Brahmer Calls for Better Incorporation of Precision Medicine in Lung Cancer

Julie R. Brahmer, MD

There may be potential for immunotherapy in lung cancer beyond PD-1/PD-L1 and CTLA-4 inhibitors, said Julie R. Brahmer, MD, but first, researchers need to gain a better understanding of resistance mechanisms or lack of response in these patients, which will ultimately lead to a more precision medicine approach.

However, there has been recent progress in difficult-to-treat populations. For example, in small cell lung cancer (SCLC), a disease for which the treatment paradigm has remained stagnant for almost 20 years, PD-L1 inhibitors are starting to make headway. Results from the phase III IMpower133 trial demonstrated a survival advantage with the addition of frontline atezolizumab (Tecentriq) to chemotherapy with carboplatin and etoposide in patients with extensive-stage SCLC versus chemotherapy alone.¹

In the study, median overall survival (OS) was 12.3 months with chemoimmunotherapy versus 10.3 months in the control arm (HR, 0.70; 95% CI, 0.54-0.91; P = .007). Median progression-free survival (PFS) was 5.2 months in the atezolizumab arm compared with 4.3 months in the placebo arm.

Immunotherapy is also beginning to have an impact in stage III disease, based on results from the phase III PACIFIC trial. In the study, consolidation immunotherapy with durvalumab (Imfinzi) following chemoradiation therapy significantly improved survival in patients with stage III unresectable NSCLC. The median PFS was 17.2 months in the durvalumab arm compared with 5.6 months in the placebo arm (stratified HR, 0.51; 95% CI, 0.41-0.63). Two-year OS rates in the durvalumab group were 66.3% compared with 55.6% for the placebo arm (two-sided, P = .005).²

Despite these positive data, Brahmer, co-director of the Upper Aerodigestive Department in the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine, said that researchers are still struggling with the challenge of choosing which patients will derive benefit from single-agent immunotherapy versus those who will need chemotherapy, as well.

“We need to figure out how to utilize precision medicine in these patients,” she said.

OncLive: How has immunotherapy transformed the treatment of patients with lung cancer?

In an interview with OncLive, Brahmer discussed advances made with immunotherapy in the lung cancer space, highlighted challenges that still need to be addressed, and discussed ongoing research designed to determine treatment approaches beyond PD-1/PD-L1 and CTLA-4 inhibition.Brahmer: For NSCLC, immunotherapy has transformed how we treat patients. For a subset of patients with NSCLC, we are seeing long-term survival [with immunotherapy] compared with what we would see with chemotherapy by itself. In SCLC, looking at the most recent IMpower133 data with atezolizumab plus platinum/etoposide versus platinum/etoposide alone. [Researchers found that] the addition of immunotherapy improved PFS in those patients.

What unanswered questions with immunotherapy need to be addressed?

Is there potential for immunotherapy beyond PD-1 and CTLA-4 inhibitors?

Although it did not seem to improve the response rate—which was surprising to many of us—it clearly helped maintain that response for a longer period of time compared with chemotherapy alone. This [approach is] helping to improve OS as well. We would love to see more, but we are interested in seeing if these data are consistent in the future with other trials that are combining PD-1/PD-L1 inhibitors with chemotherapy. The general questions that remain are how to best pick the patients who will benefit from single-agent immunotherapy compared with those who will need chemotherapy as well. If they need chemotherapy, which combinations work best? For example, when you look at patients with EGFR mutations, we know that they are going to respond to EGFR TKIs. We need a way to have this kind of predictive marker in immunotherapy-treated patients. The potential lies in figuring out the mechanisms of resistance or lack of response in patients with NSCLC. This is, again, really getting at precision medicine. Do we just need to rev up the patient's T cells or engineer them to be able to target what is abnormal in the cancer? Do chimeric antigen receptor (CAR) T cells have a role in lung cancer? We might also be able to develop a personalized vaccine to teach the T cells what to target. If a patient has T cells that are ready to respond, maybe all we need to do is rev them up with another drug like pegylated Interleukin-10 (pegilodecakin, AM0010). Perhaps different combinations are the answer.

There is a myriad of ongoing trials—mostly umbrella trials—that are trying to decide the next treatment beyond PD-1/PD-L1 therapy based on the molecular characteristics of the cancer. [Researchers] are performing a biopsy and seeing whether the patient has issues with DNA repair, and then they would go on 1 specific combination. If they have checkpoints that are upregulated, they would go on a different combination. I hope this is promising.

Where do you see the future of treatment headed?

There is a whole lot of interest in a patient's own T cells, such as the CAR T-cell world. In solid tumors, CAR T cells have not made as much headway as we have seen in a disease like leukemia. However, in the near future, investigators will figure out how best to use these in solid tumors. The path forward is to not view lung cancer as a single disease. About 10 years ago, we figured out that squamous disease is not the same as nonsquamous disease. Immunotherapy sort of tried to bring that back together with single-agent pembrolizumab in the first-line setting, but I truly do believe that these are separate diseases and need to be studied separately, since different drugs work better for these patients. Again, we need to find ways to bring precision medicine into the mix beyond just [using this approach for patients with] driver mutations. The other key factor is trying to get patients on clinical trials.

We also need to try to bring these treatments to patients in the routine [clinical] setting and provide physicians with the support that they need to manage adverse events (AEs) associated with these drugs. Immunotherapy is not for the faint of heart. These patients can get sick just like when they became very sick back in the day with neutropenia from chemotherapy. Once we figured out how to adjust [our approach], patients did very well on chemotherapy.

We are also just scratching the surface on how to predict AEs [associated with immunotherapy] and how best to manage them. It is important to take a team approach to [manage] the AEs, even in just making sure that you help educate the nurses [on this], as they are truly on the frontlines.

References

1. Horn L, Mansfield AS, Szeczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med. 2018;379(23):2220-2229. doi: 10.1056/NEJMoa1809064.
2. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697.