Targeted Therapy Research Booms in Biomarker-Positive NSCLC

Shirish M. Gadgeel, MD, MBBS

The molecular landscape of non–small cell lung cancer (NSCLC), especially with EGFR mutations and acquired resistance, continues to get more complex as preliminary data with JNJ-372, higher-dose osimertinib (Tagrisso), and TKI combinations lead to intriguing discussions in the community, explained Shirish M. Gadgeel, MD, MBBS.

Furthermore, with the emergence of targeted therapies, biomarker testing has become a critical aspect of treatment decision making in lung cancer, Gadgeel added.

“There is no one-size-fits-all treatment option for patients with lung cancer, particularly NSCLC,” said Gadgeel. “It’s extremely important that we continue to profile tumors as thoroughly and adequately as possible so that we can initiate optimal courses of therapy.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on lung cancer, Gadgeel, a Mary Lou Kennedy Research professor in thoracic oncology, professor in the Department of Internal Medicine and the Division of Hematology/Oncology, who is also a co-leader of the Thoracic Oncology Research Program, and an associate director of the Networking and Affiliated Centers at the University of Michigan Medicine, highlighted some of the recent targeted therapy advances in NSCLC and how ongoing research is taking the paradigm to the next level.

OncLive: How would you spotlight the past year in lung cancer treatment as it relates to approvals?

Gadgeel: Several drugs received regulatory approval for NSCLC this year. Capmatinib (Tabrecta) was approved for the management of MET exon 14 skipping mutations, selpercatinib (Retevmo) was approved for RET fusion–positive NSCLC, as well as pralsetinib (Gavreto), and there was also brigatinib (Alunbrig) for frontline treatment of patients with ALK-positive NSCLC.

In the immunotherapy space, the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) was approved for patients with PD-L1–positive NSCLC. There is also the combination of chemotherapy, nivolumab, and ipilimumab as frontline treatment. Notably, in that combination, chemotherapy is only given for the first 2 cycles and is indicated for all patients with advanced NSCLC, irrespective of the level of PD-L1 positivity.

What has been most exciting to you in the EGFR-targeted arena?

Osimertinib (Tagrisso) remains the preferred treatment for EGFR-positive advanced NSCLC. This is primarily for patients with exon 19 deletions as well as those with exon 21 (L858R) mutations, which constitutes approximately 90% of all EGFR mutations.

We also now have the approval of erlotinib (Tarceva) plus ramucirumab (Cyramza), based on the phase 3 RELAY trial, which showed an improvement in progression-free survival (PFS). However, this trial excluded patients with brain metastasis, and we don’t have survival data yet. For those reasons, despite this approval, I still lean towards osimertinib as the preferred frontline agent.

There are 3 other major advances. To date, data suggest that EGFR C797S mutations and c-MET amplifications are the major mechanisms of resistance. However, we have to view these data with some level of caution, because the number of patients in the series that have been looked at is reasonably limited. It is possible that, as we obtain more data, the percentage of mechanisms of resistance may change. However, of now, C797S and c-MET amplification are the major mechanisms of resistance.

In patients whose tumors acquire C797S as the mechanism of resistance, a combination of first-generation EGFR inhibitors, such as erlotinib, plus osimertinib may provide clinical benefit. This is something that should be considered in patients. Emerging clinical trials will be evaluating agents that specifically target C797S, so we may have C797S-specific drugs in the future.

Further, data show that the combination of a c-MET inhibitor combined with osimertinib may provide clinical benefit. However, based on data from a trial that evaluated savolitinib with osimertinib, the benefit was relatively modest with an estimated response rate of about 25% and a duration of response of about 9 months.

At the 2020 ASCO Virtual Scientific Program, we had data on osimertinib at a higher dose of 160 mg compared with the standard dose of 80 mg, which showed a response rate of 24%. The median PFS was encouraging at 9.6 months, thus, we may have a targeted therapy option for patients with exon 20 mutations. Of course, it is not yet FDA approved [for this subtype], but hopefully we can build on it going forward.

Another drug that was reported in the exon 20 space is JNJ-372, which is a bispecific antibody against EGFR and c-MET. This antibody demonstrated [encouraging clinical activity]. Although we still need more data, we hope that we may have targeted agents for these patients in the near future.

Finally, there are data on adjuvant osimertinib from the ADAURA trial, which was also presented at the 2020 ASCO Virtual Scientific Program. This was a worldwide study that evaluated adjuvant osimertinib for 3 years in patients with stage IB to IIIA resected NSCLC. The primary end point was disease-free survival [DFS], which showed an extremely promising hazard ratio [HR] of 0.21. The DFS HR was 0.12 in stage IIIA patients and 0.17 in stage II patients. In the adjuvant setting, we really want to focus on improved survival rates. These are very promising data and it is possible, based on these data, the drug may receive a regulatory approval in the adjuvant setting.

What are the some newer aspects of biomarker testing to be aware of in clinical practice?

Biomarker testing has become a critical aspect of decision making, along with the management of patients with advanced NSCLC. It's very important that physicians have an understanding of what tests they’re ordering and the capabilities of the labs that are sent. Moreover, its paramount to recognize that, as some labs only provide DNA-based next-generation sequencing (NGS), some translocations may be missed.

If a DNA-based NGS test does not reveal a driver genetic alteration, an RNA-based test can be done. As such, knowledge of the test being performed is extremely crucial.

Liquid biopsies can also be used, although, the sensitivity is only around 70%. Therefore, if you do identify a targetable alteration in the liquid biopsy, one can initiate systemic therapy based on that result. Conversely, if the liquid biopsy does not reveal a targetable alteration, one needs to perform tissue-based testing.

Many of us receive PD-L1 results far earlier than molecular alteration results, so, there may be a temptation to initiate patients on either immunotherapy or the combination of chemotherapy and immunotherapy. However, it’s extremely crucial that we await the results of genetic alterations before a therapy is initiated, irrespective of the clinical characteristics of the patient.

Now, there are patients for whom there is an urgency to initiate systemic therapy and, in such patients, it’s prudent to initiate chemotherapy and not initiate immunotherapy. This is based on past reports stating that, if immunotherapy is initiated in a short period of time and switched to targeted agents, these patients may experience a higher rate of toxicity.

The best data are with osimertinib. If osimertinib is started within a short period of time after the patient has received immunotherapy agents, they may experience a higher rate of several adverse effects, particularly pneumonitis. In patients whom the physician is compelled to start therapy, those patients should be started on chemotherapy while we await the results. Once the results are available, either the patient is started on targeted therapy—if an appropriate genetic alteration is identified—or immunotherapy can be added in. Patients can be switched from chemotherapy to immunotherapy if PD-L1 levels are high.

Ultimately, molecular testing has become an extremely important aspect. It’s crucial that physicians are aware of the type of tests that are being performed and the labs where the patient's tissue are sent. Ideally, it’s important to wait for all the results to become available before therapy is initiated.

Is there any other research in this space that you wanted to highlight?

A study published in the New England Journal of Medicine showed that there has been a dramatic decline in lung cancer mortality rates from 2013 to 2016, which averaged about 6% in males and about 5.8% in females per year.

Since this happened in such a short period of time, authors are convinced that it was due to the advances in targeted therapy, particularly EGFR and ALK inhibitors, in patients with lung cancer. It did not detect an increase in the number of early-stage lung cancer cases to correlate with the reduction in lung cancer mortality. During that 3-year period, no significant increases in screening rates were noticed and no major treatment advances have occurred. The hypothesis is that this was due to changes in the management of advanced NSCLC lung cancer, specifically with targeted therapy.

This was approved before newer targeted therapies and immunotherapy agents were approved. One suspects that the reduction in mortality rates in 2019 and 2020 are even greater than what was reported in this trial.