Lung Cancer — The Nuances of Mutations & Targeted Therapies

In the last two decades, the landscape of lung cancer treatment has been dramatically transformed by the discovery of specific genomic oncogenic drivers, paving the way for highly effective targeted therapies. 

This development has not only redefined our approach to lung cancer but also offered new hope for patients facing this challenging diagnosis. Therefore, guiding therapy decisions according to oncogenic drivers has been considered the standard approach in patients with newly diagnosed lung cancer.

Dr. Mark Kris, a thoracic oncologist at Memorial Sloan Kettering Cancer Center, mentioned the importance of understanding all the aspects of cancer and the patient to whom you are offering treatment to allow you to provide the best therapy, including the search for oncogenic drivers.  

“In those cancers [oncogenic positive], the drugs we have that target the proteins that are activated by those mutations and infusions, these drugs are extremely effective, shrink the cancer 80 or 90% of the time,” Dr. Kris tells SurvivorNet. 

Targeting Mutations: Who Should Be Tested and Which Ones Matter? 

The routine use of genomic analyses, through multiplexed assays with the goal of evaluating target therapies is recommended for all patients newly diagnosed with lung cancer.

Due to health costs, some societies have proposed sequential narrow spectrum analyses testing of 3 essential alterations, namely EGFR, ALK and ROS1. 

Overall, when physicians requested molecular testing, they commonly asked for EGFR (99%), ALK (95%) and ROS1 (79%), while other alterations were requested under 50% of the time.

Apart from that, other mutations also can guide therapy, including NTRK fusions, RET, KRAS, BRAF, and MET.

Oncogenic Driver Detected: What’s the Next Step?

The discovery of oncogenic activation in certain tyrosine kinases within lung cancer tumors, particularly EGFR mutations or ALK and ROS1 gene rearrangements, has revolutionized treatment, leading to the development of targeted molecular therapies for these patients.

“You really have to find those cancers [with oncogenic drivers]  and you have to use these targeted therapies first,” says Dr. Kris. 

For each oncogenic driver detected, there are nuances that should be addressed when beginning the treatment. 

Targeted Therapy: EGFR mutation

The most common mutations involving the EGFR gene include EGFR exon 19 deletions or 21 L858R mutation. Osimertinib is approved by the FDA for the first-line treatment of patients with advanced or metastatic non-small cell lung carcinoma whose tumors have EGFR exon 19 deletions or exon 21 L858R mutation.

Treatment with an EGFR tyrosine kinase inhibitor (TKI) is typically discontinued once the disease progresses. However, some groups opt to continue EGFR TKI in patients with progressive disease who initially responded to the treatment, due to the potential risk of rapid disease progression.

The IMPRESS trial, which involved 265 NSCLC patients with an activating EGFR mutation, compared the outcomes of chemotherapy plus gefitinib versus chemotherapy alone after disease progression on first-line gefitinib. The trial results indicated that continuing gefitinib alongside chemotherapy did not extend progression-free survival (PFS) and was associated with a shorter overall survival (OS) compared to chemotherapy with placebo.

Important toxicities associated with inhibition of the EGFR pathway include a characteristic rash, diarrhea, and uncommonly interstitial pneumonitis.

Targeted Therapy: ALK rearrangements

The presence of an ALK gene rearrangement strongly predicts for sensitivity to ALK TKIs (eg, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib), and treatment with these agents significantly prolongs progression-free survival (PFS). 

For ALK-positive patients who develop resistance to or are unable to tolerate crizotinib (first choice), we recommend treatment with one of the second-generation ALK inhibitors: brigatinib or alectinib. 

In this context of ALK mutations, an ALK inhibitor treatment is typically maintained until disease progression is evident. In specific cases, such as when there is a single site of recurrence that can be managed with local therapy or in patients with very mild, asymptomatic progression, continuing the ALK inhibitor after initial signs of progression may be considered. Upon further progression, switching to a more potent next-generation ALK inhibitor or initiating standard chemotherapy may be necessary.

Treatment with the ALK inhibitors is generally well-tolerated. However, there are a number of significant toxicities that may require dose modification or treatment discontinuation, such as: gastrointestinal upset, pneumonitis, QTc interval prolongation, hypertension, myalgia, and visual disturbances. 

Targeted Therapy: ROS1 rearrangements

The ROS1 tyrosine kinase is highly responsive to inhibitors like crizotinib, which targets ROS1/MET, as well as entrectinib and repotrectinib, which target ROS1/TRK. These medications are approved by the US FDA for use in patients with ROS1 translocation, including both those who are treatment-naïve and those who have previously undergone chemotherapy.

If a patient progresses using of crizotinib, the next step is the use of lorlatinib. If the disease still progresses, it is recommended to move to non-targeted approaches (ie, chemotherapy and consideration of immunotherapy, though responses to immunotherapy are very rare).

Dr. Kris emphasizes, “You need to really do your best to learn about that patient’s cancer, by all means too. You have to learn about the person’s approach to the disease too. Some people feel better with a targeted approaches, the first approach, and by all means, it’s a reasonable thing to do, particularly if it meets a special need of the patient.”