Ramalingam Discusses Osimertinib Efficacy and the Journey to Overcome Acquired Resistance

Suresh S. Ramalingam, MD

The encouraging activity with osimertinib (Tagrisso) for patients with EGFR-mutant non—small cell lung cancer (NSCLC) continues to be highlighted in the form of prolonged progression-free survival (PFS); however, next steps are focusing on understanding the primary and acquired resistance mechanisms to the third-generation EGFR inhibitor.

Regarding its benefit, frontline osimertinib continued to show extended PFS in patients with advanced EGFR-mutant NSCLC, according to final efficacy and safety results from phase I expansion cohorts of the AURA trial that were presented at the 2019 European Lung Cancer Congress (ELCC).¹

At a median follow-up of 19.1 months, the median PFS in patients who received the third-generation EGFR inhibitor at 80 mg was 22.1 months (95% CI, 12.3-30.2) and was 19.3 months (95% CI, 11.1-26.0) for those who received it at 160 mg, leading to an overall median PFS of 20.5 months (95% CI, 13.7-26.1).

The FDA approved osimertinib as a first-line treatment for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) in April 2018.

However, studies have emerged exploring primary and acquired resistance mechanisms to osimertinib. A Chinese study presented at the meeting evaluated targeted next-generation sequencing of patients with stage IIIb-IV EGFR-mutant T790M NSCLC to detect molecular marker status.

Findings showed that of the 117 patients who received osimertinib, 82.91% developed acquired resistance, and 7.69% had primary resistance.² From the baseline samples, it was determined that there were 3 (33.33%) patients with MET amplification, 1 (11.11%) patient with BCL2L11 loss, 1 (11.11%) patient with ERBB2 amplification, 1 (11.11%) patient with PTEN mutation, 1 (11.11%) patient with EZH2 mutation, and 2 (22.22%) patients with unknown status. The data suggest that the mechanisms of this resistance could be highly heterogeneous.

“Acquired resistance to EGFR TKIs, or any other TKI for that matter, is matter of fact: it happens,” said Suresh S. Ramalingam, MD. “What we’re beginning to learn is what the resistance mechanisms to osimertinib are.”

In an interview with OncLive during the 2019 ELCC, Ramalingam, professor of hematology and medical oncology at the Emory University School of Medicine, described these findings with osimertinib, and discussed the emerging body of data exploring primary and acquired resistance mechanisms to the third-generation agent.

OncLive: Could you discuss the data we have with frontline osimertinib in EGFR-mutant NSCLC?

Ramalingam: The FLAURA study demonstrated that osimertinib was superior in terms of PFS compared with either erlotinib (Tarceva) or gefitinib (Iressa). This has resulted in FDA approval of osimertinib in the United States and many other countries in the world. The study itself was a randomized, phase III trial in 556 patients who were randomized 1:1. Osimertinib was given at 80 mg per day in the experimental arm, and patients received standard doses of either erlotinib or gefitinib.

The primary endpoint was PFS, and we had independent assessment of radiographic images. Patients in the control group could cross over if they had progression and developed a T790M mechanism of resistance, and then receive osimertinib.

It was a very well-designed, phase III clinical trial that we reported, and it showed that the median PFS with osimertinib was 18.9 months, and the median PFS in the control group was 10.2 months. This represented a 54% reduction in the risk of disease progression or death for patients treated with osimertinib.

We also saw a very favorable toxicity profile for osimertinib. Since it’s a mutation-specific inhibitor, it has less of an effect on the wild-type receptor. Finally, the overall survival (OS) data suggested that there was a favorable outcome, though, from a statistical standpoint, the results are still very immature. We found a positive hazard ratio of 0.63, which did not quite meet the statistical significance at that level of low maturity, but it was still very promising regardless. Therefore, from all standpoints, we found that osimertinib came out ahead.

One problem that we see in lung cancer—specifically in EGFR-mutated patients—is brain metastases. Therefore, any agent we choose, we want to be effective against brain metastases. We saw that in the FLAURA study with osimertinib; we saw intracranial responses. For about 20% of the patients who came into the study with brain metastases, their PFS hazard ratio was similar to the overall patient population. We also saw less disease progression in the brain for patients with osimertinib. Therefore, another key piece of information that came out from the FLAURA study is that osimertinib has activity in the brain.

Another study being presented at the 2019 ELCC focuses on real-world data on long-term survival in patients with stage IV NSCLC who harbor T790M and were treated with osimertinib. Why is this study notable?

What we’re now beginning to see, now that osimertinib has been around for almost 4 years in clinical practice, is more outcome data from a real-world setting. In the second-line setting, that was the first indication for osimertinib in clinical practice for patients with T790M acquired resistance to a first- or second-generation TKI. This is the setting where the AURA3 trial had demonstrated superiority for osimertinib over platinum-based chemotherapy.

It’s encouraging to see these long-term survival data come up. We will soon hear the survival data from the AURA3 trial sometime maybe this year or early next year, and what this all tells us is that patients with EGFR-mutated NSCLC are living longer because of better treatment options.

Another study being presented addresses potential resistance mechanisms in patients with EGFR-mutant NSCLC who develop T790M. What is important to note about this trial?

We have to think about it in two different ways. What are the resistance mechanisms when osimertinib is used in the frontline setting for EGFR-mutated disease? What are the resistance mechanisms when it’s used in the second-line setting after someone has T790M?

In the frontline setting, when we looked at the plasma samples from patients on the FLAURA study, there was not a single case of T790-mediated acquired resistance, which, mechanistically, speaks to how effective osimertinib is at blocking both the EGFR exon 19 and 21 mutations, and also T790M.

We did see some cases of secondary EGFR mutations, in the form of C797S, and we saw MET pathway amplification; approximately 20% to 25% of the patients have 1 of these mechanisms of resistance. We’re still too early in the era of frontline osimertinib to know the full spectrum of resistance mechanisms.

When you think about second-line osimertinib use, we see a slightly higher prevalence of the C797S mutation. We continue to see MET amplification, which is an important resistance mechanism in that situation. What does all this mean? Well, we have to now develop combination approaches based on the mechanisms of acquired resistance, so we can either overcome it or prevent it.

We already saw some exciting data at the 2019 AACR Annual Meeting just 2 weeks ago: combination therapy with osimertinib and savolitinib with acquired resistance seem to have a promising response rate of about 35%. When a MET inhibitor was used with osimertinib for patients with MET amplification, the response rates and duration of response were quite promising. We’re already beginning to see movement in that direction.

What do we know about frontline osimertinib treatment and mechanisms of acquired resistance?

When osimertinib is used in the frontline setting, we see a response rate of about 80%, and the median PFS is 19 months. The key question now is, “Does it result in an improvement in OS?” For that, we are waiting for the full maturation of the FLAURA study data, which we’ll have either later this year or in early 2020.

Also, when somebody develops acquired resistance, how do we overcome that? Now we go to chemotherapy after patients progress on osimertinib, but we’re already learning about MET pathway amplification, mutations of the renin—angiotensin system, mitogen-activated protein kinase pathway, and secondary EGFR mutations. All of these can have potential targeted approaches to overcome that resistance.

We’re also learning to use liquid biopsies to understand resistance mechanisms, and perhaps there’s a possibility down the road to prognosticate patients early on during the course of treatment and be in a position to adapt therapies even before they acquire resistance mechanisms. That is another key area of interest.

The good news is osimertinib is a very well-tolerated drug compared with the previous generations of EGFR inhibitors. That allows us to develop combinations based on osimertinib and have them come at a safe tolerability profile for patients, and that provides new opportunities to understand and develop strategies against resistance mechanisms.

What is next in the clinical management of patients who progress on first-line osimertinib?

The key question is, “Can we go from osimertinib to another TKI based on resistance mechanisms rather than going to chemotherapy?” Early evidence of that came from the TATTON trial that was reported, which recently showed that combining a MET or a MEK inhibitor could be a potential way to delay acquired resistance, or use it to treat acquired resistance mediated by those pathways. That’s clearly the next level of investigation about what is the best way to salvage patients who develop resistance to osimertinib.

I look at it even at a broader setting. Can osimertinib be used in earlier stages of lung cancer to cure patients? A phase III study in patients with locally advanced, surgically unresectable disease has just been launched a few months ago, the LAURA trial, where patients get chemoradiation and are then randomized to osimertinib or no TKI.

The other key study in this space is in the adjuvant therapy setting for patients who’ve had surgical resection. This study, called ADAURA, has already completed accrual, where patients either received osimertinib or not after surgery and adjuvant chemotherapy.

In the United States, we’re pursuing the ALCHEMIST study, which is also asking a similar question of EGFR inhibition versus no EGFR inhibition in patients undergoing surgery. The goal there is now to leverage the exciting results from metastatic disease to improve cure rates for patients with earlier stages of lung cancer.

References

1. Yang J, Ramalingam S, Lee C, et al. Osimertinib as first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC): Final efficacy and safety results from two phase I expansion cohorts. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract 122P.
2. Xu C, Wang W, Zhu Y, et al. Potential resistance mechanisms using next generation sequencing from Chinese EGFR T790M+ non-small cell lung cancer patients with primary resistance to osimertinib: A multicenter study. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract 114O.

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