Efforts to Target Actionable Alterations in Lung Cancer Abound, Emphasizing Need for Testing

Tony S. K. Mok, MD, BMSc, FRCPC, FASCO

With the rise of actionable mutations in lung cancer, the role of molecular testing has become increasingly important, according to Tony S. K. Mok, MD, BMSc, FRCPC, FASCO, and as more targeted agents emerge in the treatment landscape, the results from these tests must be used to inform clinical decisions.

“Molecular testing to find a targetable mutation is already an important part of our daily practice. However, the process of finding these mutations may not be easy,” said Mok. “I believe we have a moral obligation to give it our best try. We need to obtain the best tissue or blood sample [that we can] and then use molecular testing to [identify] whether an oncogene driver [is present] so that we can select the appropriate treatment for each patient.”

In an interview with OncLive, Mok, chairman of the Department of Clinical Oncology and Li Shu Fan Professor of Clinical Oncology at The Chinese University of Hong Kong, discussed the actionable mutations that have been identified in the lung cancer space, the agents that have been developed to target them, and the importance of genetic testing to provide personalized care.

OncLive: What are some of the latest developments that have been made for patients with EGFR-mutated NSCLC?

Mok: In the EGFR-mutant lung cancer space, we have 3 generations of therapies available. First-generation agents include erlotinib (Tarceva) and trametinib (Mekinist). Second-generation agents include afatinib (Gilotrif) and dacomitinib (Vizimpro). Finally, we have the third-generation agent, osimertinib. Each of these agents have their own set of special features; however, we now must determine whether there is one subgroup that may benefit more from one particular therapy than the others. For example, it’s understood that osimertinib may have superiority in patients who have brain metastases.

Osimertinib is currently under exploration as an adjuvant treatment in the ADAURA trial. Could you speak to this research and its significance? Will you be discussing this option with your patients?

If there was an Oscar Award for the arena of lung cancer in 2020, then it would probably go to the ADAURA trial. This study was published in The New England Journal of Medicine and reported the use of osimertinib in the adjuvant setting for patients with resectable EGFR-mutant NSCLC.

The primary end point of the trial was disease-free survival (DFS) in patient with stage II/IIIa disease. There was a hazard ratio of 0.17. Now, with the DFS and impressive hazard ration, there is a reasonable chance that it may translate into an overall survival (OS) benefit.

I believe that every patient with resectable EGFR-mutant lung cancer should be informed about the study. The question of whether we should wait for OS data is debatable. However, the way I see it is, if a patient doesn’t know about this [potential option], then they don’t have a choice. What would happen if we do end up finding an OS benefit years later, but we had not informed our patients? This is an important study and our patients should be informed about it.

Because osimertinib has become such a key player in the treatment of this patient subset, resistance to the agent has become a key challenge. What is some of the work that is being done to overcome this?

In the upcoming years, I believe that will be the focus of many efforts: the management of osimertinib (Tagrisso) resistance. As demonstrated during the 2020 ASCO Virtual Scientific Program and the 2020 ESMO Virtual Congress, there have been several exciting advancements.

For example, there is the use of bispecific antibodies that target both EGFR and MEK mutations. When [amivantamab (JNJ-61186372; JNJ-6372) was] used with lazertinib, there is a response rate of about 36%, which is encouraging for patients who have already [progressed on] osimertinib.

The other approach is to use an antibody-drug conjugate [ADC]. Another report from ESMO looked at the use of patritumab deruxtecan [U3-1402], which is an ADC that targets HER3; this agent also demonstrated a response of about 25%. I believe there’s a lot of room for development when it comes to using different modalities to target patients who are resistant to osimertinib.

Beyond EGFR, could you highlight some of the other advances that have been made with regard to targeting actionable disease in lung cancer?

In terms of BRAF mutations, it’s quite standard to use the combination of trametinib and dabrafenib (Tafinlar) in patients with BRAF V600E–positive disease, either in the first- or second-line setting. [It’s also important to remember the] resistance mechanism that has been reported [with this approach].

We have also seen exciting data in terms targeting ALK mutations. Two new compounds have been explored in phase 3 studies that turned out to be positive. For example, the CROWN study evaluated the role of first-line lorlatinib (Lorbrena), the central nervous system efficacy that we saw, and how the use of this agent compares with other second-generation TKIs.

With regard to ROS1, beyond crizotinib (Xalkori), there’s entrectinib (Rozlytrek) and erlotinib. [We are examining] what the role of these agents will be in the management of ROS1-positive lung cancer.

Could you expand on how the agents targeting ROS1 mutations compare with one another?

Crizotinib was evaluated in about 50 patients who harbored ROS1 mutations, and we saw a high response rate of about 72% and a PFS of about 19 months. Stepping into the present, there are now additional studies to consider.

Lorlatinib was also able to target ROS1 and was included in the report by Benjamin Solomon, MD, of Peter MacCallum Cancer Centre, and colleagues, were also able to demonstrate a high efficacy, as well. Even after [progressing on] crizotinib, there was a response rate of over 30% [with this agent]. Entrectinib (Rozlytrek) is also used to ROS1 and has been associated with a high response rate.

What has been learned about BRAF V600E mutations? What approaches are you using for patients who harbor this mutation?

BRAF V600E in a driver oncogene, which we know from melanoma. However, this could also occur in lung cancer, in about 3% of patients. Why V600E? It’s because this transformation will add on to the growth signal that is actually controlled by the BRAF pathway. To adequately inhibit this [mutation, we needed] dual targeting.

As such, trametinib plus dabrafenib has been shown to be better than dabrafenib monotherapy. Now, [with this approach], there is an associated response rate of 60%, in the first- or second-line settings, and the median PFS is about 10 months. We should not miss the opportunity to identify a BRAF mutation, because patients can benefit from this inhibition.

With all of these advances made with targeted therapies, could you highlight the significance of molecular testing in the field?

Molecular testing has become a standard of care. The first target [that was discovered was] EGFR but, in a relatively short time, we were able to identify ALK and ROS1. As such, [those targets] have now become a part of daily practice, as well.

However, it doesn't stop there. There are also BRAF V600E and MET 14 skipping mutations. In the future, we could potentially target HER2, RET, and NTRK in this space. Instead of testing just one [mutation] at a time, we could test for all of them from the start.

There is still some debate around who should receive next-generation sequencing (NGS) early on; however, in the United States, it’s common for patients with lung cancer to undergo NGS from the start, before treatment initiation.