Combo Strategies, Sequencing Research Ongoing in EGFR-Mutant NSCLC

Raja Mudad, MD, FACP

Since the frontline FDA approval of the third-generation EGFR TKI osimertinib (Tagrisso) in April 2018, it has become the most commonly used EGFR inhibitor in non—small cell lung cancer (NSCLC), explained Raja Mudad, MD, FACP. However, first- and second-generation EGFR inhibitors still maintain roles and are being explored in combination, he added.

“In this day and age in the United States, a majority of patients should receive osimertinib in first-line therapy, unless they have an uncommon mutation,” said Mudad, a founding partner at Florida Precision Oncology.

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Regarding combination strategies, the RELAY trial examined the dual blockade of EGFR and VEGFR pathways versus EGFR inhibition alone in patients with EGFR-mutant NSCLC. Patients who were randomized to receive erlotinib (Tarceva) plus ramucirumab (Cyramza) versus erlotinib alone had a median progression-free survival (PFS) at 19.4 months versus 12.4 months, respectively (HR, 0.591; 95% CI, 0.461-0.760; P <0001). Additionally, the median duration of response was 18.0 months for erlotinib/ramucirumab compared with 11.1 months for erlotinib alone.

In an interview during the 2019 OncLive State of the Science Summit^TM on Non—Small Cell Lung Cancer, Mudad discussed the available EGFR inhibitors and sequencing challenges for patients with EGFR-mutant NSCLC.

OncLive: Could you discuss the impact of osimertinib since its frontline approval in 2018?

Mudad: At this point, we only have one approved third-generation TKI for EGFR-positive tumors: osimertinib. The first advantage [of osimertinib] is that it overcomes the resistance mutation, which is commonly one of the mechanisms of resistance of prior agents.

Osimertinib also has good central nervous system penetration. This drug is extremely active in the brain with incredible responses—to the point where we have changed our practices. Instead of delivering whole brain radiation to patients who are asymptomatic, we consider starting a TKI and following closely.

Given the agent's potency, what is the relevance of earlier-generation agents?

At first glance, everyone’s gut feeling is: why would we even worry about other agents? There are several subgroups of patients who may be best served by other agents. The best example is [those with] uncommon EGFR mutations. All of these drugs except afatinib (Gilotrif) have been tested in patients with the 2 most common EGFR mutations. Afatinib was tested in all patients and about 9% of patients have uncommon EGFR mutations. It is currently the only drug we know that has activity in uncommon EGFR mutations. If a patient has an uncommon mutation, afatinib would be the drug of choice—not osimertinib.

Additionally, if you start someone on osimertinib and they experience a major adverse event, then you have to stop and decide which agent to use next. We don't have data that look at a second-generation agent following a third-generation [EGFR inhibitor]. I personally look at which mutation [the patient] has. If a patient with an exon 19 deletion cannot receive osimertinib, my drug of choice is afatinib. I've had a lot of experience with it, but one could argue that dacomitinib (Vizimpro) is also a very active drug.

In some patients who fail third-generation agents who have developed a certain type of mutation, sometimes that mutation can re-sensitize them to first-generation drugs. Therefore, there is also a possibility of reusing a first-generation drug in specific patient subgroups.

The RELAY trial examined the use of erlotinib, a second-generation EGFR TKI, in patients with NSCLC. What is the significance of these findings?

The RELAY trial looked at adding ramucirumab to erlotinib to see if they work better [in combination]. The RELAY trial took patients who have an EGFR mutation, and the PFS between single-agent erlotinib plus placebo versus erlotinib plus ramucirumab was 19.4 months versus 12.4 months, respectively. Additionally, there was a significant elongation of PFS in single-agent erlotinib that is not as long as we would see with single-agent osimertinib.

Toxicity for the 2-drug regimen had more toxicity related to VEGF inhibition, such as bleeding or thrombosis. At this point, our job is to find the ideal way of combining and sequencing [agents] to do better than what we do now with single agents. One possibility is to start with a second-generation, or a first-generation EGFR inhibitor plus a VEGF inhibitor, and follow that up with a third-generation EGFR inhibitor. The current trials now are looking at osimertinib combined with ramucirumab or bevacizumab (Avastin).

Are there standardized sequencing strategies for EGFR TKIs in NSCLC?

No, sequencing at this point is not something that has been studied. It's all retrospective. In countries where osimertinib is widely available, such as the United States, the majority of new patients receive osimertinib. In countries where osimertinib is not available in first-line treatment but is available in the second-line setting, meaning those patients have the option of being on a first- or second-generation [EGFR inhibitor]. My preference would be a second-generation [EGFR inhibitor].

What trials are you looking forward to seeing the results of in this space?

We know patients [with EGFR mutations] do not respond well to single-agent immunotherapy. EGFR-mutant tumors are cold tumors that do not have infiltrating lymphocytes or a lot of neoantigens. Current trials are looking into dual checkpoint blockade, such as ipilimumab (Yervoy) and nivolumab (Opdivo), in EGFR-positive patients who fail osimertinib.

Trials are also looking at combinations of chemotherapy and immunotherapy. In the IMpower150 trial, we showed that patients who received the quadruplet therapy of carboplatin, paclitaxel, bevacizumab, and atezolizumab (Tecentriq), there were significant benefits in a EGFR-positive subset. This has to be confirmed in a prospective trial. These will be practice-changing data because, at this point, we do not have a recommended strategy for dealing with immunotherapy and chemotherapy combinations in EGFR-positive patients.

In real-world practice, is it reasonable to hypothesize that patients who failed an EGFR inhibitor would qualify to receive quadruplet therapy?

In general, yes, because the population of patients with EGFR-positive tumors tend to be younger, nonsmokers, and have no comorbidities. They are typically well-suited for aggressive therapy. I have treated several patients who have failed TKIs with the quadruplet therapy.

The biggest question with the quadruplet therapy is the [physical] cost. I also wish [the quadruplet] used a less toxic drug, such as pemetrexed versus paclitaxel.

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; abstr 9000). doi: 10.1200/JCO.2019.37.15_suppl.9000.