Lopes Describes Approach for Discontinuing Immunotherapy in Metastatic Lung Cancer

Gilberto Lopes, MD

Immunotherapy should be continued for up to 2 years in patients with metastatic lung cancer who are responding to the treatment, unless they experience disease progression or excessive toxicity, according to Gilberto de Lima Lopes, MD.

Patients with stage III disease usually receive immunotherapy for 1 year, as was established by the phase 3 PACIFIC trial, said Lopes. Results from PACIFIC showed that durvalumab (Imfinzi) significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with placebo in patients with stage III, unresectable non—small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy.¹

“[However], for patients who are receiving immunotherapy for metastatic disease, there are a few general rules. For one, if a patient experiences progression of disease or excessive toxicity, they should stop the drugs,” said Lopes. “However, if they have a response, they can continue treatment for up to 2 years. Then, at that time, we need to have a discussion with the patient and explain what the downsides and upsides of continuing and stopping therapy are.”

Based on data from the phase 2/3 KEYNOTE-010 trial, Lopes said that two-thirds of patients who received pembrolizumab (Keytruda) for 2 years continued to respond to the treatment even after it was stopped. Specifically, at 43 months of follow-up, pembrolizumab continued to prolong OS versus docetaxel in patients with previously treated PD-L1—expressing advanced NSCLC, with manageable long-term safety.² Additionally, most patients who completed the 35 cycles of pembrolizumab were reported to have a durable response to the treatment.

In an interview with OncLive, Lopes, medical oncologist, medical director of International Programs, associate director of Global Oncology in the Sylvester Comprehensive Cancer Center, and associate professor of clinical medicine at the University of Miami, discussed the appropriate duration of immunotherapy in lung cancer, treatment-related adverse events (AEs), and remaining challenges in the space.

OncLive: How do you approach duration of treatment with immunotherapy in lung cancer?

Lopes: For patients who are receiving immunotherapy for metastatic disease and are responding, they can continue treatment for up to 2 years; however, if they experience disease progression or excessive toxicity they should stop the drugs. At 2 years, we need to have a discussion with the patient to discuss the pros and cons of either continuing or stopping therapy. I tend to try to convince patients to stop immunotherapy, but many do not want to. Our standard is stopping treatment for progression or toxicity and we can continue [pembrolizumab] for 2 years and then stop. For other drugs, we really did not have [data from] the clinical trials [to guide us], so we tend to continue [patients on treatment] until progression or toxicity.

What is your reasoning for stopping treatment with immunotherapy after 2 years?

The [biggest one is] AEs; some patients start experiencing chronic AEs, such as fatigue or arthralgias. We also face the issue of costs and the sustainability of our healthcare system. These drugs are not cheap. When we can stop them, especially if patients are still benefiting, there is an added reason to do that from a systems perspective.

The data set that we have from KEYNOTE-010, which is the most mature data we have for patients who received therapy for 2 years, is that two-thirds of patients continued to respond even when we stopped [immunotherapy]—especially if we did [stopped it] after 2 years [of treatment]. I would not want to stop treatment at 1 year because we have one trial with nivolumab (Opdivo), which showed that patients who continued immunotherapy for more than 1 year seem to have a better PFS outcome; there was even a trend toward better OS, so usually I do not like to stop immunotherapy before reaching the 2-year mark. That being said, it does seem to be safe to stop immunotherapy after 2 years, especially if patients experience mild AEs.

What are some of the AEs that patients experience with immunotherapy?

Within the first few months of treatment, AEs are not that common. We do see mild events, such as fatigue, and, on occasion, we see severe AEs, such as pneumonitis or transaminitis. What we do see commonly, but is manageable, is endocrinopathies, especially thyroid. As we move on and patients continue treatment, we will usually find a different set of AEs; fatigue becomes a lot more important and arthralgias and rash become common, as well. Most patients are bothered by these symptoms.

You mentioned the KEYNOTE-010 trial. Could you speak to the significance of those data?

KEYNOTE-010 randomized patients who had already failed first-line platinum-based chemotherapy to receive either pembrolizumab or chemotherapy. The trial showed that patients who received pembrolizumab for 2 years, about two-thirds of them had continued response months after the trial and after the drug was stopped. We also saw that about 40% of patients who progressed after pembrolizumab was stopped, experienced a new response when the drug was restarted. This makes us comfortable that treating patients with immunotherapy for 2 years is a reasonable strategy.

What are the next steps for when a patient progresses on immunotherapy?

For patients who progress after first-line chemotherapy/immunotherapy or immunotherapy alone, we tend to try to get patients on clinical trials. However, the standard of care today would be docetaxel with or without ramucirumab (Cyramza).

What are some of the key remaining challenges still faced in this space?

The greatest challenge is determining which patients actually need all these approaches. Unfortunately, currently, we do not have any good biomarkers or clinical characteristics that could tell us which patients could get only immunotherapy or chemotherapy alone. Patients with a PD-L1 score of greater than 50% do better, maybe even better with a PD-L1 score of greater than 90%, but the numbers are not comfortable enough for us to not consider chemotherapy plus immunotherapy for these patients, as well.

What biomarker research is being done in this space?

Several biomarkers are being studied beyond tumor mutational burden and PD-L1. We have the presence of STK11, and we have recently shown that patients with KRAS mutations respond well to chemoimmunotherapy and immunotherapy alone. I believe that we will soon have algorithms that will help us make decisions.

What is the key takeaway from your talk?

The key takeaway is that we have to continue monitoring our patients and we always have to balance the benefit of what we do with the potential AEs [that come with the treatments given]. Of course, [we also need to balance the benefit with] cost, as well.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Eng J Med. 2018;379:2342-2350. doi:10.1056/NEJMoa1809697
2. Herbst RS, Garon EB, Kim D-W, et al. Long-term in the KEYNOTE-010 study of pembrolizumab (pembro) for advanced NSCLC, including in patients (pts) who completed 2 years of pembro and pts who received a second course of pembro. Ann Oncol. 2018;29(suppl 10):x42-x43. doi:10.1093/annonc/mdy511.003