Broader Testing Options Pave the Way for Increasingly Tailored Lung Cancer Treatments

Karen Reckamp, MD

­­­­­­The efficacy of targeted therapies for patients with lung cancer relies on detailed testing approaches found only in DNA- and RNA-based sequencing assays to identify specific mutations, according to faculty from an OncLive^® State of the Science Summit^™ on precision medicine in lung cancer.

The event, chaired by Karen Reckamp, MD, professor of medicine, director of the Division of Medical Oncology, associate director of Clinical Research, and medical oncology director of the Lung Institute at Cedars-Sinai Medical Center, focused on the importance of comprehensive next-generation sequencing (NGS) when testing for biomarkers, the significance of liquid biopsy, treatment opportunities for patients with EGFR, KRAS, ALK, and RET abnormalities, and clinical trials that signal improved patient outcomes.

Reckamp was joined by her colleagues:

• Eric Vail, MD, director of Molecular Pathology, assistant professor of pathology and laboratory medicine, Cedars-Sinai Medical Center
• Andrew Horodner, MD, chairman of the Tumor Board, vice-chair of the Oncology Committee, Torrance Memorial Medical Center
• Ronald B. Natale, MD, medical director of the Clinical Lung Cancer Program, professor of medicine, Cedars-Sinai Medical Center
• Sukhmani K. Padda, MD, associate professor of medicine, director of Thoracic Medical Oncology, Cedars-Sinai Medical Center
• Sepehr Rokhsar, MD, division clinical chief of Medical Oncology, Cedars-Sinai Medical Center
• Ani S. Balmanoukian, MD, director of Thoracic Oncology and associate director of the Phase 1 Immune-Oncology Program, the Angeles Clinic and Research Institute; oncologist, Cedars-Sinai Medical Center

Below, Reckamp, Vail, Horodner, Natale, Padda, Rokhsar, and Balmanoukian summarize the main messages from their presentations.

Testing for Biomarkers: A Review of Options

Vail: I gave a broad overview of the different ways of conducting biomarker testing, focusing on single-gene testing vs broad-gene testing. Single-gene testing includes, [for example,] a [polymerase chain reaction (PCR)] test for an EGFR mutation or a FISH [fluorescence in situ hybridization] test for an ALK [fusion] vs doing some type of NGS.

Our goal should be to get people tested for all the FDA-approved biomarkers before we jump to making sure everyone participates in big [panels]. There is some clinical utility in the big panels. But a 50-gene DNA and RNA panel that targets the vast majority of all the biomarkers that [have associated agents that are] FDA approved or will be FDA approved is more helpful than trying to do single-gene testing. You get the bulk of [the information] in that early panel.

Everyone who has lung cancer should be getting tested for all these biomarkers. [Guidelines support testing,] and they all say broad-based molecular profiling or NGS is preferred to single-gene testing.

For NGS, there are 2 different ways to do the testing besides broad and narrow: DNA and RNA or DNA only. DNA-only panels lose sensitivity for fusion-based events. Any time 2 different genes come together, or anytime an intergenic fusion happens inside the gene itself, the test sensitivity is lower. The preferred mechanism [in these cases] is RNA-based testing.

We should test every patient with lung cancer with at least an NGS panel that covers all the FDA-approved biomarkers and the [pending] biomarkers as well. [A forward-looking perspective] is good. Most of the [biomarker] panels that are available right now are very targeted to lung cancer. I would recommend a DNA and RNA panel because it’s more accurate than a DNA-only panel.

It is exceptionally important to have local expertise in testing and biomarkers at the pathology and laboratory level. It is our obligation as laboratorians to assist our colleagues in this endeavor because it is rapidly changing, important, and clinically useful. Setting up reflex testing, and testing all patients for all the biomarkers, can assist with [creating treatment plans].

Incorporation of Liquid Biopsy into Clinical Practice

Reckamp: I talked about liquid biopsy and where it fits in our algorithms. The gold standard is still tissue biopsy. For histology, we do need tissue biopsy to get the full diagnosis. But with molecular components using plasma, positive results are usually just as accurate as [results obtained from tissue].

When do we use liquid biopsy? Up front, we need to shoot to get our histologic diagnosis. However, if tissue is negative or nondiagnostic, [such as instances where there’s insufficient tissue,] understanding the genomics of the tumor through the blood is generally helpful, especially for patients with metastatic disease.

We know we can increase the number of patients who receive biomarker-directed therapies when we add liquid biopsy to tissue [biopsy]. False negatives [generally happen] when there’s insufficient DNA shedding into the plasma. False positives generally [happen because of] contamination, technical factors, and clonal hematopoiesis. For the most part, when you have a positive result in the blood, it is something that can be treated, meaning blood [biopsy] can be just as much of a gold standard as tissue [biopsy]. Blood is easier to test, and we can test it at multiple time points.

We’re seeing some practical uses [for liquid biopsies] and moving this into the clinic. Especially in the early stage, we may prevent patients from being treated who don’t need to be treated and preferentially treat those patients who do need it. Liquid biopsies are an alternative option for molecular testing, especially when tissue is insufficient.

We may move this testing into diagnosis, as well. Immune correlates and additional markers are still necessary and need to be validated, but liquid biopsies are a promising biomarker to help us effectively treat more of the right patients with less toxicity.

Precision Medicine in the Perioperative Setting

Horodner: I talked about targeted therapy and immunotherapy and how some exciting clinical trials and data have revolutionized how we should treat [non–small cell lung cancer (NSCLC)] both preoperatively and postoperatively. I also showed some data looking at adjuvant osimertinib [Tagrisso], adjuvant atezolizumab [Tecentriq], and neoadjuvant nivolumab [Opdivo], and I presented some data about ongoing neoadjuvant trials looking at osimertinib, immunotherapy, and tiragolumab, which targets TIGIT.

The FDA has approved both osimertinib and atezolizumab in the adjuvant setting. The [phase 3] ADAURA trial [NCT02511106] showed a significant improvement in [disease-free survival (DFS)] in patients treated with osimertinib, leading to the FDA approval of that drug [in that setting]. Overall survival [OS] data are still maturing, but in general, osimertinib is very well tolerated in the metastatic setting.

[The phase 3 IMpower010 trial (NCT02486718)] led to the FDA approval of atezolizumab [in the adjuvant setting], which has now become the standard of care and is part of [National Comprehensive Cancer Network (NCCN)] guidelines.

In the neoadjuvant setting, nivolumab is now on the scene in combination with platinum-based chemotherapy. This combination is approved in the preoperative setting for patients with resectable lung cancer that is either 4 cm or node positive.

Some upcoming neoadjuvant studies include the [phase 3] NeoADAURA trial [NCT04351555], which is opening soon and will look at neoadjuvant osimertinib. Also, the [phase 2] GO42501 trial [NCT04832854], which is looking at a combination of atezolizumab and tiragolumab, is currently enrolling.

EGFR and EGFR Exon 20 Targeted Approaches

Natale: X-ray crystallographic studies finally allowed for progress in the development of effective treatments for patients with exon 20 insertion mutations in EGFR and homologous mutations in HER2. Amivantamab[-vmjw (Rybrevant)], a bifunctional EGFR/MET antibody, and mobocertinib [Exkivity], a first-in-class TKI, are FDA approved. They produced objective response rates [ORRs] in 40% and 25% of patients respectively, with manageable toxicity profiles.

Poziotinib produces objective responses in about 20% to 25% of patients with EGFR exon 20 mutations, and in 35% of patients with HER2 exon 20 mutations. This drug is likely to be approved for the latter [population] within the next year. Furmonertinib [Ivesa], tarloxotinib, and BLU-451 are early in development, but are also very promising.

KRAS-Targeted Approaches

Padda: Sotorasib [Lumakras] is now the standard of care for previously treated [patients with] advanced KRAS G12C–mutant NSCLC, and there are many other G12C inhibitors in development. Both mutant-specific inhibitors beyond G12C and pan-KRAS inhibitors are being developed. Innumerable combination studies are ongoing, one of the most interesting being one with immunotherapy. There are also specific immunotherapeutic approaches, such as mRNA vaccines and CAR T-cell therapy approaches that are emerging, which is exciting.

New Data in Other Targets: ALK, MET, and HER2

Rokhsar: There have been many strides in lung cancer, [and treatment is becoming] more complicated. Whether the mutation is ALK, MET, or HER2, it’s not just about having the alteration, it’s about having which alteration. [For instance,] in ALK, which mutation status are we seeing? Regarding MET, I specifically talked about MET exon 14 skipping alterations, [which require a different treatment than] MET amplification. Similarly, in HER2: Are we talking about HER2 overexpression or HER2 mutations?

Many upcoming studies are going to be looking at specific alterations in patients, and it will be interesting to see what comes out. Many great drugs are coming into development that will hopefully make the lives of our patients a lot better.

Targeting RET in NSCLC

Balmanoukian: I talked about the molecular basis of RET alterations, targeting RET with multikinase and selective kinase inhibitors, and mechanisms of resistance. I highlighted the complexity of lung adenocarcinoma in the NSCLC landscape, as well as the treatments that are available for patients with RET fusions.

The [phase 1/2] ARROW trial [NCT03037385] led to the FDA approval of pralsetinib [Gavreto]. This trial specifically looked for RET fusion­–positive patients with NSCLC who had prior platinum therapy. In July of 2019, the trial was amended to expand eligibility to patients who were treatment naïve, allowing the enrollment of patients who had better performance statuses, making the population more reflective of real-world patients. Patients responded regardless of whether brain metastases were present at the time of enrollment, and the drug has good activity overall.

The other therapy that’s available is selpercatinib [Retevmo], which was FDA-approved based on the [phase 1/2] LIBRETTO-001 trial [NCT03157128]. This trial [is enrolling] patients who had RET fusion–positive NSCLC. Overall, selpercatinib has been well tolerated, especially with dose reduction.

Multiple resistance mutations have been reported, including the gatekeeper mutation and the solvent front mutations. TPX-0046 is a next-generation RET inhibitor that is structurally differentiated and has a broader range of mutation coverage. This therapy is currently being evaluated in the ongoing [phase 1/2] SWORD-1 trial [NCT04161391], which shows promising early data, suggesting that TPX-0046 may have a role in the progression setting.