New Targets, New Hopes in Lung Cancer Treatment — 2019

In non-small cell lung cancer, personalized treatments directed at molecular targets using targeted drugsare very important. In less than 15 years, many targets and anticancer drugs developed against them have entered clinical use. These treatments have extended disease control in people with advanced lung cancer to averages of up to 2 years. New drugs are being developed from the outset, day by day, to address resistance mechanismsthat may arise against these drugs.

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The MET MUTATION in Lung Cancer

One of these mutations, the MET exon 14 mutation occurs in non-small cell lung cancer at a rate of 3-4% . The phase II study of a highly selective "MET inhibitor" called capmatinib was GEOMETRY mono-1, one of the noteworthy presentations at the ASCO 2019 Congress. The study enrolled patients with inoperable lung cancer at stage 3 and stage 4 . A total of 97 previously treated patients were included. All of these patients had a MET exon 14 mutation . The study showed the following:

• In previously treated patients, the overall response rate (complete and partial responses) was 40%, and the disease control rate (complete response, partial response and stable disease) was 78%.
• In patients who had never received treatment, the overall response rate was 68% and the disease control rate was 96%.
• The median duration of disease control was 5.5 months in previously treated patients and 10 months in patients who had never received treatment.
• This study also enrolled patients with brain metastasis. An intracranial response was observed in 54% of the 13 patients with brain metastases.
• Side effect profiles most frequently included peripheral edema (swelling of the hands/arms and feet/legs), fatigue and nausea, while the serious side effect rate was only 4.5%.

In conclusion, another good targeted agent has been developed for patients carrying this mutation. It could enter clinical use independently of previously used treatments and is also effective against brain metastases.

The RET MUTATION in Lung Cancer

Another mutation, an alteration in the RET gene, occurs in non-small cell lung cancer at a rate of 1-2% . Currently available treatments (chemotherapy, immunotherapy, etc.) have not achieved the desired success in patients with RET-altered lung cancer.

BLU-667 was evaluated in a study that enrolled 120 patients with non-small cell lung cancer carrying a RET mutation.

• 90% of the patients had previously received chemotherapy.
• The treatment response rate was 60% overall and 71% in patients who had never received treatment.
• The drug BLU-667 established its effectiveness / treatment response independently of prior treatment regimens, the location of the RET gene alteration and brain metastases.
• Treatment-related side effects were generally low-grade and manageable. 7% of patients experienced drug-related side effects such as pneumonia, mucositis (mouth sores), colitis or low blood counts, which required them to discontinue treatment.

Following the results of this study at ASCO 2019, the United States Food and Drug Administration (FDA) considered this agent a breakthrough therapy for patients with non-small cell lung cancer who were RET mutation-positive and whose disease had progressed after cisplatin-containing chemotherapy. It appears likely to receive FDA approval soon.

The study is ongoing in untreated patients with RET-positive lung cancer and in other RET-positive cancer types.

TAK-788 in Non-Small Cell Lung Cancer With an EGFR Exon 20 Insertion Mutation

EGFR mutation -positive non-small cell lung cancer patients have an exon 20 insertion mutation in approximately 6% of cases. Unfortunately, however, there is no approved effective targeted agent for this patient group. The EGFR tyrosine kinase inhibitors currently used effectively for other EGFR mutation types have low response rates and a short duration of disease control of around 2 months in patients carrying this mutation.

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TAK-788 is a selective inhibitor developed against the EGFR exon 20 insertion region. Its study, evaluating 28 patients, included previously treated patients.

• 54% of patients had received 3 or more lines of prior treatment. Brain involvement was present in 43% of patients.
• The study found an objective response rate of 43% and a disease control rate of 86%.
• The median duration of disease control was 7.3 months.
• The rate of treatment discontinuation due to treatment-related side effects was 14%, and the most common side effect was diarrhea(18%).

In conclusion, this agent demonstrated effectiveness through its response rate and duration of disease control in patients with an EGFR exon 20 insertion who had received multiple lines of treatment. The results of the ongoing EXCLAIM study in patients who have received fewer than 2 lines of treatment will clarify this drug's importance in the coming period.

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Other New Treatment Strategies in Lung Cancer

The RELAY Study Evaluating Erlotinib and Ramucirumab Combination Therapy

As is known, combination treatment strategies acting on two different targets have demonstrated effectiveness in many cancer types. EGFR -mutated non-small cell lung cancer patients have long been treated with the targeted agent erlotinib , one of the most important choices for first-line treatment or after chemotherapy. Studies combining two different mechanisms to identify a more effective treatment are increasingly being undertaken. In lung cancer patients with an EGFR mutation, study results evaluating EGFR inhibitors together with drugs that inhibit angiogenesis (tumor blood vessel formation), or with chemotherapy, were presented at ASCO 2019.

The first of these studies evaluated the combination of erlotinib and ramucirumab .

This phase III study demonstrated better progression-free survival (the duration of disease control) in the combination treatment arm.

Looking at the details of the study: 

• The study enrolled 449 previously untreated patients diagnosed with metastatic non-small cell lung cancer carrying an exon 19 deletion or exon 21 (L8585R) mutation.
• 77% of patients were Asian, 63% were women and 54% had an exon 19 deletion.
• Patients were assigned to erlotinib plus ramucirumab or erlotinib alone.
• Patients receiving combination therapy had an additional 7 months of disease control (19.4 versus 12.4 months, p<0.0001), a statistically better result, and a longer response duration (18 versus 11 months; p=0.0003). However, no difference in overall survival was found between the groups.

The Problem of Treatment Resistance in EGFR Mutation-Positive Patients

• The most important problem in our patients taking erlotinib is the development of new mutations. The most common of these genetic alterations is the T790M mutation. The RELAY study also assessed this genetic alteration in patients. An analysis after disease progression found a T790M mutation in 43% of patients receiving ramucirumab and 47% receiving placebo (p=0.84, no statistically significant difference).
• Regarding side effects, serious side effects were 18% more frequent in patients receiving ramucirumab (72% versus 54%).

We eagerly await the detailed publication and overall survival data from this study. Important questions include the level of response in patients with brain metastases and their quality-of-life scores during treatment. We will have to wait for answers.

The Combination of Gefitinib and Chemotherapy

Another study of combination treatments evaluated the use of the EGFR inhibitor gefitinibtogether with chemotherapy. In non-small cell lung adenocarcinoma, one of our frequently preferred chemotherapy regimens is the combination of carboplatin and pemetrexed . Adding gefitinib to this two-drug chemotherapy regimen was shown to be a more effective treatment strategy.

• A total of 350 patients with EGFR mutations were enrolled. Patients assigned to the chemotherapy arm received a total of 4 cycles of chemotherapy together with gefitinib. 
• Regarding response rates, adding chemotherapy to gefitinib increased the treatment response rate by an additional 12% (75% versus 63%),
• and extended the time to disease worsening by an additional 8 months (16 versus 8 months).
• Unlike the other study, the chemotherapy combination arm in this study also showed better overall survival . 
• As expected, serious side effects were 25% more frequent in patients in the combination arm. Diarrhea, fatigue and reduced blood counts were the most common.

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From previously reported studies of the next-generation EGFR inhibitor osimertinib, we know that it is a very effective first-line treatment strategy. Together with these new combination studies, we will learn over time which patients should receive a combination, which should receive first-line osimertinib and which should receive it with chemotherapy. Until the results of these studies are announced, we can at least establish a sequence based on the available data. When planning treatment, let us remember that drug side effects are as important as effectiveness and that planning must be individualized.