New Designations and Efficacy Demonstrations Push the EGFR+ NSCLC Paradigm Forward

Timothy F. Burns, MD, PhD

The utility of EGFR TKIs in select subgroups of patients with EGFR-mutant metastatic non–small cell lung cancer (NSCLC), as well as their role in the adjuvant setting, are beginning to be teased out, explained Timothy F. Burns, MD, PhD.

“We have very good EGFR inhibitors,” said Burns. “When patients progress, most of the [resistance] mechanisms are not through EGFR, so we’re clearly hitting the target hard enough However, the medications do not work forever. We are not curing our patients in the metastatic setting with an EGFR-directed TKI.”

Currently, the third-generation EGFR TKI osimertinib (Tagrisso) is heralded as the frontline standard of care in the metastatic setting, but only recently has the agent demonstrated its efficacy in the adjuvant setting.

On October 20, 2020, the FDA granted osimertinib a priority review designation to a supplemental new drug application for the adjuvant treatment of patients with early-stage EGFR-mutated NSCLC following complete tumor resection with curative intent. The indication was based on findings from the phase 3 ADAURA trial, which showed that osimertinib induced a 79% reduction in the risk of disease recurrence or death vs placebo in patients with stage IB to IIIA NSCLC (HR, 0.21; 95% CI, 0.16-0.28; P < .0001).¹

With regard to earlier-generation EGFR TKIs, findings from the phase 3 RELAY trial led to the May 2020 approval of ramucirumab (Cyramza) and erlotinib (Tarceva) for the frontline treatment of patients with EGFR-mutant metastatic NSCLC. The combination induced a 41% reduction in the risk of disease progression or death compared with erlotinib alone (HR, 0.59; 95% CI, 0.46-0.76; P < .0001).²

With the approval of ramucirumab/erlotinib, certain questions have been brought to light. Specifically, whether patients from Asia and those with L858R mutations, who did not derive a significant benefit from osimertinib, should be treated with the combination regimen.

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Burns, an assistant professor of medicine and associate program director for Research in the Hematology/Oncology Fellowship Program in the Department of Medicine, Division of Hematology/Oncology at the University of Pittsburgh Hillman Cancer Center, discussed findings from the FLAURA and ADAURA trials, dissected the role of osimertinib in EGFR-mutant NSCLC, shed light on remaining questions in the field, and spoke to some of the most intriguing emerging agents in the space.

OncLive®: What is the overall prevalence of EGFR mutations in NSCLC and how does it compare with the prevalence of other actionable mutations?

Burns: The most common type of NSCLC that we see is nonsquamous NSCLC or adenocarcinoma of the lung. About one-third of those patients will have a targetable oncogenic driver identified by molecular testing [at presentation]. The most common [driver mutation] that is targetable is the EGFR mutation, which we have known about since 2005. About 17% of patients are going to have targetable EGFR mutations. Some patients will present with EGFR mutations that are not targetable, but the vast majority [of EGFR mutations] are targetable.

How are patients with EGFR mutations treated with regard to targeted therapies?

The clear standard-of-care treatment of EGFR-mutant disease is targeted therapy, usually with a TKI that [targets] EGFR. Over the past few years, we’ve had a number of advances [in this setting]. Most importantly, [we brought] our best drug, osimertinib, into the first-line setting. The FLAURA trial, which compared osimertinib to older first- and second-generation TKIs, showed a clear survival benefit in giving osimertinib first. This was important because there was a debate in the field of whether we should give our best drug first or [use] it [later] because it worked in about half of patients [who had already received] these older-generation drugs. Based on survival and tolerability, [up-front osimertinib] was a clear favorite. It’s now the standard of care.

Although osimertinib showed a progression-free survival [PFS] benefit across subgroups, patients who came from Asia or had an L858R mutation essentially had no benefit [with osimertinib]. Giving osimertinib was no better than giving the older generation drugs in terms of survival. We don’t know what to do with those data.

At this time, in general, most people are still choosing osimertinib over the older-generation drugs just based on tolerability. Even though those subgroups of patients may not have a survival benefit, most [medical oncologists] are using osimertinib.

What questions remain regarding EGFR inhibitors?

The biggest question is: How do we take this extended lifespan and try to change it into cure? That is what we are facing now. We’ve hit the boundary of coming up with a better EGFR-directed TKI because we are hitting the target hard enough. We aren’t getting a lot of resistance in the EGFR gene. Rather, it is usually in other pathways.

The path forward seems to be with combinations at the time of resistance based on [the resistance mechanism] or trying to move these combinations to the frontline setting.

How do you go about optimally sequencing EGFR-directed TKIs?

In my opinion, and this is supported by the overall survival [OS] data, it’s clear that the majority of patients [should receive] osimertinib first as opposed to giving a first- or second-generation TKI. [Up-front osimertinib] is clearly superior in terms of PFS and OS.

There is some thought that giving erlotinib and ramucirumab, which was recently approved based on the RELAY trial, may be better, but we don’t have the OS data for that [combination]; we only have the PFS data. [Erlotinib and ramucirumab was evaluated] in a different population [than osimertinib was]. In FLAURA, 20% of patients had brain metastases [vs] no patients on the [RELAY] trial. Most patients who received erlotinib and ramucirumab had better performance status. We can tell that because the control arm did a lot better than we would have expected.

The best [drug] we have is osimertinib. That being said, the PFS is only 19 months and the OS is a little over 3 years. We can do a lot better.

Could you elaborate on the role of osimertinib in the frontline setting for patients with NSCLC?

We know that osimertinib is the standard of care in the first-line setting––that is based on the FLAURA data, which showed PFS benefit and OS benefit. The median OS was approximately 38 months compared with around 31 months in the comparator arm. Based on the studies that have been done, it is clear that osimertinib is a more tolerable drug with less rash, liver enzyme [abnormalities], and diarrhea vs first-generation TKIs.

This is despite patients staying on [osimertinib] a lot longer because they were doing well. Osimertinib was designed against the EGFR-mutant protein, whereas the first-generation TKIs were designed against wild-type EGFR, which is present in all of our skin and gut cells.

Osimertinib was granted a priority review designation by the FDA in October 2020 for use in the adjuvant setting. How could that designation affect the role of osimertinib? What makes the findings from the ADAURA trial controversial?

The ADAURA trial was looking at osimertinib in the adjuvant setting. [The study enrolled] patients with stage IB through IIIA disease. Patients who got resected could have received chemotherapy if it was appropriate. Then, they were randomized to standard of care, which was just observation with scans, vs 3 years of osimertinib.

The big issue with the ADAURA trial was that its independent data monitoring committee unblinded the study earlier. The results of this study were presented during the 2020 ASCO Virtual Scientific Program and have since been published in the New England Journal of Medicine.

Why wouldn’t we [give osimertinib] in the adjuvant setting? At least 2 earlier clinical trials looking at erlotinib, as well gefitinib [Iressa], failed to show a survival benefit [in this setting]. They showed that they could delay recurrence, but as soon as the patient stopped the drug, the curves came together. We were just delaying recurrence rather than curing patients.

By giving adjuvant osimertinib, are we curing patients? There was a lot of excitement around the ADAURA trial because the chance of disease recurrence was reduced by 80%, so the hazard ratio [HR] was .20. This benefit was observed across all subgroups. In addition, if you look at stage II and stage III patients who are at a higher risk for recurrence, there was an 83% reduction and an 88% reduction, respectively. That is quite impressive and unlike anything that we were used to seeing. There is a lot of enthusiasm because over time, that reduction could translate to a survival benefit, although we don’t know that yet. Because the study was stopped early, we are waiting for some of these data.

In addition, osimertinib has already shown a benefit in terms of central nervous system recurrence and recurrence of brain metastases. That is obviously a major problem. It isn’t a surprising finding; osimertinib is a very good drug in the metastatic setting for targeting brain metastases. Now, we are seeing that bear out in the adjuvant setting.

The controversy is that we have a highly active drug in an incurable disease in the metastatic setting that may be curable [when the agent is used] in the adjuvant setting. We don’t have all the data, and it is going to take years to [acquire] those survival data. Additionally, all patients who were on the trial when it was stopped early could cross over to osimertinib, which means that the control arm is not really a control arm anymore. We may never know if there is a real survival benefit of [osimertinib].

The FDA has now granted a priority review designation [to osimertinib], which means they have to act on whether the agent gets approved in the adjuvant setting within 6 months. I would expect that a decision will be made sooner than that.

How did the PFS data from the RELAY study compare between patient subgroups?

The RELAY study looked at the combination of ramucirumab and erlotinib vs erlotinib. Erlotinib is a standard first-generation TKI and, at the time of the study, was one of the standards of care. RELAY was the right study to do at the time. It has been known for a long time that inhibiting angiogenesis may help in EGFR-mutant disease.

The RELAY study did not allow patients with brain metastases to enroll. Additionally, these patients were receiving ramucirumab, so they had to have a little better performance status than the patients on the FLAURA trial; in FLAURA, more patients had an ECOG performance status of 1 compared with RELAY, and 21% of patients had brain metastases.

In the RELAY study, we saw a PFS benefit of 19.4 months, which is similar to FLAURA. However, the control arm did better by about 2 months; the control arm was about 12 months. That makes sense if patients with brain metastases weren’t included, patients had better performance status, and patients were eligible for antiangiogenic therapy.

The other issue is that there is increased toxicity by adding ramucirumab. The grade 3 toxicity rate was 72% vs 54% [in the control group], so [ramucirumab] comes at a cost.

There was a lot of interest in terms of subgroups, and a lot of data have been presented about how the PFS data favored all subgroups across the board, including those from Asia and the L858R-mutated patients. The HRs were about .6, which is pretty good. However, if we compare apples to apples, the HRs for PFS were better in FLAURA. At this point, some arguments have been made to use [ramucirumab/erlotinib] in Asian patients or those with L858R mutations, but the hazard ratios still favor FLAURA.

Obviously, we are anxiously awaiting the OS data. Perhaps the addition of ramucirumab will have a benefit for the Asian and L858R-mutant populations, but that has yet to be determined.

With the swell of targeted therapy options, where does chemotherapy fit into the paradigm? Is there any rationale to utilize immunotherapy alone or in combination with chemotherapy in patients with EGFR mutations?

Chemotherapy has and will be a backbone after a patient progresses on targeted therapy and there are no other options. Today, when a patient progresses on osimertinib, we often recommend a biopsy because there are multiple targetable mechanisms. Oftentimes, we may be adding a targeted therapy.

However, at some point, patients aren’t going to have a targetable alteration. [In that case], a platinum doublet has been the cornerstone of treatment for EGFR-mutant disease for over a decade. We know that EGFR-mutant patients do better with a platinum doublet. The question is: Do you add anything to that platinum doublet?

IMpower150 looked at adding immunotherapy to chemotherapy, which is a standard of care for patients with non-oncogenic drivers. The study combined carboplatin, paclitaxel, bevacizumab [Avastin], and atezolizumab [Tecentriq]. These data were recently updated this year.

The trial did include EGFR-mutant patients, though it was a relatively small number of patients. They found that patients with an EGFR-sensitizing mutation seem to have a PFS benefit; the HR was about .6. The median OS was 29.4 months [with the quadruplet] vs 18.1 months [with carboplatin, paclitaxel, and bevacizumab alone]. The HR did cross 1 because it was a small group of patients, but those are the only data we have for adding immunotherapy to chemotherapy.

Interestingly, no benefit was seen in the group that did not get bevacizumab but got carboplatin, paclitaxel, and atezolizumab; so, we need to use all 4 drugs.

This regimen can be more difficult to tolerate than some of our other regimens where we don’t have data. Historically, we know that EGFR-mutant disease will not respond to immunotherapy alone. If we are going to use immunotherapy, the recommendation would be to give it with a platinum doublet because the only phase 3 data we have today is from IMpower150.

What options are available for patients who develop resistance to osimertinib?

That is really where the field is heading. We do recommend biopsy upon progression on osimertinib for several reasons. Today, we have approved therapies or clinical trials [against] several [resistance] mechanisms. One of the least common [resistance mechanisms] is a second-site EGFR mutation called C797S. That is a mutation that prevents the drug from binding. If a patient has that mutation, after getting osimertinib, they can go back to first-generation TKIs because they will work against [C797S]. If a patient has [C797S] and not T790M, which we don’t see much of anymore, they can just go back on first-generation TKIs.

The other major resistance mechanism is MET amplification, which we used to see with the earlier generation compounds. Now we are seeing [MET amplifications] about 20% of the time. A lot of excitement [has mounted] about [MET amplifications] because clinical trials are ongoing through multiple companies. Results were recently presented and published from the [phase 1b] TATTON study, which looked at osimertinib plus selumetinib. The response rates were in the range of 30% to 40% in patients who progressed on osimertinib simply by adding the MET inhibitor.

Many of these trials are ongoing. A couple of other drugs [are being evaluated] that are targeting EGFR and MET together, including a bispecific antibody called JNJ-372. A HER3-directed antibody-drug conjugate called U3-1402 also showed activity [in this setting].

In addition, we have targets for other pathways, such as RET, which is a relatively uncommon translocation that we see. However, after EGFR-mutant disease, we do see [RET mutations], and we now have 2 FDA-approved RET inhibitors. Clinical trials looking at those agents and looking at adding a RET inhibitor to osimertinib [are planned].

Multiple efforts are underway, so we encourage people to biopsy their patients upon progression before putting them on chemotherapy. The next step is to try to move these combinations up earlier if we find that they work well.

Are there any other nuances with regard to treating patients with EGFR-mutant disease that should be taken into account?

A key thing to realize in the frontline setting with molecular testing in EGFR- and ALK-positive tumors is that we often need to start therapy before the molecular testing comes back. Many of us in the field have seen that if you give immunotherapy alone or in combination with chemotherapy, and then realize that the patient has an EGFR or ALK mutation, their rates of [toxicity] are much higher with the EGFR inhibitor. For EGFR-mutant patients, the rates of pneumonitis are between 20% and 30%. Similar rates of hepatitis are seen with ALK inhibitors. We recommend that if you have to start therapy, start with chemotherapy for the first cycle and wait for the molecular testing to come back. If you know that they are ALK and EGFR negative, add the immunotherapy agent in the second cycle of chemotherapy.

References

1. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5
2. Nakagawa K, Garon EB, Seto T, et al. 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