Pivotal PD-1 Treatment Helps Change Standard of Care in Lung Cancer

Oncology, ONCOLOGY Vol 35, Issue 12,
Pages: 791-793

“Having the opportunity to work within the industry in that sort of capacity, and then seeing a drug translate into clinical benefit in the clinic, was very exciting and gratifying.”

Since the first information regarding single-agent PD-1 inhibitors were presented at the American Society of Clinical Oncology Annual Conference a decade ago, immune checkpoint inhibitors (ICIs) have been widely used in the treatment of non–small cell lung cancer (NSCLC).

In an interview with ONCOLOGY®, Julie R. Brahmer, MD, MSc discussed her integral role in developing these therapies and how she overcame doubts that they wouldn’t work in certain patient populations.

Brahmer spoke about the development of the PD-1 inhibitor nivolumab (Opdivo) and how her career progressed since working on a pivotal trial that brought it to the lung cancer space. She also revealed what she believes are next steps in ICI research, detailed potential new therapies that could be practice-changing in the lung cancer space, and shared why she doesn’t think more anti–PD-1 agent are necessary.

Q: Ten years ago, did you have any idea how big the research around PD-1 inhibitors would become?

A: Throughout my career of being a part of drug development teams, I certainly was used to being principal investigator on many phase 1 first-in-human trials that just never went anywhere or didn’t show activity. [Some] drugs would make it out of the phase 1 trials and into further development. With the advent of PD-1 [inhibitors], seeing an inkling of activity was exciting to be a part of since, particularly in NSCLC, most investigators in the community at large felt that lung cancer was not an immunogenic cancer and immune therapy of any type would never work. That [overarching] feeling, at least for the oncology community, continued until the [results of the first phase 3 study to show efficacy]. And even at that point, a lot of clinicians felt it was a fluke. Now, seeing that there are groups of patients within lung cancer being significantly affected—as well as patients with other cancers, such as [those with] microsatellite instability [MSI]–high colon cancer or [other] MSI-high tumors—it’s certainly exciting and gratifying to know that I was a small part of the development of something that could have an effect on patients who otherwise had minimal treatment options.1

Q: When did you allow yourself to stop being skeptical about how the trials were progressing?

A: For me, it was [initially] during the phase 2 trials, where we saw consistent activity, and then in the first phase 3 trials in the second-line treatment setting, where it clearly did outperform chemotherapy. As an oncologist, I felt comfortable when it was in phase 3 trials, but even before that, when we saw patients whose disease had melted away and did not come back for months to years, I felt like this was something that would be around [for a while] and we just had to figure out who should receive it.

Q: What was your specific role in these trials?

A: I’m a medical oncologist and I do phase 2 drug development in oncology, and my subspecialty is specifically in patients with thoracic malignancies: lung cancer and mesothelioma. Those are the patients who I see in clinic. I was the principal investigator at Johns Hopkins of the first-in-human phase 1 trial of nivolumab [NCT00441337]. Back then it was MDX-1106, so it didn’t even have a name. I was also a part of the next phase 1 trial, and then with other investigators took that into a phase 3 study [NCT01642004] comparing it with chemotherapy in patients with metastatic lung cancer [in the second-line setting].2

Q: Was this your first time working through a phase 3 trial?

A: Yes, it was. That was always a career goal—to be part of something that was just coming out of the lab, being tested for the first time, then taking that drug into a phase 3 setting, and then getting it approved. Certainly, havingthe opportunity to work within the industry and then seeing a drug translate into clinical benefit in the clinic was very exciting and gratifying.

Q: The most recent approval of an ICI came in October with atezolizumab (Tecentriq) in the adjuvant setting for NSCLC. How quickly do you think this will be utilized, and will there be reluctance in this setting?

A: Particularly in the second-line treatment setting where immunotherapy first got started, it was easily taken up because people are looking for something new to use. [They want] something that is touted to be less toxic, or toxic in a completely different way [than traditional therapies], and that has a clinical benefit [showing] that if it works, it will last for a long time, not just for a few months.

Obviously, that led to taking these agents into the first-line treatment setting. Realizing that a subset of patients benefited from the single-agent PD-1 or PD-L1 antibodies and trying to increase the response and duration of response in more patients, led to combining it with chemotherapy. Seeing the power in the metastatic setting [resulted in] bringing those sorts of drugs into the locally advanced setting, and now into the adjuvant setting after surgery.

My colleague, Heather Wakelee, MD, [deputy director of the Stanford Cancer Institute and the division chief of medical oncology at Stanford University], presented the atezolizumab study at the American Society of Clinical Oncology Annual Meeting this year.3 It’s great to be able to see immunotherapy [have an] impact on patients with early-stage disease NSCLC. We’re seeing the power of immunotherapy and that the immune system does play a role in disease control. Hopefully, at least early on, we’re seeing increased chances of a cure or at least disease-free survival in that early-stage disease as well.

Q: What are we learning about adverse effects (AEs) of ICIs and the proper way to manage them?

A: For the most part, oncologists are getting comfortable in treating patients with these inhibitors. Certainly, the toxicities are typical for immune responses. There are always nuances to these toxicities, and certainly the guidelines help give us a framework to treat or mitigate the AEs. We’re learning more about who we can safely treat or how to best use these therapies in patients with preexisting autoimmune diseases, as well.

Q: Regarding molecular testing strategies, what new tests are available and useful because of these agents?

A: Since we have targeted therapy, or tyrosine kinase inhibitors [TKIs], that have been developed specifically for multiple different mutations, [the presence of] EGFR mutations are now being used in the adjuvant setting [to guide therapy]. We want to go over testing, who to test, and what tests are best in the metastatic setting.We always struggled with finding if we have enough tumor tissue, and then trying to get those results as quickly as possible so that we can get the patients on the right treatment to begin with and control their disease. Now, sometimes], we do use blood-based cell-free DNA testing platforms to try to get those results quickly.

Q: Looking forward, what are the next steps in immunotherapy research?

A: [To start, we need to] drill down on who can get away with receiving just single-agent immunotherapy and who will be those long-term responders. We’ve done [a lot] thus far with driver mutations—coming up with what we call “precision medicine” for those patients—and [we now need to] switch that over to develop precision medicine for the other patients receiving immunotherapy. We’re on the road, but over the next 10 years, we’ll accomplish that, and then we’ll also have a better idea of which combinations patients should receive.

A bunch of different combination ICIs are being tested, looking at a cellular therapy, and who should receive that, as well as which patients still need to rely on chemotherapy to get their disease under control. We’ll see these answers over the next 5 to 10 years. In the short term, we’ll see how best we should sequence [therapy], [figure out if] we should give everything upfront to these patients to give them their best chance of response, and [determine if] that affects their long-term disease control. Studies are ongoing there.

Q: Can you discuss the PD-1 and PD-L1 inhibitors in development, those that aren’t FDA approved yet?

A: I don’t think we need more drugs that target PD-1 or PD-L1. However, we all hope that having more drugs in the marketplace that act on the same pathway, and act in very similar fashion, will help drive down prices for our patients. We also must be practical when talking about drug development. For some companies, it’s easier to have their own PD-1 or PD-L1 antibody and start adding to it rather than trying to contract with other companies and deal with the complexity of having to use another company’s [agent], so I get why it’s being done. If it were just automatically free, you could use whatever you wanted and have no legal issues or data rights. We probably don’t need ten PD-1 or PD-L1 inhibitors in the clinic. I’m in favor of trying to do anything we can to speed up development of some of these newer checkpoints beyond PD-1 and PD-L1 inhibitors.

Q: If a patient has a genetic alteration that has a targeted drug, might a clinician ever be able to give immunotherapy first instead? Is any research being done?

A:Patients with driver-mutated tumors who were never smokers are typically given a TKI. Where it gets harder is in patients with KRAS G12C mutations; there, ICIs as a single agent have [resulted in] a decent response rate, in the 30% to 40% range. That’s where we need a study to be able to compare head-to-head what is best to give these patients first.

Many of us are a bit hesitant about potential AEs when we’re giving immunotherapy first in these patients for whom we plan to give a TKI next. Just because you stop an immunotherapy agent doesn’t mean that its effects will be gone quickly. It takes a while for the antibody to get out of your system—let alone the effects on the immune system that can last for months to years. Sometimes when we add a TKI and these patients stop immunotherapy, we can see more unusual AEs or increased AEs or more liver function abnormalities than we would typically expect; in some cases, [there are] risks and what we call pneumonitis inflammation of the lungs. [Pneumonitis inflammation] is complex in some of those patients, but the standard patient with an EGFR mutation, RET fusion, or ALK fusion tends to not do well with single-agent immunotherapy. We really rely on TKIs and feel that those patients, because of the high response rate to TKIs, can receive those first.

Q: What trials in the lung cancer space have the potential to be practice-changing?

A: I’m excited to see some of the ICIs called TGIT [T-cell immunoreceptor with immunoglobulin and ITIM domains]. Some anti-TGIT antibodies are being added to PD-1 or PD-L1 antibodies. Some of the early phase 2 studies show increased response rates in patients with PD-L1–high disease who do not need chemotherapy at all to achieve that response. I’m excited to see those results in that group of patients and seeing more drugs that we can use to target some of these driver mutations and ways to get around [any] resistance that occurs. I’m excited to see a lot of these drugs in this space, particularly the KRAS space [and] the EGFR space. There’s an opportunity to improve care for these patients, and I’m excited to see some of the new drugs that are being developed.


References

1. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167-3175. doi:10.1200/JCO.2009.26.7609

2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. doi:10.1056/NEJMoa1504627

3. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non–small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):abstr 8500. doi:10.1200/JCO.2021.39.15_suppl.8500