Addressing Questions Left Unanswered by PACIFIC in Stage III NSCLC

Lyudmila A. Bazhenova, MD

Consolidative therapy with durvalumab (Imfinzi) after concurrent chemoradiation resulted in a significant survival benefit in patients with unresectable stage III non—small cell lung cancer (NSCLC). Although additional studies have provided further insight on responses per PD-L1 expression and the optimal timing of durvalumab, there are many outstanding questions that need to be addressed, explained Lyudmila A. Bazhenova, MD.

“I would like to see questions answered regarding the duration of therapy,” said Bazhenova. “Do patients need 1 year of durvalumab or can we get away with 6 months? Furthermore, durvalumab is given every 2 weeks, which is very difficult on our patients. Instead, can we give durvalumab every 4 weeks?”

Research must also focus on whether there are additional subgroups that the drug might show benefit in and if there are other agents, such as vaccines or cellular therapy, that durvalumab might be combined with and could increase efficacy, she added.

Moreover, the timing of targeted therapy in the face of metastatic progression is another question that remains unanswered, with current understanding limited to retrospective data.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Bazhenova, medical oncologist, professor of clinical medicine, University of California, San Diego, discussed the phase III PACIFIC trial and clinical scenarios that warrant further investigation in the field of stage III NSCLC.

OncLive: Could you discuss the PACIFIC trial and how that led to a new standard of care for patients with stage III unresectable NSCLC?

Bazhenova: The PACIFIC trial took patients with unresectable stage III NSCLC who were treated with chemotherapy and radiation therapy and then randomized them to receive durvalumab versus undergo observation. The study showed an improvement in overall survival (OS) in patients who received durvalumab.

Since the original trial presentation and publication, there have been 3 additional studies that were reported in smaller conferences. One of those studies looked at the efficacy of durvalumab based on PD-L1 expression ≤1% and ≥1%. The second study looked at the timing of durvalumab. Emerging data show that giving durvalumab sooner after the completion of chemoradiation might be more effective. The caveat is that this was not a preplanned randomization strategy, so there certainly could be a bias in that data set. If I have a patient who tolerated chemotherapy and radiation therapy well and recovered quickly, I'm finding myself giving the patient immunotherapy sooner than I was before.

There are also some data on pneumonitis [developing] after durvalumab. Patients who receive TKIs after progressing on immunotherapy have a potential risk of pneumonitis. For example, [consider] a patient who was on durvalumab and then recurred with metastatic disease. If they have an EGFR mutation, how do you reconcile the data with pneumonitis? Should you start them on osimertinib (Tagrisso) right away, or should you wait 3 or 4 months after the last dose of durvalumab before giving them osimertinib?

We don't have an answer to that question, but it is something I’m thinking about. I might consider giving a couple cycles of chemotherapy for those patients before considering osimertinib. People are looking at the durvalumab studies and at the incidence of pneumonitis if the patient received TKIs after completing durvalumab.

Is there rationale to explore concurrent chemoradiation and immunotherapy?

Certainly, we should explore concurrent chemoradiation therapy and immunotherapy. The problem here could be pneumonitis, because as a patient receives radiation therapy, they are at increased risk for pneumonitis; durvalumab might exacerbate that. Researchers are also actively looking at exploring the use of neoadjuvant approaches, which we know is safe. We don't know at this point if a neoadjuvant approach would be better than a consolidation approach.

Could you elaborate on the data regarding the use of TKIs after durvalumab?

The only data we have right now comes from a retrospective, single-institution study that looked at sequencing immunotherapy and EGFR TKIs. The [author] found that the risk of immune-related adverse events is higher if osimertinib is used within 3 months after immunotherapy. [That risk] decreases if the agent is used 3 to 12 months after [immunotherapy], and it's not existent if you start TKIs 12 months after completing immunotherapy. It is interesting that he did not seem to show the same pattern with either gefitinib (Iressa) or erlotinib (Tarceva), which is contrary to data from a trial led by Aaron Lisberg, MD, of Ronald Regan UCLA Medical Center, which showed at least 1 case of fatal pneumonitis after pembrolizumab (Keytruda). For patients who have to start therapy right away, where I don't have time to wait for molecular testing, I tend to give them chemotherapy. I’ll wait for the molecular testing to come back, and if it's negative, then I may add immunotherapy to the third or fourth cycle of treatment.

For those who prefer to start treatment with immunotherapy, can preemptive steroids be given?

That’s a very good question that we don’t have the answer to. We don't know what the best thing to do is. Should we give preemptive steroids or wait 3 months and then give osimertinib, during which period you could technically give chemotherapy? Chemotherapy still works in patients with stage IV lung cancer.

What is the importance of extensive molecular testing for patients with stage IV NSCLC?

Sometimes patients will get tested for EGFR, ALK, and ROS1, but they will not be tested for BRAF or NTRK. There are other molecular abnormalities such as RET, HER2, and MET exon 14 skipping mutation. Although we don’t have any FDA-approved drugs for those patients at this point, there are very effective drugs [being evaluated] in clinical trials.

For example, LOXO-292 is one of the RET inhibitors that has shown a 70% response rate for patients with stage IV NSCLC who have a RET fusion. The majority of those responses are very durable. We don't have a median duration of response rate yet; at 1 year, more than 80% of patients were still responding. It's an oral drug, which is very convenient and does not result in a lot of adverse events. It is very important for us to not miss any of those mutations. We don’t want to limit ourselves by just looking at EGFR, ALK, and ROS1.

What else still needs to be addressed in this setting?

Patients with unresectable stage III lung cancer have a very low likelihood of cure, despite everything else that we have. The recurrence rate is pretty high, and our only chance to change the recurrence rate is when we're giving curative therapy. Anything we can do to improve upon the new standard of care, which durvalumab now represents for patients with unresectable stage III, would be very welcome.