Sukhmani K. Padda, MD, director of thoracic medical oncology at Cedars-Sinai Medical Center, discusses how she selects treatment following osimertinib (Tagrisso) resistance in patients with non–small cell lung cancer.

Reassessing the patient's molecular tumor profile is an important step that needs to be taken after a patient progresses on osimertinib, Padda explains. A number of methods can be utilized including liquid biopsy and circulating tumor DNA, which can provide an assessment of all tumor sites throughout the body that shed their DNA into circulation.

Another step that needs to be considered is tumor biopsy, Padda says. This step is even more important following progression on osimertinib, as the rate of histologic transformation appears to be reported at slightly higher rates than first- and second-generation drugs. It is important that a transformation to small cell lung cancer, squamous cell carcinoma, or even pleomorphic undifferentiated cancers is not missed, Padda concludes.



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Sukhmani K. Padda, MD, discusses treatment selection following osimertinib resistance in patients with non–small cell lung cancer.

Dr. Padda on Selecting a Therapy Following Osimertinib Resistance in NSCLC

Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses next steps for treatment of patients with 

-positive non—small cell lung cancer (NSCLC).

Moving forward, the therapies used in this space will have to be increasingly precise, Padda says. Based on preliminary examination of plasma samples taken from patients enrolled in the phase III FLAURA study, it is becoming clear that a tailored approach needs to be taken for each individual case.

In order to better understand mechanisms of resistance to osimertinib (Tagrisso), there is an ongoing phase II trial called ELIO in which investigators are evaluating plasma samples from patients treated with the frontline drug. Padda says investigators are looking at pretreatment plasma samples, samples taken during the course of treatment, and samples taken at the time of progression. In the FLAURA study, she adds, investigators did not consistently biopsy patients at the time of progression. ELIO is addressing this, as well as the instances where patients develop histological transformation to squamous NSCLC or small cell lung cancer.

Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses next steps for treatment of EGFR-positive non–small cell lung cancer.

Dr. Padda on Next Steps for Treatment of EGFR+ NSCLC

Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses novel combinations in the treatment of patients with 

The third-generation EGFR TKI osimertinib (Tagrisso) has emerged as a highly effective frontline option for these patients, with encouraging central nervous system activity. However, despite the agent’s efficacy, these patients will still progress at some point. Beyond the frontline setting, investigators are exploring combinatory approaches. Padda says that among the most interesting strategies under investigation are EGFR TKIs in combination with EGFR monoclonal antibodies.

In fact, Padda adds that this was a promising strategy before the rise of osimertinib in the second-line setting. With patients who progressed on erlotinib (Tarceva) or gefitinib (Iressa)—with or without evidence of T790M&mdash;when they went on to receive this combination, investigators saw responses in both of those categories. Similar approaches are now being studied following osimertinib resistance.

For example, osimertinib plus necitumumab (Portrazza) is being evaluated in a trial sponsored by National Cancer Institute. Another trial, led by Leora Horn, MD, MSc, of Vanderbilt University Medical Center, is evaluating the use of afatinib (Gilotrif) plus necitumumab.

Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses novel combinations in the treatment of patients with EGFR-positive non–small cell lung cancer.

Dr. Padda on Novel Combinations for EGFR+ NSCLC

Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses the need for approaches to treatment for patients with 

-positive non—small cell lung cancer (NSCLC) who have developed resistance to frontline osimertinib (Tagrisso).

The third-generation EGFR TKI osimertinib has emerged as the standard frontline therapy for this patient population, based on encouraging data from the FLAURA study. Thoracic oncologists are also impressed by the unprecedented central nervous system penetration seen with osimertinib. However, the next challenge for research is deciding what to do when patients progress on this targeted therapy.

There were data recently presented at the 2018 ESMO Congress, Padda says, which showed that there are 2 acquired mechanisms of resistance that patients develop. C797S, the most common, prevents the binding of osimertinib to the disease, and MET amplification is also seen. The biggest hurdle with these mechanisms, she explains, is that they are very heterogeneous and tend to happen concurrently. With progression on first- and second-generation TKIs, patients would usually develop a dominant resistant mechanism that could be treated as a second driver mutation.

Currently, when a patient progresses on frontline osimertinib, physicians have to rely on platinum doublet chemotherapy. However, there are several ongoing studies looking at more effective combinatory approaches.

Sukhmani Padda, MD, assistant professor of medicine, Stanford University Medical Center, member, Stanford Cancer Institute, discusses therapy beyond osimertinib in the treatment of patients with EGFR-positive non–small cell lung cancer.

Sukhmani Padda, MD

Articles

Dr. Padda on Selecting a Therapy Following Osimertinib Resistance in NSCLC

Dr. Padda on Next Steps for Treatment of EGFR+ NSCLC

Dr. Padda on Novel Combinations for EGFR+ NSCLC

Dr. Padda on Overcoming Resistance to Osimertinib in EGFR+ NSCLC