«We need to identify and specifically target genetic alterations»

In patients suffering from non-small cell lung cancer (NSCLC), tyrosine kinase inhibitors (TKI) are a precious therapeutic option, e.g., in targeting genetic rearrangements in anaplastic lymphoma kinase (ALK) or C-Ros oncogene 1 (ROS1). Among the broad range of ALK/ROS1 inhibitors already available, choosing the adequate therapeutic approach can be a challenge for physicians. We talked to Alex Friedlaender, MD, oncologist from the Clinique Générale Beaulieu, on how he tailors treatment options to the individual patients’ need and about his presentation on this very question at the International Lung Cancer Summit (ILCS) 2021.

For which mutations/translocations do you test your lung cancer patients routinely?

A. Friedlaender: Any time I have a patient with lung adenocarcinoma, I do a next-generation sequencing (NGS) panel. We use a large panel to look for epidermal growth factor receptor (EGFR), ALK, ROS1, BRAF, RET, MET, neurotrophic tyrosine receptor kinase (NTRK) and KRAS alterations, among others. If the patient suffers from a squamous cell carcinoma, we only do an NGS panel if he/she has very little or no smoking history or is very young. Otherwise, the pre-test probability of finding an alteration is extremely low.

In how many of your NSCLC patients do you observe ALK or ROS1 rearrangements? Which clinical features do patients with ALK or ROS1 translocations frequently show?

A. Friedlaender: These are both fairly rare rearrangements. ROS1 rearrangements appear in about 2% of patients, while ALK rearrangements appear in about 4%. This is also what I observe in my practice – I treat a few patients with these rearrangements per year. Clinically, these patients are generally younger. Additionally, ALK or ROS1 translocations are more common among non-smokers and women. They mainly occur in lung adenocarcinomas.

Are there any patients showing both ALK and ROS1 rearrangements?

A. Friedlaender: They are mutually exclusive and initially do not happen at the same time. However, one rearrangement can occur as a resistance mechanism during treatment of the other one.

What is the gold standard for treatment of ALK- or ROS1-rearranged NSCLC?

A. Friedlaender: The gold standard for treatment of patients with ALK rearrangements is a second or third generation inhibitor. To me, alectinib, a second- generation ALK TKI, is the standard medication in these cases. If a patient progresses and still has an ALK alteration and/or no off-target alterations, we would follow with lorlatinib, a third-generation ALK/ROS1 TKI.

For ROS1-rearranged lung cancers, there is not so much of a gold standard. I usually start with the first generation TKI crizotinib, then sequence TKIs upon progression. However, if a patient shows brain involvement, I would consider a different drug upfront, as crizotinib does not have good brain penetration characteristics.

What are the greatest differences between the three generations of ALK/ROS inhibitors?

A. Friedlaender: The inhibitors of the second and the third generation, respectively, have much better brain penetration than first-generation agents. In my opinion, that is the biggest difference. Additionally, each of the therapies shows slightly different side effects, so we adjust the TKI treatment based on patient characteristics such as pre-existing health problems. Of course, cancer characteristics play a big role in therapeutic decision making. For example, if the patient shows significant, symptomatic brain involvement, this may push us towards a third-generation treatment upfront.

How do you choose an adequate therapeutic approach for the individual patient?

A. Friedlaender: When considering brain metastases, if the patient shows just a single or only a few lesions, we can go for radiotherapy. If there is a much more significant involvement of the brain, systemic therapy will be most important. In these cases, the most appropriate therapy is the one with the highest likelihood of working in the brain. For example, for ALK-rearranged patients, this appears to be lorlatinib, while for ROS1-rearranged patients, the therapeutic option of choice would be entrectinib or lorlatinib. If there is no brain involvement, the side effect profile is decisive for the therapeutic approach to help tailor the treatment to the patients and their disease.

How often does resistance against a certain ALK/ROS1agent occur?

A. Friedlaender: Resistance will naturally occur in all the patients. This is part of the challenge: If we administer the best treatment upfront, will it be better than a sequence of TKIs? That is why we do not yet have a clear answer to the question of what the best upfront approach may be.

When resistance occurs, a new tissue sample is needed to be able to determine what is causing the resistance. Then the treatment can be tailored accordingly. This is essential as it allows us to administer a more patient-adapted treatment.

What do you think about the fourth-generation ALK/ROSinhibitors currently under development, e.g., «double mutant active» ALK TKI?

A. Friedlaender: They are very promising, but I would like to see more clinical results. When diseases are rare like the ALK/ROS-rearranged lung adenocarcinoma, it is difficult to conduct large studies. This is why we are still lacking profound clinical data.

Could you finally shortly sum up the key message of your talk at the ILCS?

A. Friedlaender: My key message was that there are many genetic alterations in lung cancer and that these alterations must be searched for in all patients who could potentially have them. This includes all patients with lung adenocarcinoma and patients with squamous cell carcinoma with no smoking history or at a young age. It is very important to administer a treatment targeting these rearrangements, as the standards we use for other patients, such as chemotherapy and immunotherapy, do not work very well in these cases. If we do not administer targeted agents, we are drastically reducing the life expectancy of these patients. Thus, we urgently need to identify and specifically target the alterations. The treatment really has to be adapted based on patient and disease characteristics.

We know from real world studies that unfortunately, in a lot of places patient do not receive an adequate investigation of the genetic tumor profile and therefore do not receive optimal treatment. In Switzerland, however, patients with lung cancer generally receive the necessary work-up, leading to the right diagnosis and, hopefully, targeted treatment options.

Thank you very much for talking to us!