Lyudmila A. Bazhenova, MD

Lyudmila Bazhenova, MD, a medical oncologist and professor of medicine at UC San Diego Health, discusses targeted therapies for patients with HER2-mutated non–small cell lung cancer (NSCLC).

HER2, which is a common biomarker in other disease types such as breast cancer, can be targeted in patients with lung cancer. Agents that targeted the HER2 exon 20 insertion mutations have been investigated in clinical trials, including trastuzumab deruxtecan (Enhertu), poziotinib, pyrotinib, and neratinib (Nerlynx).

Investigators in the phase 2 DESTINY-Lung01 trial (NCT03505710) of trastuzumab deruxtecan observed an objective response rate (ORR) of 55%, median progression-free survival (PFS) of 8.2 months, and median overall survival (OS) of 17.8 months. Bazhenova notes that pneumonitis was reported as an adverse event (AE) in 26% of patients in the trial. Trastuzumab deruxtecan has been approved for patients with breast cancer and has been granted priority review for patients with NSCLC.

Other agents have shown efficacy, but not to the degree of trastuzumab deruxtecan, according to Bazhenova. In the phase 2 ZENITH20 study (NCT03318939), poziotinib showed a 27.8% ORR, while pyrotinib had an ORR of 19.2%, median PFS of 5.6 months, and median OS of 10.5 months in a phase 2 trial (ChiCTR1800020262). Neratinib plus temsirolimus had an ORR of 19% in the phase 2 PUMA-NER-4201 trial (NCT01827267).

 There are several HER2 perturbations you can find in lung cancer. HER2 can be overexpressed, amplified, or mutated. Currently, the majority of the [patients with HER2-mutated lung cancer] actually have mutations in HER2 called exon 20 insertions. And for this we have the efficacy of trastuzumab deruxtecan, which was recently published in the 

, showing ORR of 55%, median PFS of 8.2 months, and median OS of 17 months.

[What is] important to note is that one of the AEs of trastuzumab deruxtecan is pneumonitis, which was seen in approximately 26% of the patients. So once, if the drug gets approved and we start using it in lung cancer, it is very important to be aware of the pneumonitis as [an] AE.

 There are a couple of other medications being developed [for] the HER2 exon 20 insertions and those are poziotinib, pyrotinib, and neratinib, but the efficacy data looks pretty inferior, at least on a cross-trial comparison compared with trastuzumab deruxtecan.

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Lyudmila Bazhenova, MD, discusses targeted therapies for patients with HER2-mutated non–small cell lung cancer.

Trastuzumab Deruxtecan Shows Promising Efficacy for HER2-Mutated NSCLC

Lyudmila A. Bazhenova, MD, a medical oncologist and professor of medicine at UC San Diego Health, discusses targeted therapies for patients with 

-mutated non–small cell lung cancer (NSCLC).

 mutations include class I, II, and III types. Class I mutations include the V600E mutation, which has a targeted therapy available using the combination of dabrafenib (Tafinlar) and trametinib (Mekinist).

An open-label non-comparative phase 2 trial (NCT01336634) determined that this combination had efficacy for both pretreated and previously untreated patients with 

 V600E-mutated NSCLC. The overall response rate (ORR) was 68% for the pretreated patients and 64% for treatment-naive patients, and the median progression-free survival (PFS) was 10.2 months for pretreated patients and 10.8 months for previously untreated patients. This combination is now a frontline option for patients who test positive for 

This combination has not shown efficacy for class II or III 

 mutations, Bazhenova says. However, ongoing trials of BRAF dimer inhibitors and RAF dimer breakers could offer new approaches to treating these patients with targeted therapies.

 mutations, which are currently separated into 3 classes: class I, class II, class III. Your class I mutation is your typical 

 with 600E mutations where we have data on the efficacy of dabrafenib and trametinib in both first-line setting and the second-line setting showing ORR of 64%, the median PFS of [10.8] months [as first-line therapy]. So, in my practice, I use dabrafenib/trametinib in newly diagnosed patients.

We also know that if you do not have a class I mutation, so-called non-V600E mutations, dabrafenib and trametinib usually do not have any efficacy, so those patients should not be treated for those with those compounds. There are clinical trials with a new class of drugs, which are called BRAF dimer inhibitors and RAF dimer breakers that could be appropriate for those patients.

Lyudmila A. Bazhenova, MD, discusses targeted therapies for patients with BRAF-mutated non–small cell lung cancer. 

Treatments for BRAF-Mutated NSCLC Depend on Class of Mutation

Lyudmila A. Bazhenova, MD, a medical oncologist and professor of medicine at UC San Diego, discusses targeted therapies for patients with 

 mutations are found in 3% to 5% of patients with lung cancer. There are 2 separate, significant 

Bazhenova says that 2 drugs, capmatinib (Tabrecta) and tepotinib (Tepmetko), are approved by the FDA for patients with 

 exon 14 skipping mutations. Tepotinib was approved for patients with advanced or metastatic NSCLC based on the phase 2 VISION study (NCT02864992), which showed an overall response rate (ORR) of 46% and a median duration of response (DOR) of 11.1 months.

In the GEOMETRY Mono-1 study (NCT02414139), investigators found that capmatinib had an ORR of 41% and a DOR of 9.7 months in patients who had 1 or 2 previous lines of therapy, and 68% ORR in patients and a DOR of 12.6 months in patients who were treatment naive.

Acccording to Bazhenova, amplicon-based next-generation sequencing (NGS) DNA assays may not detect 

 exon 14 skipping mutations reliably. Recent studies have shown that RNA-based assays may find these mutations at a significantly higher rate, making these targeted therapies available to more patients.

 exon 14 skipping mutations, it is important to notice that [these mutations] happen in approximately 3% to 5% of patients with lung cancer. We have 2 separate [mutations]: 

 amplifications. Currently, our approved drugs are only approved in 

 exon 14 skipping mutations. And those are capmatinib based on [the GEOMETRY Mono-1] study and tepotinib based on the VISION study, which showed ORR of about 45% on tepotinib, and 68% in treatment-naive and 41% in pretreated patients in the capmatinib study.

The medications seem to have durable responses, which were reported anywhere from about 10 to 12 months. I think the caveat [is], what’s important to understand is 

 exon 14 skipping mutations is that they can be missed on a DNA assay, especially if your DNA assay is using amplicon-based NGS. And there [were] data that I presented from Memorial Sloan Kettering [Cancer Center], showing that if you do an RNA-based assay, you actually pick up more 

Lyudmila A. Bazhenova, MD, discusses targeted therapies for patients with MET-mutated non–small cell lung cancer. 

MET Exon 14 Skipping Mutations in NSCLC Respond to Targeted Therapies 

Lyudmila Bazhenova, MD, medical oncologist and professor of medicine at UC San Diego, discusses targeted therapies for patients with 

 mutations are present in about 30% of patients with NSCLC, according to Bazhenova. Sotorasib (Lumakras) has been approved by the FDA as second-line therapy for targeting the 

 mutation that is present in 13% of patients with NSCLC. The single-arm phase 2 CodeBreaK 100 trial (NCT03600883) of sotarasib showed an objective response rate (ORR) of 37% and a median progression-free survival (PFS) of 6.8 months.

In the phase 2 KRYSTAL-01 trial (NCT03785249), investigators found an ORR of 43% in patients treated with adagrasib (MRTX 849), another 

-targeted agent, but other data are not yet available, and this agent is not yet approved. Bazhenova says both drugs had an adverse event (AE) profile of gastrointestinal (GI) toxicities including diarrhea, nausea, and vomiting.

In both studies, a small number of patients with both the 

 mutation showed a higher ORR than the overall patient population: 50% with sotorasib and 64% with adagrasib. Bazhenova says that co-mutations could help determine the best possible choice of treatment if this association is substantiated by more clinical data.

 mutations are seen in approximately 30% of patients with non–small cell lung cancer. The specific mutation that we can target today is a 

 mutation, which happens in approximately 13% of patients with lung cancer. And we have sotarasib approved, which is currently approved in second-line therapy in patients who have failed platinum doublet and that has shown a response rate of 37% and median PFS of [6.8] months. Right behind sotarasib, not yet approved, but looks promising as well, is adagrasib, which showed the ORR of [43%]. And we do not yet know any data on median PFS or median duration of response because the medication is a little bit earlier in development. What we have learned from both of those compounds is that the majority of the [AEs] are GI toxicities, such as diarrhea, nausea and vomiting.

 We're also learning very interesting information about significance of co-mutations in patients with 

, and in both of the studies with sotarasib as well as adagrasib. Although on a very small number of patients, we have seen that patients who have a co-mutation in 

 tend to have a higher response rate compared to all patients in general. Again, this is very early, additional trials are needed to confirm that, but I find it's actually quite interesting that maybe co-mutations will make a difference on how we decide where to use sotarasib in patients with 

Lyudmila Bazhenova, MD, discusses targeted therapies for patients with KRAS-mutated non–small cell lung cancer.

Targeted Agents Show Efficacy in KRAS-Mutated NSCLC

Lyudmila A. Bazhenova, MD, medical oncologist and professor of Medicine at the University of California San Diego, explains the impact of having larotrectinib (Vitrakvi) results in a lung cancer cohort, as seen in a presentation of data from 14 patients, given during the 2020 World Conference on Lung Cancer (WCLC) Singapore.

Prior to WCLC, the data available for larotrectinib covered solid tumors generally, Bazhenova explains. Despite not having results from a lung cancer cohort, the larotrectinib data were convincing and the drug has been widely used for the treatment of TRK fusion-positive solid tumors. Bazhenova says the efficacy of the drug appears to be similar across all solid tumor types.

The key benefit of now having around larotrectinib specifically in the TRK fusion-positive lung cancer population is that oncologists can tell their patients what to expect with the drug, Bazhenova explains. According to the data, patients can achieve a response rate of up to 77%.

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Lyudmila A. Bazhenova, MD, explains the impact of having larotrectinib results in a lung cancer cohort, as seen in a presentation of data from 14 patients, given during the 2020 World Conference on Lung Cancer Singapore.

Outcomes of Larotretinib Confirmed in TRK Fusion-Positive Lung Cancer

 The ALTA-1L trial had built-in health-related quality-of-life end points. Brigatinib showed an increase in median time to worsening quality-of-life scores of almost 27 months, versus 8 months with crizotinib. Also, patients who were randomized to brigatinib had a longer duration of improvement in quality of life, which is expected because the durability of response on the brigatinib arm was much better than the durability of the response on the crizotinib arm.

My personal experience is very consistent with what the quality-of-life metrics show in the study. In patients who have 

-fusion non–small cell lung cancer, once you start them on ALK TKIs [tyrosine kinase inhibitors], you’ll usually see improvements in cancer-related symptoms within 2 to 3 weeks. That’s what was shown in brigatinib. The median improvement in cancer-related symptoms was higher in the brigatinib arm compared with the crizotinib arm, again consistent with the fact that brigatinib may have deeper responses than crizotinib.

-mutant non–small cell lung cancer, in my opinion, is a poster child for drug development in oncogenic driven tumors. In a very short time from the discovery of 

 fusions, we now have 5 ALK tyrosine kinase inhibitors approved. Even though those medications are actually quite effective and responses are durable, we still can improve on those in the first line. There have been some thoughts on maybe testing the combination of tyrosine kinase inhibitors and chemotherapy to see if adding chemotherapy to tyrosine kinase inhibitors will improve outcomes.

What still is unsettled in patients with stage IV non–small cell lung cancer who have 

 fusions is how to correctly sequence agents. For example, if you give the patient alectinib as a first-line therapy, what should your second-line choice be? Should you go to lorlatinib, which has data, or should you try brigatinib first and then go to lorlatinib later?

I do want to put in a plug for something that’s called the Lung Cancer Master Protocol. There is an NCI [National Cancer Institute] effort going on right now trying to learn what the correct sequencing is, so when the patients are treated with ALK tyrosine kinase inhibitors, upon progression a biopsy is performed and treatment assignment is done based on what was found in the post-progression biopsy.

For example, if you find that the patient has a 

 amplification, it makes complete sense to use crizotinib as a second-line drug because crizotinib should have ALK efficacy and also inhibits MET. At this point, the sequencing is pretty much trial and error, and we do not have any results from the comprehensive clinical trials telling us what should be our drug A and what should be our drug B.

A 58-year-old woman presented with cough, fatigue and anorexia

Chest x-ray showed multiple left upper lobe mass and mediastinal lymphadenopathy

Chest/abdomen/pelvic CT scan confirmed left upper lobe mass measuring 6.2 cm

PET scan showed PET positivity in bilateral LUL mass and mediastinal LN

MRI of the brain showed widespread scattered small lesions; consistent with multifocal brain metastases

Bronchoscopy with transbronchial biopsy of the left upper lobe confirmed lung adenocarcinoma

Patient was started on brigatinib 90 mg qDay for 7 days; well tolerated; dose was increased to 180 mg qDay