Most of the time, tests in tissue and blood [samples] showed the same results, but about 13% of patients had a driver mutation noted only [in] the tissue and not in the serum. In about 13% of patients [with a] noted mutation in the circulating tumor assay in the blood but not in the tissue itself, regardless of how the mutation was noted, the response to the targeted therapy was appropriate.⁴ My takeaway is that if you find an activating mutation in circulating tumor DNA, you can act on it and it’s real.

In this case of a never-smoking Asian man, I would have a high suspicion that he had the EGFR mutation. If I did a circulating tumor DNA assay and I didn’t find anything, then I would send off tissue and probably start with carboplatin/pemetrexed [Alimta] and not add immunotherapy up front because my suspicion is so high. If you don’t find [a mutation] either in the tissue or the blood and are suspicious, then it’s probably worthwhile to look a bit deeper.

Do you test blood samples and tissue samples at the same time?

Most circulating tumor DNA assay results are back within a week, and sometimes it takes about a week to get [a tissue] biopsy set up, so I have done that [because] you can get the results faster. Typically, if I get a result on the blood test, then I won’t order the tissue [biopsy]. But if I don’t get a result with the blood test, then I’ll have that [tissue biopsy] order [pending].

What options would you consider for frontline therapy? Do you prefer to use osimertinib [Tagrisso] up front or to withhold it in case an EGFR T790M mutation develops during the period the patient is taking a first-generation TKI?

Say you start with a first- or second-generation TKI, and then upon progression you look for the T790M mutation and then come in with osimertinib. We’ll look at the frontline osimertinib data and what happened to the people on the control arm, which was [treatment with] gefitinib [Iressa] or erlotinib [Tarceva]. We do not have data comparing osimertinib and afatinib [Gilotrif] or dacomitinib [Vizimpro] [as first-line therapy] and I think we’ll see those data directly. The RELAY trial [NCT02411448] studied erlotinib with ramucirumab [Cyramza] as frontline [therapy], and [in May 2020] erlotinib plus ramucirumab received FDA approval.⁵ [In] the NCCN guideline, osimertinib and the other TKIs are listed as category 1 [recommendations]. Erlotinib plus ramucirumab is also listed in the guideline.²

What is the most significant barrier to prescribing these medications?

I haven’t had instances where patients haven’t been able to get their targeted agent, but sometimes the patient needs support in filing for the appropriate patient-assistance programs and foundations. With so many oral drugs [available], some of the foundations that we initially relied on don’t have enough money to cover their patients. That being said, most patients have been able to get their therapy, in my experience at least, within a week or 2.

What data support the use of osimertinib as first-line treatment for patients with EGFR-mutated NSCLC?

The FLAURA trial [NCT02296125] [compared] first-line osimertinib versus standard of care for [patients with] EGFR-mutant advanced NSCLC. It was randomized to compare [osimertinib] with erlotinib or gefitinib based on prescriber choice. [The EGFR mutations allowed were] exon 19 and exon 21 [L858R]. Patients were stratified by mutation type and by race, Asian or non-Asian. Brain metastases were permitted and [the patient’s condition] had to be stable. Patients were not able to [receive] steroids and [continue] on the trial, but they were permitted at trial entry.⁶ The primary end point was progression-free survival [PFS]. [I will also go over] the overall survival [OS] data.

The PFS data [show] a highly significant difference in favor of osimertinib versus standard of care, with a median PFS [for osimertinib] of 18.9 months [versus median PFS for standard of care, 10.2 months; HR, 0.46; 95% CI, 0.37-0.57; P <.001]. The PFS benefit was seen regardless of EGFR mutation subtype.⁶

There also was an OS benefit [when] comparing osimertinib with the standard of care. The median OS [with osimertinib] was 38.6 months [versus median OS with standard of care, 31.8 months; HR, 0.80; 95% CI, 0.64-1.00; P = .046]. [At 24 months] OS was 74% for osimertinib versus 59% for standard of care. [More than] half the patients [54%] in the osimertinib group were alive at the 3-year mark.⁷

The crossover [effect] is a big question. [Patients in the trial] could cross over [from standard of care] to osimertinib. As part of the trial, patients who were randomized to a first-generation TKI [could receive a subsequent therapy after discontinuing the assigned treatment]. Of the patients [in the standard-of-care group] who received a subsequent therapy, about half (47%) went on to receive osimertinib.⁷ With half of them receiving osimertinib, the survival benefit still persisted, and the main concern I have would [be] the sequencing strategy [in] some patients. [In this] clinical trial, 31% of all patients randomized to the standard-of-care arm [received osimertinib as subsequent therapy, but] not all of [the patients in this arm] went on to receive subsequent therapy.⁷ That could also be why the survival benefit was more pronounced with osimertinib; some patients who potentially could have had access to the drug didn’t get it. That being said, the prevalence of a T790M mutation after gefitinib or erlotinib [treatment] is about 50%, so they did capture many of these patients.

Interestingly, the OS [result] did not hold statistical significance with the subset analysis in the Asian population and in [patients with] exon 21 mutations. Anecdotally, most of us think exon 21 mutations may perform [better] than exon 19 mutations. There definitely was a PFS benefit with osimertinib. This didn’t translate into OS in the final analysis, although this was powered by a different mutation subtype.

What data support using ramucirumab plus erlotinib as first-line therapy for patients with EGFR-mutated, metastatic NSCLC?

[The FDA approved] ramucirumab plus erlotinib for frontline [treatment of] metastatic NSCLC on May 29, 2020.⁵ The RELAY trial was a randomized phase 3 trial [of ramucirumab plus erlotinib for treatment of EGFR-mutated NSCLC]. The same mutations were allowed in the RELAY trial as in the FLAURA trial.⁸

One significant difference in the inclusion criteria was that patients with brain metastases were not [included] in the RELAY trial, but they were [included] in the FLAURA trial. Brain metastasis is a huge problem for [patients with] EGFR and ALK [mutations], with the prevalence of CNS [central nervous system] disease at some point in their treatment course close to 50%. Patients [in the RELAY trial] did not have brain metastases at baseline, which is a notable difference with the FLAURA trial.⁸

The randomization was 1:1 between ramucirumab plus erlotinib versus placebo plus erlotinib. Treatment was carried on until progression, with the primary end point being PFS. We do not yet have OS data for this regimen. The PFS curves [show a] significant [difference between groups]. Median survival is [similar to that of] the FLAURA trial with a highly significant HR [median PFS: ramucirumab plus erlotinib, 19.4 months; placebo plus erlotinib, 12.4 months; HR, 0.59; 95% CI, 0.46-0.76; ^P < .001].⁸

The subgroup analyses, at least for PFS, [show] no hint at a difference between [patients with] exon 19 deletions and [those with] L858R [exon 21] mutations [exon 19: HR, 0.65 (95% CI, 0.47-0.90); exon 21: HR, 0.62; 95% CI, 0.44-0.87]. [Results were] also stratified between [patients of] East Asian and other [races], and both of those groups [showed a] significant benefit of having ramucirumab added to erlotinib [East Asian: HR, 0.64; 95% CI, 0.49-0.83; non–East Asian: HR, 0.61; 95% CI, 0.36-1.01].⁸

The adverse events of special interest [were those] we typically see when we add a vascular endothelial growth factor receptor agent, [including] bleeding or hemorrhage, hypertension, and proteinuria. Overall, the adverse events were thought to be manageable.⁸

[The investigators also assessed] EGFR T790M mutation rates after disease progression. They checked for the T790M mutation at baseline and did not find it in the patients entered in this trial. They looked at liquid biopsies [at baseline and at] a 30-day follow-up after progression. The T790M mutation rate was what they expected at 30 days after progression [mutation rates: ramucirumab plus erlotinib, 43% (95% CI, 30%-58%); placebo plus erlotinib, 47% (95% CI, 36%-58%); P =.85], suggesting that patients with T790M mutations could go on to receive osimertinib after their erlotinib/ramucirumab regimen.⁸

Do you agree with the choice of therapy for this patient?

This patient received frontline osimertinib. As we mentioned for the RELAY trial, he also would have been eligible for erlotinib plus ramucirumab. A Japanese trial of erlotinib plus bevacizumab [(Avastin) for patients with EGFR-mutated NSCLC] showed a PFS benefit,⁹ [but] adding bevacizumab to erlotinib [did not improve OS] in a United States cooperative trial [NCT01532089].¹⁰ Ongoing frontline trials in this space include adding carboplatin and pemetrexed to osimertinib [NCT02151981] based on data showing improvement in survival by adding carboplatin and pemetrexed to gefitinib.¹¹ There are ECOG trials adding bevacizumab to osimertinib [NCT04181060] and adding ramucirumab to osimertinib [NCT03909334].

How do you treat patients with NSCLC that is resistant to first-line osimertinib?

With increasing reports of small cell and squamous transformation in EGFR-mutant NSCLC, I try to get a tissue biopsy, especially if there’s a central lymph node that’s grown quite a bit and [the patient has] a lot more disease burden in their chest.

Our practice has seen a few small cell transformations. I have a patient who’s had a squamous cell transformation, too. I think it does happen and it may influence your next therapy. I try to do tissue biopsy, but we can also find resistance mechanisms with liquid biopsy. That’s a good strategy if [tissue] biopsy cannot be easily obtained.

[In a study of] 62 patients with EGFR-mutant NSCLC who received frontline osimertinib, next-generation sequencing [was performed] on tumor tissue before and after [osimertinib administration]. Known mechanisms of quiet resistance [to EGFR TKIs] were identified in 41% of patients. The on-target EGFR 724S mutation was seen in 1 of 27 patients (4%). There were some other off-target mutations with MET, KRAS, BRAF, and RET.¹² There have also been case reports of ALK rearrangements in various fusions.

We’re participating in the ORCHARD trial [NCT03944772], obtaining biopsies from patients [who have cancer] progression with osimertinib. [The study has] arms for patient [allocation depending on] different molecular targets. If there is no target, [the patient is] randomized to receive chemotherapy plus durvalumab [Imfinzi]. If you have a patient on osimertinib upon progression, we’d love to see them for the molecular targeted options after [the cancer has] progressed. I have heard from some of my colleagues at Massachusetts General Hospital and Memorial Sloan Kettering Cancer Center that [when] they found some mutations, [such as] ALK rearrangement, they have been able to get dual TKIs approved by insurance, but it can take some time because it is expensive.

How would this patient’s 100% PD-L1 expression affect your choice of therapy after failure of the first TKI treatment?

What we know about patients with driver mutations [is that] the benefit of an immune checkpoint inhibitor versus docetaxel is not that pronounced. PD-L1, interestingly, is expressed through downstream activity of the EGFR-activating mutation. It may not be the same mechanism as a tumor hiding from the immune system. That’s why I don’t typically use checkpoint inhibitors in the front line for these patients. A couple of small studies looked at frontline PD-L1 treatments in patients with EGFR-positive tumors, and they were both stopped for futility because it didn’t seem to be a good strategy.

If a patient has [no more] targeted treatment options, I think [immunotherapy] could be reasonable. The IMpower150 trial [NCT02366143] was the only trial of frontline platinum doublet plus immunotherapy that included patients with a history of EGFR or ALK inhibitors. The trial combined carboplatin, paclitaxel, atezolizumab [Tecentriq], and bevacizumab as quadruplet therapy for those patients.¹³

There is some debate [as to] how much the immune checkpoint inhibitors work. I probably would not use them as single agents [and would] probably add them to the platinum doublet chemotherapy. But we try to look for [mechanisms] of resistance that we can target and keep people on osimertinib longer. The other thing that we’re doing commonly, and you could argue there [are] some data supporting this strategy, is to treat patients with oligometastatic progression and extend time on their TKI.

_References:

_{1. 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}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 1.2021. Accessed November 30, 2020. https://bit.ly/2KHxJPR}

_{3. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504}

_{4. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(2):173-180. doi:10.1001/jamaoncol.2018.4305}

_{5. FDA approves ramucirumab plus erlotinib for first-line metastatic NSCLC. FDA. Updated June 1, 2020. Accessed October 19, 2020. https://bit.ly/3obLWDV}

_{6. 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}

_{7. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662}

_{8. Nakagawa K, Garon EB, Seto T, et al; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5}

_{9. Maemondo M, Fukuhara T, Saito H, et al; North East Japan Study Group. Final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations. Abstract NEJ026. J Clin Oncol. 2020;38(suppl 15):9506. doi:10.1200/JCO.2020.38.15_suppl.9506}

_{10. Stinchcombe TE, J.nne PA, Wang X, et al. Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFRmutant non-small cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5(10):1448-1455. doi:10.1001/jamaoncol.2019.1847}

_{11. Mok TS, Wu YL, Ahn MJ, et al; AURA3 Investigators. Osimertinib or platinumpemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674}

_{12. Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11):2654-2663. doi:10.1158/1078-0432.CCR-19-3563}

_{13. 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}