Approaches Under Study to Prolong Immunotherapy Response in Lung Cancer

Luis E. Raez, MD, FACP, FCCP

Checkpoint inhibitors have shown tremendous benefit for patients with newly diagnosed metastatic non–small cell lung cancer (NSCLC), stage III unresectable NSCLC, and relapsed/refractory small cell lung cancer (SCLC), explained Luis E. Raez, MD, FACP, FCCP, who added that the next frontier of research includes evaluating other checkpoints and concurrent use with chemoradiation.

“The new versions of the PACIFIC study [NCT02125461] are exciting where we are moving immunotherapy to concomitant treatment [in stage III disease]. Instead of chemoradiation followed by immunotherapy, it’s more exciting to believe that maybe we can add immunotherapy to chemotherapy, or replace the chemotherapy [entirely],” said Raez in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

In the interview, Raez, medical director and chief scientific officer at Memorial Cancer Institute of Memorial Healthcare System, discussed the focus of the virtual meeting, which covered frontline immunotherapeutic options in NSCLC, management strategies for patients with stage III disease, targeted approaches for patients with EGFR- and ALK-positive NSCLC, and how the field of SCLC is navigating newly available therapies.

OncLive^®: What has been the effect of immunotherapy on metastatic NSCLC, with benchmarks now reaching 5 years?

Raez: It’s a very exciting time for us because we have several options. We have 8 regimens that are available for patients with newly diagnosed metastatic lung cancer without actionable mutations or gene alterations. That is amazing compared with the 3 or 4 chemotherapy regimens we had 20 years ago that were associated with a very low survival.

The 5-year survival data from KEYNOTE-024 [NCT02142738] with pembrolizumab [Keytruda] is amazing. It’s amazing that with chemotherapy, we used to cure maybe 5% of these patients with metastatic disease. Now, the 5-year data for pembrolizumab show that the cure rate can go above 20%, depending on the level of PD-L1 the patient has, which is extremely exciting.

In my own practice, I am following around 12 patients who have already finished the 2 years of conventional immunotherapy and are now under observation, and the tumors have never returned. This opens the possibility that not only are patients surviving at 5 years but that they are getting cured because they are surviving without the need of more immunotherapy or chemotherapy.

How can research address the population of patients who do not derive prolonged benefit from immunotherapy?

Now, with chemoimmunotherapy regimens, everybody enjoys about 1 year or more of progression-free survival [PFS]. Unfortunately for 50% of the patients, they’re probably not going to reach 18 months [of PFS], meaning that 50% of the patients, probably after enjoying immunotherapy for more than 1 year, before the second year are going to fail it.

That’s a tremendous unmet need, because after patients have enjoyed a very good quality of life for about 1 year now have to go back to the old route of chemotherapy that can barely give us the option to find maybe another year before the end. That is why there is an unmet need there.

[However,] we have the options because we are only using 2 different types of checkpoint inhibitors––PD-1/-L1 and CTLA-4 inhibitors if you want to add ipilimumab [Yervoy]––when we have more than 20 or 30 types of checkpoint inhibitors that are in development that we really need to speed up and bring to the frontlines of therapy.

Your colleague, Janakiraman Subramanian, MD, of Saint Luke’s Cancer Specialists, discussed stage III NSCLC, where concurrent chemoradiation followed by immunotherapy is the current standard of care. Do you see that changing soon?

We have 5-year data showing how we can improve the survival of these patients to more than 10%, but maybe we don’t need to use chemotherapy; instead, maybe immunotherapy and radiation can be safe and effective.

We are already in the first stages [of evaluating concurrent immunotherapy and chemoradiation]. At the 2021 ASCO Annual Meeting, [we saw] many presentations [showing that] chemoimmunotherapy and radiation seems safe. Maybe we don’t need the chemotherapy. Perhaps we can give the immunotherapy and radiation and get various successful outcomes. Then, patients don’t have to be exposed to chemotherapy anymore. That’s why that area of PACIFIC is very exciting, because there is a lot of room also for improvement. We are not really curing 50% of these patients; we were very close with PACIFIC, but we still have another 50% of patients who we need to cure and who we need to find better strategies for.

Briefly turning to targeted therapy, for patients with an EGFR exon 20 alteration, how has amivantamab-vmjw (Rybrevant) helped fill an unmet need?

Amivantamab is a very interesting drug and one that fills a very important unmet need because for patients with EGFR exon 20 mutations, we didn’t have anything other than chemotherapy. However, the response rate [with amivantamab] is not as good as the TKIs [in the common EGFR mutations] that we use for frontline treatment. That’s why the agent has been positioned for second-line use first.

Maybe the solution is to combine amivantamab with other agents like lazertinib that can enhance the response rate so we can put this agent into the frontline setting. It’s frustrating when you know you have an exon 20 mutation for which we have a drug, but we still have to give the patient chemotherapy first. But that’s the way the drug was approved, and most drugs sometimes get approved in the second-line setting and then moved into the frontline setting as soon as we have the data that [support that].

For amivantamab, the solution is to do a combination with another agent, either another checkpoint inhibitor or targeted agent so we can [move the agent into the] frontline [setting] because we really would like to see it as a frontline therapy, so we don’t have to use chemotherapy anymore in these patients.

Another one of your colleagues, Alberto Chiappori, MD, of Moffitt Cancer Center, discussed the management of SCLC. How have agents like checkpoint inhibitors and lurbinectedin (Zepzelca) overcome some of the historical challenges of treatment?

There is a lot of unmet need for SCLC. We don’t have an actionable genetic aberration. There are no mutations or fusions [for which we have a targeted agent]. With some of these genetic aberrations like RB1, the problem is that we don’t have an agent that can effectively target [the aberration]. That puts us at a disadvantage compared with NSCLC.

The other problem is that although immunotherapy is effective, increasing the outcomes compared with chemotherapy, patients still have a short PFS. Only one line of immunotherapy is really used nowadays and is mostly chemoimmunotherapy for patients with metastatic disease. Then there is no chance to give more immunotherapy because all the approvals have been withdrawn. That is why there is a lot of unmet need.

New agents were discussed at the meeting, such as lurbinectedin, which is probably less toxic than the old standard of care, topotecan. Lurbinectedin is a new option for second-line SCLC. It’s interesting because in SCLC, the last drug that was approved was many years ago. We don’t have a lot of approvals; we just got lurbinectedin and immunotherapy. Lurbinectedin is probably equivalent to topotecan in the second-line setting, but is less toxic and easier to use, so most doctors will likely now prefer the new second-line standard to the old second-line standard. We’re in a very difficult situation with SCLC, but lurbinectedin is probably a better option than all options that we have for this indication.

There’s still a lot that needs to be done. We need more agents and more immunotherapy with different mechanisms of action that can really give our patients with SCLC a better chance to fight.