Melissa Johnson, MD, Shares Insights on Lung Cancer Clinical Trials, ‘Practice-Changing’ Treatments

Dr. Johnson, director of lung cancer research at Sarah Cannon Research Institute, discusses clinical trials of interest in lung cancer, particularly recent data presented at the European Society for Medical Oncology (ESMO) Congress 2023, and shares “practice-changing” treatment options for patients.

You lead the lung cancer clinical trial portfolio across the Sarah Cannon Research Institute. What are some ongoing trials you have your eye on?

That is such a good question. I think the frontline space is almost like a soap opera right now. There are so many trials, and different strategies are being evaluated. I will outline just a few for you.

First, can we bring some of these targeted therapies into the frontline setting and combine them with immunotherapy? That is one of the current standards of care. There are a number of trials trying to do this. In particular, the one that comes to mind is KRAS G12C inhibitors plus immunotherapy. It would be great if we could treat patients in the frontline setting with targeted therapy and immunotherapy and not have to give them chemotherapy. That is an area that I am watching with a lot of enthusiasm.

Another area is whether these antibody-drug conjugates (ADCs) can leapfrog from the second-line space, where they are likely to be approved first, into the first-line setting in combination with immunotherapy and maybe also in combination with platinum therapy. There are a number of trials and sponsors that are trying to do this as well. It would mean that some of the chemotherapy drugs that we have used for a long time—pemetrexed for nonsquamous patients and paclitaxel for squamous patients—potentially get relegated to that second-line space because these new ADCs beat them out.

Finally, there are bispecifics that are threatening to take the place of the PD-1 and PD-L1 inhibitors that have been in the frontline setting for about 5 years. Whether those drugs harness a little bit more of the patient’s immune system so that they can generate more of an antitumor immune response is the question. Can those drugs be combined safely with chemotherapy?

There is a consistent theme across all three of those strategies—is more better? We are just going to have to wait and see.

What are the continued challenges and/or unmet needs in lung cancer clinical trials?

The truth is that there are more trials than lung cancer patients to participate in them. That is a challenge. It does seem as though some of these buckets of trials are evaluating the same question—different KRAS G12C inhibitors with immunotherapy or different trophoblast cell surface antigen 2 (TROP-2) ADCs in combination with platinum and immunotherapy, for example. I think a big unmet need is when are we going to start working together a little bit more?

Right now, investigators work together in cooperative group trials. At Sarah Cannon Research Institute, we have a large physician-based network that spans one in five patients treated on cancer clinical trials across the country. Now, we need some movement on the part of the pharmaceutical companies to work together to answer similar questions in order to move forward so we will have enough patients to answer the trial question.

What are the unmet needs in lung cancer treatments, particularly beyond the first-line setting?

Many patients are still not eligible for clinical trials. Many patients are still receiving chemoimmunotherapy and maybe one other line of therapy. The truth is we are not curing patients with metastatic disease.

One of the most significant unmet needs that stands out to me is that patients are developing brain metastases with drugs that may or may not cross the blood-brain barrier. That is probably an unmet need in terms of treatment, but it is also an unmet need in terms of clinical trials because most clinical trials will exclude patients with brain metastases that are untreated. Sometimes patients have not had their cancer brain metastases treated for a variety of reasons. In order to answer questions, we need to begin to liberalize our inclusion and exclusion criteria in clinical trials to include more patients. I think allowing patients with asymptomatic, untreated brain metastases might be one way to do that.

Were there any data released at ESMO 2023 that excited you?

There were so many great scientific abstracts reported at ESMO 2023. The two that jump out to me are the ALINA trial, in which patients with resected non-small cell lung cancer (NSCLC) with ALK rearrangements were randomized to receive the ALK tyrosine kinase inhibitor (TKI) alectinib or chemotherapy. Those data showed an 80% reduction in risk of disease recurrence or death in the patients who were treated with alectinib compared with chemotherapy. That finding corresponded to the risk of central nervous system (CNS) recurrence, which was also 80% reduced for patients who received the TKI.

This is a practice-changing study. It will lead to the identification of many more patients with resected cancer who can be treated for the goal of cure with alectinib as opposed to being treated for the goal of palliation or disease control in the metastatic setting. This is a win for patients.

Another trial that sticks out to me is KEYNOTE-671, which was also in the resected lung cancer space. I would not say this trial was practice-changing, but I would say it was practice-affirming, at least in the United States. CheckMate 816 was a previously approved trial in which patients got chemotherapy and immunotherapy prior to surgical resection. It resulted in improved disease-free survival, event-free survival, and major pathologic response.

That trial changed the standard of care. Most patients with stage II or III cancer will at least be considered for chemoimmunotherapy, carboplatin, another chemotherapy drug, and nivolumab, in the case of CheckMate 816.

The PEARLS trial showed that after surgery, the addition of adjuvant pembrolizumab would improve survival as long as patients had received four cycles of chemotherapy. The way I explain KEYNOTE-671 to the physicians in our network is that it combined those two trials. In KEYNOTE-671, patients received platinum chemotherapy plus immunotherapy upfront, they went to surgery, and then they received more immunotherapy out back.

I would say in the community, we have been doing this for a while based on the results of the other two trials I mentioned. KEYNOTE-671 affirms our ability to do that. It seems to me this trial will result in most patients getting immunotherapy preoperatively and postoperatively.

What are your thoughts on TROP-2-directed treatment?

This is a new area. TROP-2 is ubiquitously expressed in particular lung cancers, NSCLC and, it turns out, small cell lung cancer (SCLC) as well. We heard some other exciting results. Datopotamab deruxtecan versus docetaxel second-line treatment for patients with NSCLC improved progression-free survival, with a hazard ratio of 0.75.

The surprising result of this trial was that the benefits seemed to be confined to the nonsquamous patients. In subgroup analysis, the squamous patients did not do that well. We also saw a smaller report of TROP-2 ADCs in SCLC with sacituzumab govitecan, and it likewise showed response rates in the 30% to 40% range, with a duration of about 6 months. It may not be just NSCLC where TROP-2-directed therapy is promising, but also SCLC.

Are there any other treatment targets or combinations that you think would be useful in NSCLC or SCLC?

I could go on for a long time about the abstracts from ESMO 2023. I will mention just one more, which was the HER3 ADC patritumab deruxtecan. At the World Conference on Lung Cancer, it was reported that the response rate for patients was around 30% for those with EGFR-mutated NSCLC. At ESMO, it was reported that patients treated with patritumab have responses in the brain about 30% of the time. The systemic disease control is recapitulated in the CNS. Said another way, if you are using patritumab deruxtecan for patients with EGFR-mutated cancers after osimertinib, it will work in the body as well as the brain. That is a great step forward. ADCs are big molecules. We were not sure if they crossed the blood-brain barrier the way TKIs do, and these data would suggest that they do have activity in the CNS. It is an additional therapy to give hope to our patients.