In an interview with Targeted Oncology, Chul Kim, MD, MPH, discussed the results from the phase I/II trial evaluating the combination of an EGFR TKI and Src inhibitor in <em>EGFR</em>-mutant NSCLC. He also highlighted other important advances in the treatment of lung cancer, including the evolving role of circulating tumor DNA to detect disease progression.
Chul Kim, MD, MPH
The combination of dasatinib (Sprycel) plus osimertinib (Tagrisso), an EGFR tyrosine kinase inhibitor (TKI), demonstrated a generally well-tolerated safety profile in treatment-naïve patients withEGFR-mutant nonsmall cell lung cancer (NSCLC), according to an open-label, phase I/II trial that was presented at the 2019 World Conference on Lung Cancer (WCLC).
The phase I portion of the trial was designed to establish a phase II dose. The trial included 2 dose levels of either 80 mg osimertinib once a day (QD) plus 50 mg dasatinib two times a day (BID) and 80 mg QD plus 70 mg BID dasatinib. Investigators believed that the combination of osimertinib with the Src inhibitor could lead to a synergistic effect in this patient population to help overcome osimertinib resistance.
Overall, there were no new safety signals, and the combination had evidence of anticancer activity. The most common toxicities, which were mostly grades 1 or 2, included pleural effusion (n=6), AST elevation (n=5), ALT elevation (n=5), rash (n=5), and diarrhea (n=4). Two patients had grade 2 pleural effusion, and 1 patient had grade 3 pleural effusion. Grade 3 treatment-related adverse events included pleural effusion, fatigue, neutropenia, anemia, and headaches.
In April 2018, osimertinib was approved by the FDA for the frontline treatment of patients with NSCLC harboringEGFRmutations of either exon 19 deletions or exon 21 L858R substitution mutations. This approval led to an enrollment decrease in the clinical trial evaluating the combination with dasatinib.
“The trial is closed for enrollment at this point,” said Chul Kim, MD, MPH, lead author, “but we believe that the Src inhibitor plays a role in either overcoming the resistance to osimertinib in the primary resistant setting or whether it came also overcome acquired resistance. This will need to be determined with future trials.”
In an interview withTargeted Oncology, Kim, an attending physician atMedStar Health,Georgetown University Hospital, and an assistant professor of medicine at Georgetown University, discussed the results from the phase I/II trial evaluating the combination of an EGFR TKI and Src inhibitor in EGFR-mutant NSCLC. He also highlighted other important advances in the treatment of lung cancer, including the evolving role of circulating tumor DNA (ctDNA) to detect disease progression.
TARGETED ONCOLOGY: Could you provide some background to this study?
Kim:This is a phase I trial of osimertinib in the first-line setting for patients with EGFR-mutated NSCLC who were treatment-naïve. The rationale behind this study was that the Src pathway has been associated with resistance to EGFR TKI treatment. Dasantinib, being the Src inhibitor, was added to osimertinib, which is 1 of the standard options forEGFR-mutant NSCLC to see whether the combination could boost the effect of osimertinib.
TARGETED ONCOLOGY: What were the findings?
Kim:We enrolled 10 patients in the phase I portion. The treatment was generally well-tolerated. We have seen side effects mainly from dasantinib, and the most common side effect was pleural effusion, which is a known side effect of dasantinib. In terms of efficacy, we saw an 80% objective response rate (ORR), and only 1 out of 10 patients had intrinsic resistance, which is defined as progressive disease or stable disease with less than 4 months as best response in the first-line setting.
We saw encouraging results. However, after approval of osimertinib as first-line treatment, accrual became slower, so we stopped the trial. The trial is closed for enrollment at this point, but we believe that the Src inhibitor plays a role in either overcoming the resistance to osimertinib in the primary resistant setting or whether it came also overcome acquired resistance. This will need to be determined with future trials.
TARGETED ONCOLOGY: Are there any other combinations that appear to benefit this patient population?
Kim:After osimertinib treatment, we see various pathways of resistance. Sometimes we see fusions, such asBRAFor RETfusions, and there has been a report of combining targeted therapy to osimertinib to overcome resistance to those types of settings. For example, there was a case report of 2 patients who developed RET fusion-positive NSCLC after they were treated with osimertinib for their EGFR-mutant NSCLC.RETfusion was the driver mutation, and what they showed was that by adding a RET-specific inhibitor, they were able to overcome the resistance to the RETfusion or even the resistance mechanism.
TARGETED ONCOLOGY: Could you discuss your data supporting the role of ctDNA in lung cancer?
Kim:The ctDNA is a very promising tool to monitor disease progression and evolution in NSCLC. We had 20 patients with theEGFR-mutant NSCLC enrolled in a clinical trial of local ablative therapy at the National Institutes of Health. There were 20 patients, and at baseline and subsequent clinical follow-up, we serially collected blood and saliva samples at each time point. We analyzed blood by the droplet digital (DD) PCR and next-generation sequencing (NGS). We also looked at the ctDNA in the saliva sample in collaboration with colleagues at the University of California, Los Angeles. The NGS testing was done with our partner, a ctDNA company. What we did was for each patient, we looked at whether there was a correlation between DD PCR, NGS on blood, and then ctDNA on saliva.
The study results show that there was a correlation between studies. What was remarkable was that the DD PCR rise pattern can tell us which patient may progress clinically. Out of 14 patients who had a clinical progression, 9 patients had an early ctDNA rise. POn average, we detected the ctDNA rise 3 months earlier than with the clinical evaluation. We believe the ctDNA can be used to monitor disease. The big question is whether we can improve patient outcomes by intervening with the molecular progression. That probably requires a bigger study or a randomized trial to show that.
TARGETED ONCOLOGY: What are some ongoing challenges with using ctDNA in this space?
Kim:One of the issues is, of course, cost. It’s not cheap to sequence patients multiple times. Also, some patients have tumor driver mutations, and it is challenging to track their disease because we do not have anything to monitor with. Those are the major challenges.
There are exciting roles for ctDNA that are emerging. One is to use the ctDNA in the early disease setting. For example, after surgery, we may be able to use ctDNA to detect early recurrence of disease. That is 1 of the areas where ctDNA can play a role. In the metastatic setting, as described in our study, we believe that with sensitive ctDNA technology, we believe we are able to detect molecular progression before clinical progression. We may be able to use that information to treat the patients, so I believe the future of ctDNA testing is bright.
TARGETED ONCOLOGY: What next steps are necessary for making ctDNA more widely used?
Kim:For lung cancer, ctDNA has been used to detect molecular alterations at baseline. The correlation between ctDNA and tissue has been evaluated by multiple studies now. Clinically it can be very useful in terms of detecting targetable mutations. In my clinic, I have detected many targetable mutations well before the NGS, or tissue-based genotyping, results were available. I was able to act on the results using the ctDNA information, and those patients had good success.
The role of ctDNA at this point is mainly limited to detecting targetable mutations at baseline. For example, we can detectEGFR,ALK, andROS1by using ctDNA technology. However, in the future, I believe there will be a bigger role for ctDNA, such as for monitoring disease in the metastatic setting as described in our study because we believe that by using ctDNA, we can detect molecular progression before clinical progression is detected.
The second emerging role of ctDNA is quite exciting in the early disease setting where you can use ctDNA to detect early recurrence of disease well before clinical progression or recurrence. However, for us to use ctDNA in the early disease setting or locally advanced setting, we need larger, prospective studies, and eventually, a randomized trial to show the utility of ctDNA in these settings.
TARGETED ONCOLOGY: Overall, what are some important advances in lung cancer recently?
Kim:There have been great advances in the past few years in the field of lung cancer. [At this meeting,] we saw a presentation from the CASPIAN study where they used the platinum doublet chemotherapy and durvalumab in patients with extensive-stage small cell lung cancer (SCLC). They showed there was an OS benefit in adding durvalumab to platinum doublet chemotherapy. There was a modest improvement in overall survival and progression-free survival. For SCLC, there is more work to do, and we need to improve further to build upon the currently available strategies to improve outcomes for those suffering from SCLC.