Lopes Shines a Light on the Explosion of Targeted Therapies in Lung Cancer Treatment Arsenal

Gilberto Lopes, MD

Now that several targeted agents have acquired regulatory approval across settings in the lung cancer paradigm, real-world considerations for the utilization of these agents in practice are warranted, and determining how they fit in and measure up with other available options in the arsenal is necessary to optimize their use, according to Gilberto Lopes, MD.

“It is important to highlight how much lung cancer has changed [over the years], and how much the treatment of [the disease] has changed,” Lopes said. “Now, we have several new options, immunotherapy drugs as well as targeted agents for several molecular alterations, that are available and can improve the quality and the length of life for our patients.”

The Institutional Perspectives in Cancer webinar on lung cancer focused on important progress made in targeting RET fusions, ALK aberrations, KRAS G12C alterations, and EGFR mutations in lung cancer, as well as advances made in frontline small cell lung cancer (SCLC) treatment.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, Lopes, the interim chief, Division of Medical Oncology at Sylvester Comprehensive Cancer Center, discussed the latest developments made in the treatment of patients with NSCLC whose tumors harbor genetic alterations and the clinical implications of recent regulatory approvals.

OncLive®: For patients with EGFR-positive NSCLC, one of the most notable advances has been the data observed with adjuvant osimertinib (Tagrisso) in the phase 3 ADAURA trial (NCT02511106). Now that it is approved, what are some real-world considerations for using this agent in practice?

Lopes: Since approval has been granted by the FDA, most insurance companies do provide for [the drug]. Access is not necessarily an issue, but it can become an issue in terms of a patient’s copay. Copays are certainly a big part of what our patients are worried about. The drug is expensive, so that is one [factor to be aware of].

In terms of efficacy, it is clear that, at least in terms of disease-free survival [DFS], this is an active drug. Of course, the jury is still out in terms of overall survival [OS] benefit, but we will have data on that in the next few years. In terms of toxicity, this is a drug that is easier to tolerate than the first-generation EGFR inhibitors like gefitinib [Iressa] and erlotinib [Tarceva], so [safety] is not an issue, overall.

However, when using a drug in the adjuvant setting, we do end up having to be a bit more careful. Patients do complain more about certain adverse effects [AEs] that they might not have cared about if they were trying to control disease that is incurable, but that they do [care] when [they have] disease [for which we are] trying to prevent a recurrence.

One AE that we do need to worry when a drug is given in the adjuvant setting is heart failure. The jury is still out in terms of [whether] heart failure is more common in patients who receive osimertinib or not, and more data are being generated on this.

Shifting to those whose tumors harbor RET fusions, what were the updated data from the phase 1/2 ARROW trial (NCT03037385) examining pralsetinib (Gavreto)?

[Data from] the ARROW trial were [recently] published in Lancet Oncology, and an update was shared in a poster presentation during the 2021 ASCO Annual Meeting. The main [takeaway] is that the response rates are very impressive. [Approximately] 70% of patients responded to pralsetinib, just as they respond to selpercatinib; these are the 2 drugs that we have on the market right now for patients with RET-positive NSCLC.

Now, we also have evidence of activity in the central nervous system [CNS], and we do see quite clearly that these responses are of a long duration. That was one of the [significant] updates [from the trial], that the median duration of response with pralsetinib was approximately 2 years.

How do you choose between pralsetinib and selpercatinib in clinic?

Currently, we do not have any clear-cut criteria to [determine] whether we should use one agent over the other. Response rates are very similar, and responses in the CNS are [comparable]. In fact, when looking at the data [for both drugs] side by side, we saw that the results were quite comparable. [As such], right now, it is very hard for us to say that we should use one vs the other.

For patients with KRAS G12C–mutant NSCLC, sotorasib (Lumakras) recently received approval based on data from the phase 2 CodeBreaK 100 trial (NCT03600883)?

The ‘undruggable’ [mutation] finally became something that we can treat. [With the] approval of sotorasib, we can now treat our patients with KRAS G12C–mutant NSCLC. Sotorasib is an active drug. The response rates that we have seen [with this agent] are not quite as high as what we see with newer generation ALK or EGFR inhibitors for patients with those respective mutations, but they are quite comparable to the rates we used to see with the first-generation inhibitors.

This [agent] is clearly an [improvement] over what we used to [give patients] before, and it is the first active therapy that we have for patients with KRAS G12C mutations. It’s important to note that these drugs, sotorasib and other drugs that are under development [in this space], are not active in other mutations. These are not TKIs; they are inhibitors of that specific KRAS G12C mutation. We cannot treat patients [whose tumors harbor] other mutations [with this drug].

Shifting to patients with ALK-positive disease, lorlatinib obtained regulatory approval for this population, and based on the data from the phase 3 CROWN trial (NCT03052608), it is now also indicated for use in the first-line setting. Do you foresee challenges to using this agent up front?

Lorlatinib has quickly become our go-to drug for patients with refractory ALK-positive disease. However, yes, is going to have a little bit of difficulty moving into the first-line [setting] for 2 main reasons. First, this is an added drug. We already had alectinib [Alecensa] and brigatinib [Alunbrig] approved [for use] in that setting. Beyond that, the safety profile for lorlatinib is a little bit different [from the other agents], and [we are] a little bit more concerned about patients [being on the agent for a long period of time]. However, it is an active drug, and it is one more option that we have for our patients.

Would you say that lurbinectedin (Zepzelca) is one of the biggest developments recently made in SCLC? What’s the clinical significance of this approval on the paradigm?

Lurbinectedin is a [recently] approved drug in the realm of SCLC. For years, we had nothing new to treat our patients [with]. Of course, we have immunotherapy with 2 approved agents, and [now,] we also have lurbinectedin for those in whom first-line therapy has failed. It is an effective drug. We see response rates of approximately 20% to 25% in patients with platinum-resistant disease, and of approximately 40% in patients with platinum-sensitive disease. It is clearly an active drug, and it is an approved option that we can now use for this population.