Ramucirumab Demonstrates PFS Efficacy in Lung Cancer With EGFR Mutations

Karen L. Reckamp, MD, MS

During a virtual Targeted Oncology Case-Based Roundtable event, Karen L. Reckamp, MD, MS, director, Division of Medical Oncology, associate director, Clinical Research, Cedars-Sinai Medical Center, discussed the improvement in progression-free survival (PFS) achieved with ramucirumab in patients with EGFR-positive lung cancer.

Targeted Oncology^TM: What are the current recommendations for which genes to test when doing molecular testing in the frontline setting in patients with NSCLC?

RECKAMP: At a minimum now—the list is growing—we want to test for EGFR, ALK, ROS1, BRAF, MET exon 14, RET fusions, and PD-L1. Generally, this is best accomplished through a broad-based next-generation sequencing [NGS] approach, which will minimize tissue use, potential wastage, and also cost. This also allows for the identification of rarer mutations, such as NTRK, which should be evaluated if others are negative. The 22C3 assay is preferred for PD-L1 at this time, due to indications for pembrolizumab [Keytruda].

What is the recommended treatment for a patient with an EGFR L858R mutation like this one?

I think these are data that [most oncologists know] fairly well—the FLAURA trial [NCT02296125], which established frontline osimertinib [Tagrisso] over the first- and secondgeneration EGFR TKIs [tyrosine kinase inhibitors]. These were treatment-na.ve patients with activating exon 19 or 21 mutations with a performance status of 0 or 1, and stable CNS [central nervous system] metastases were permitted. Five hundred fifty-six patients were enrolled, and they got either osimertinib or gefitinib [Iressa] or erlotinib [Tarceva] as the standard of care. The primary end point was PFS.¹

PFS was significantly higher for osimertinib at 18.9 months [versus] with a standard of care [of only] 10.2 months, and a hazard ratio of 0.46, which led to this becoming frontline therapy for most patients with EGFR-mutated NSCLC.

The overall survival [OS] data, presented recently and published just this past year, showed a median OS of 38.6 months for osimertinib and 31.8 months for standard of care. This was statistically significant with a P value of .046 and a hazard ratio of 0.8—significant, not spectacular, but it definitely favored the osimertinib.²

Looking at the subgroups, most of the subgroups were favored for osimertinib, slightly less for the L858R and for those patients who had CNS metastases, and patients who had Asian race were crossing the 1 line. [That was] part of the reason why this has not had the same kind of uptake in the Asian countries.

Looking at first and second subsequent therapies, for patients who received first-line standard of care, a large proportion received osimertinib, so 47% received osimertinib as second-line therapy. Then subsequent second-line therapies, largely chemotherapy, [were received by] patients who [had] received osimertinib; potentially [these patients] did not receive more subsequent therapy. Having osimertinib as a second-line option increased the number of therapies that patients received.

What are other treatment options in the frontline setting for such patients?

In May and during the summer of 2020, we had a number of FDA approvals for NSCLC, and one of those approvals was ramucirumab [Cyramza] and erlotinib.

The RELAY trial [NCT02411448] was a similar first-line trial [in patients with] stage IV EGFR activating mutations, exon 19 or L858R, [and a] performance status of 0 to 1. In this study, different from some of the other TKI frontline studies, brain metastases were excluded. Patients were randomized to either ramucirumab/erlotinib or placebo plus erlotinib, and this is every-2-week dosing treated until progression or unacceptable toxicity, and the primary end point was PFS.³

What we found was improvement in PFS in the ramucirumab and erlotinib arm, with 19.4 months versus 12.4 months, a hazard ratio of 0.59, and 1-year PFS rates of 72% versus 51%.⁴

Across subgroups there was similar [PFS] improvement in both exon 19 and L858R [mutations], crossing the midline for [those with a disease stage] other than stage IV and for other EGFR testing method; but for the most part, they have all stayed to the benefit of the combination of ramucirumab and erlotinib.

By EGFR mutation type, exon 19 [had a] significant improvement in PFS at 19.6 versus 12.5 months [HR, 0.651; 95% CI, 0.469-0.903], and for L858R, [PFS rates were] similar at 19.4 versus 11.2 months [HR, 0.618; 95% CI, 0.437-0.874]—so, similar benefit regardless of EGFR mutation type.³

Efficacy by mutation type [showed a] 1-year PFS rate in the 70% range versus [approximately] 50%; response rates were similar, maybe slightly higher in the exon 21 [group]. Disease control rates were quite high across the board, duration of response was similar, and median duration of response was higher for the ramucirumab and erlotinib arm.⁵

As far as toxicity, we know when we add VEGF receptor inhibitors, we have increased toxicity and, probably not surprising, we saw more bleeding or hemorrhage [55% vs 36% with erlotinib alone]. One was grade 4, 2 were grade 3, but we’ve also seen this in patients who received placebo. Hypertension was higher, mainly low grade [46% vs 12%, respectively], but about a quarter of patients [experienced] grade 3 events, no grade 4 events; proteinuria, as you may also expect. The rate of interstitial lung disease or pneumonitis was not higher in either arm.⁴

T790M rates post progression were similar in both arms; as we might expect, the post-progression mutational status would not necessarily change, as they’re both receiving erlotinib.

What resistance mutations arise from osimertinib treatment?

A Memorial Sloan Kettering [Cancer Center] study published in Clinical Cancer Research looked at specifically frontline resistance to osimertinib.⁶ There were 62 patients, and they had tumor [samples] before osimertinib and after progression. They found about 41%, 11 patients, had no mechanisms of acquired resistance. Only 1 of 27 [resistance mutations] was an on-target EGFR G724S mutation, and there were multiple off-target mechanisms, 5 out of 27—MET alterations, KRAS mutation, BRAF fusion, and RET fusion, all of which have been described before. The MET amplification [rate] was about 7% of patients [FIGURE].⁶ Transformation also occurred [to] small cell, squamous, and pleomorphic disease.

I think the impressive thing here is the large portion, 59% of patients, who have unknown mechanisms of resistance. I would also say that a lot of the data we have thus far for resistance, because it takes time to publish the data, involve patients who had relatively early levels of resistance. I think that’s why you don’t see the on-target C797S quite as frequently as you might expect. I do expect that as we see later resistance studies come out, because patients are just starting to develop resistance. We’re somewhere around 2 to 2.5 years since the approval of frontline osimertinib, so I think that we’re going to learn a lot more about this 59% and that this [table] will start to change, and we’ll start to see more of the on-target acquired mutations in the population of patients who develop the late-onset resistance. [That remains] to be seen. This is somewhat anecdotal from my population.

_References:

_{1. 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}

_{2. 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}

_{3. Nakagawa K, Garon EB, Seto T, et al. RELAY: a multinational, double-blind, randomized phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15):9000. doi:10.1200/JCO.2019.37.15_suppl.9000}

_{4. 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}

_{5. Nakagawa K, Nadal E, Garon EB, et al. RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type. Ann Oncol. 2020;31(suppl 4):S838. doi:10.1016/j.annonc.2020.08.1608}

_{6. 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}