Multidisciplinary Team Discusses Practical Treatment Options in NSCLC

A Satellite Session hosted at City of Hope (COH) brought together a multidisciplinary panel of experts focused on the treatment of non–small cell lung cancer (NSCLC). Medical oncologists, pharmacists, and radiation oncologists gathered to discuss how the treatment of different types of immunotherapies, including pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), and atezolizumab (Tecentriq), play a role either as monotherapies or combination therapies for patients with NSCLC.

The panel was led by Ed Sanghyun Kim, MD, MBA, physician in chief at COH Orange County, vice physician in chief at COH National Medical Center, professor in the Department of Medical Oncology and Therapeutics Research, and Construction Industries Alliance COH Orange County physician in chief chair.

He was joined by Lihong Wu, MD, assistant clinical professor in the Department of Medical Oncology and Therapeutics Research; Krushangi Patel, MD, assistant clinical professor in the Department of Medical Oncology and Therapeutics Research; Arya Amini, MD, associate professor in the Department of Radiation Oncology and chair of Thoracic Radiotherapy; Danny Nguyen, MD, assistant professor in the Department of Medical Oncology and Therapeutics Research; Sudarsan V. Kollimuttathuillam, MD, assistant clinical professor in the Department of Medical Oncology and Therapeutics Research; Kim Nguyen, PharmD, APh, BCOP, clinical pharmacist; George Bernard Semeniuk III, MD, clinical professor in the Department of Medical Oncology and Therapeutics Research; Nicole Fahmy, PharmD, clinical pharmacy specialist; Percy Lee, MD, vice chair of clinical research in the Department of Radiation Oncology, medical director of Orange County and Coastal Region Radiation Oncology, and professor in the Department of Radiation Oncology; and Ravia Salgia, MD, PhD, professor and chair in the Department of Medical Oncology and Therapeutics Research and Arthur and Rosalie Kaplan Chair in Medical Oncology.

Efficacy Observed Across Key Trials

Kim / A little bit of a quick, superficial data dive on the phase 3 KEYNOTE-407 trial [NCT02775435].¹ This was a randomized trial using pembrolizumab/carboplatin with paclitaxel or nab-paclitaxel for 4 cycles, followed by pembrolizumab, again for up to 31 cycles vs the placebo control. The 5-year overall survival [OS] and progression-free survival [PFS] numbers show a significant difference in both OS and PFS. The median OS with PD-L1 of less than 1% gets a little tighter on the curves; they start coming together a little bit more in certain areas, but still a median benefit, and the HR is over 0.8.

The phase 3 KEYNOTE-189 trial [NCT02578680] changed a lot of things, using pembrolizumab with carboplatin and pemetrexed or with cisplatin, followed by pembrolizumab/pemetrexed maintenance vs the placebo control.² The PD-L1 expression was stratified, and the 5-year median OS and PFS showed a meaningful difference, with 22 months vs 10.6 months for OS and PFS more than doubling. For those with PD-L1 less than 1%, again, showing a benefit here of the immunotherapy plus the chemotherapy vs the placebo.

We have the phase 3 EMPOWER-Lung 3 trial [NCT03409614], so this was a randomized phase 3 study where it used cemiplimab [Libtayo] with a platinum doublet for 4 cycles, [compared with] placebo control.³ OS here was 21.1 months vs 12.9 months, and the PFS was 8.2 months vs 5.5 months. When you start looking at histology, so nonsquamous vs squamous, you’re seeing benefits on both sides with OS, with the cemiplimab plus the chemotherapy. The 2-year median OS with PD-L1 less than 1% was worse for the cemiplimab arm in both nonsquamous and squamous.

The phase 3 IMpower150 trial [NCT02366143] had 3 arms: arm A, which was atezolizumab/carboplatin/paclitaxel [followed by atezolizumab maintenance]; arm B was atezolizumab/carboplatin/paclitaxel and bevacizumab, followed by the atezolizumab/bevacizumab doublet; and arm C, which was the control arm, was carboplatin/paclitaxel/bevacizumab, followed by bevacizumab maintenance.⁴ PD-L1 was captured with IHC [immunohistochemistry] expression, which could be any status, and then looked at follow-up. When you looked at the combination vs the control, so the 4-drug vs the control arm, you saw some benefits, very borderline statistical significance with the final OS, an HR of 0.84 with the 3 [drugs] and 0.80 with the 4-drug combination, the medians were in the right direction in both of those arms. When you looked at the wild-type population with PD-L1 less than 1%, you can see the curves just collapsing here with median OS, a little bit of separation, but not much in the 4-drug regimen.

The phase 3 CheckMate 9LA trial [NCT03215706] is another randomized open-label phase 3 study against patients who are stratified into PD-L1 of less than 1%, greater than 1%, 1% to 49%, and greater than 50%.⁵ You use both squamous and nonsquamous here. This was randomized with nivolumab, ipilimumab, and chemotherapy for 2 cycles. The chemotherapy was just given for 2 cycles. Chemotherapy every 3 weeks for 4 cycles with optional pemetrexed maintenance. If the patient had squamous [histology], then they received the carboplatin-paclitaxel or one of the other platinum regimens. There was a favorable trend with the OS of almost 16 months vs 11 months, and then PFS was trending in the direction of 6.7 months vs 5.3 months. When you look at the 6-year median OS by histology, the curves remain separated. The median OS was 14.5 months vs 9.1 months for squamous, and for nonsquamous histology, it was 17.8 months vs 12.0 months. In those with a PD-L1 less than 1%, the median OS was 17.7 months vs 9.8 months. When you look at the treatment-related adverse effects [AEs], the discontinuation rate was 17% [for all study drugs], and the toxicities were predictable here.

After [reviewing] this, who’s going to get dual immunotherapy [IO] plus chemotherapy?

Wu / With low PD-L1 expression and good performance status, I will do both.

Danny Nguyen / The less than 1% for sure in the squamous [population] seems to benefit particularly well.

Salgia / I would just add on those with SMARCA4 mutation, those with CDKN2A, and RBM10 is the newest one we identified. They do poorly with the single-agent immunotherapy with chemotherapy, so I like the dual IO.

Semeniuk / I love the idea of dual IO, and that’s what I usually do. Adding chemotherapy, though, does add a lot of toxicity to the dual IO. [I believe] there was a 2% to 3% death rate on the CheckMate 9LA regimen vs just doing the dual IO. I take that into [account]. If I had an excellent performance status, a younger patient who wanted to go for it, then I would do that. Usually, what I do is just add the CTLA4 to the PD-1.

Kim / From a pharmacist’s perspective, are we managing those toxicities adequately while you’re seeing that? What are you observing from this?

Kim Nguyen / It’s multifactorial. It takes a lot of different coordination and just making sure that we’re trying to be one step ahead. Checking in with patients after chemotherapy is what my team does. If [the patient] records any signs or symptoms, just let the [doctor] be aware.

Radiation Treatment

Kim / Ravi, you have some scientific backing in the disruption of the microenvironment and the agitation of the environment?

Salgia / Percy and Arya have done this. They continue to do low-dose radiation or normal radiation.

Lee / The concept makes sense with the idea that radiation or any cytoreductive therapy could release an antigen. Some of the studies have been disappointing in an oligometastatic setting. When you can consolidate all sites, that makes the most sense. Just fundamentally, if you’re given chemotherapy, IO, or dual IO, and they have residual disease and they’ve done well, you’ve got 3 to 4 sites, you can consolidate them and then give them some interval of lack of treatment.

Amini / It’s all well said. Radiation oncology is helpful early on, even in these cases. We had the phase 2/3 ALLIANCE [A082002] trial [NCT04929041] open at COH, which is PD-L1 negative, any systemic therapy-based dual IO, IO, chemotherapy, and it’s plus or minus low-dose stereotactic body radiation therapy to stimulate the immune response.⁶ It’s a simple 8 Gy times 3. The phase 2 part is almost closed. It varies depending on our goals and…is patient-to-patient dependent.

Semeniuk / Are there any biomarkers for radiation?

Lee / There was a test, and it’s not for efficacy, it’s for toxicity. It’s developed by this scientist at UCLA who cheek-swabbed [patients], and they’ve shown some people who are more susceptible to radiation toxicity. It’s early [still].

Amini / Dose-wise, for radiation, there’s more data, but for biomarkers, there’s some level of different resistance for radiation. Hopefully, we tailor our radiation, maybe a little bit more like medical oncology does, where we’re not just doing the same dose for every mutation.

Semeniuk / Some tumors are radio-resistant; it’s just based upon natural history and what’s happened to that histology.

Kim / Danny, Sudarsan, I’ve heard from the other medical oncologists. Do you like radiation in the setting of immunotherapy or consolidation?

Kollimuttathuillam / If I find that there is no diffuse disease, I always [get a radiation oncologist involved] just to have an opinion. They might come in later down the road, especially if the patient has a good response.

Danny Nguyen / I refer to Arya and Percy all the time. I like to use radiation to consolidate in the metastatic setting and for oligoprogressive disease, not only for patients with PD-L1, but for our molecularly driven patients as well. I’m not too keen on trying to elicit an abscopal effect or anything like that, but there’s a lot of clear data to suggest that radiation can be involved at this point.

Toxicity Management

Kim / Theoretically, there should be more toxicity with these dual IO strategies and chemotherapy, but the data may be speaking a little bit differently here in the trials.

Fahmy / From my experience with monitoring patients, there are more toxicities, and you have to look at the duration of when certain toxicities show up. Oftentimes in the beginning, you’re managing the rash, fatigue, thyroid issues, but toward the end of the line, you do start to see some severe colitis and hepatitis. Overall, our management when we discuss with providers is very different, and it also at times leads to a bigger discussion on when you have to stop treatment and, oftentimes, [whether] you rechallenge. [There are all] these questions that we don’t necessarily have answers to, but we can help be part of that discussion. It’s just a matter of trying to get control of these toxicities early on so that you don’t have to [pause] therapy.

Kim Nguyen / I agree. I would say in the real world, [pembrolizumab], is generally well-tolerated. The first issue we’ll see is thyroid issues, which we’re lucky enough to just refer down the hallway to our endocrinology team. I would say the CTLA4 [therapies] are where we see the most toxicity by cycle 2. After the first dose, by cycle 2, you can see [alanine transaminase] elevations. Oftentimes, a patient may not be able to finish the fourth dose of ipilimumab, for example. It’s usually those agents that are very toxic, even from the beginning. Nivolumab and pembrolizumab are very well-tolerated.

Danny Nguyen / The toxicity profiles across the trials are expected. If anything, it highlights how we have too many of the same trials, of chemotherapy plus random IO, and then trying to prove that it’s better than what’s already been done. That complicates why we’re having this discussion. How are you going to pick cemiplimab over [pembrolizumab] over nivolumab and all that? [Looking at] the toxicity profiles, I don’t think there’s anything new that’s gained from all this.

Semeniuk / It’s hard to do cross-trial comparisons. Supposedly, cemiplimab has less of an incidence of pneumonitis than the others. I’ve given a lot of higher doses of ipilimumab in melanoma, and that’s a lot more difficult. Using lower dose ipilimumab, I find, is usually well tolerated if patients are well-educated, and they know when to call when they start having immune-related toxicities. They have to be proactive.

Salgia / Can I ask a question to the PharmD colleagues? Does it make a difference for IV [intravenous] immunotherapy vs the [subcutaneous]? The atezolizumab and the nivolumab, as an example?

Kim Nguyen / In terms of the different formulations IV or [subcutaneous], the studies that resulted show differences in the efficacy and safety profile, just with some of the formulations that have been coming out.

Salgia / Toxicity-wise, is it better managed?

Kim Nguyen / It’s about equal. Other than maybe the risk of an infusion reaction. Then, you have the other caveat of [things] like injection site reactions.

Pearls of Wisdom from the Conversation

Kim Nguyen / From a pharmacy standpoint, IO would be great if we had a way of predicting toxicity. If there’s a way for us to predict based on the patient that will allow us to better control the patient’s treatment and their outcomes.

Semeniuk / All the studies [presented] highlight and underscore the importance of immunotherapy and how it’s changed the OS. I was in training, and 5-year survival rates were 4%, typically, or under 5%. Now we’re seeing 5-year survival rates of 20% and higher, up to 25%, which is truly remarkable. The biggest unmet need, besides biomarkers, is that the PD-L1 less than 1% group, and for me, one takeaway is that I try to add CTLA4 when I can. I’m hesitant about doing it with chemotherapy all the time, but that’s a group that does benefit from CTLA4.

Fahmy / From all the chemotherapy plus IO doublet vs single, it’d be nice to see if we had one potential option to give most patients, at least predictability-wise, [and] you could follow a group that only received one form of IO. That way, if there are variations related to toxicity, then you would know exactly where they came from.

Lee / I was fascinated by the discussion of [subcutaneous] and home delivery, and then how to catch the toxicity. I’m sure companies are working on biometrics. If someone’s heart rate or their respiration rate is going up, there are 3 things that kill people: colitis, pneumonitis, and probably hepatitis. Where did [the biometrics] capture it? They’re not going to show up at the clinic; they’re showing up too late. Don’t rely on the patient to tell you that they’re in trouble.

Salgia / I like what other countries are doing, like India, where they can’t afford IO, so they dose de-escalate. Are we sure we’re giving the right amount of drug, and can we de-escalate? Why do we give it for 2 years? That’s a big gap for me. Can we stop at 3 months or 6 months? Those are all big questions we have to answer over the next few years.

Kollimuttathuillam / The one thing that I see in all these studies is that the immune checkpoint inhibitor is a game changer in lung cancer. I also see a theme that they improve the survival, they improve the PFS, but I’m not convinced that any of these regimens are truly different. There might be subgroups where one might be better than the other. For example, low PD-L1, where dual immune checkpoint inhibitors might be better, but a lot of these trials have been trying to repeat the same stuff and coming up with similar conclusions. We have gotten comfortable with managing the common AEs of immune checkpoint inhibitors, but sometimes we still have challenges in managing the rare stuff like myocarditis. I don’t usually think about it when I see a patient with those AEs. Overall, the biomarker space for immune checkpoint inhibitors seems like a huge unmet need. We don’t know who responds well and who doesn’t.

Danny Nguyen / I appreciate that you listed all the regimens and the benefits and their OS rates, and it just highlights that a lot of the regimens are the same as chemotherapy plus IO. Right now, my practice is just to give most of these patients chemotherapy plus [pembrolizumab]. It was nice that you highlighted a good instance where we would be giving a dual IO plus chemotherapy. That’s practice changing for me, and we need more studies to answer these questions because otherwise, I can just see the community giving platinum [chemotherapy] plus pembrolizumab.

Amini / From the radiation standpoint, we can do better as a field, trying to understand how to fractionate, whether we can break up the radiation a little bit more, what to treat, and what dose to treat with [for] immunotherapy. Maybe we don’t have to give a full dose all at once. Maybe it’s giving a little sprinkle here, and a couple of months later, sprinkling a couple there. We have a trial that breaks it apart in the middle, halfway through with the 5 treatments, which is considered bad as a field, and got funding for it because it’s just a little different, and a lot of people are thinking that way. There’s some work to be done.

Patel / I don’t use as much dual IO without chemotherapy as maybe the data supports, so that’s a nice pearl. I will throw in there a little bit since I'm a community oncologist, and I do see other tumor types, [that] there have been some data in other tumor types, like colorectal cancer, about the order of chemotherapy and IO, and the role of IO in making chemotherapy a little bit more effective if used earlier. [That’s] not to say that that data doesn’t exist in lung cancer, but certainly if I am nervous about giving all 4 agents at the same time in a dual immunotherapy-chemotherapy regimen, I do consider the order and sometimes will cherry-pick which agent I give at which cycle based on patient tolerance and my prediction of how the disease will respond based on when I give which agent. None of that is data-driven, so I think that would be great to have trials looking at the order in lung cancer or in multiple tumor types.

Kim / COH is one of these areas where we can see a lot of collaboration between our campus sites and our regional sites. We continue to strive to make that stronger, and now we’re not just a Southern California system; we’re a national system in 4 states. The challenge is to be very synergistic in how we approach patients so that there’s a common protocol that we can do.

References

1. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. J Clin Oncol. 2023;41(11):1999-2006. doi:10.1200/JCO.22.01990
2. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023;41(11):1992-1998. doi:10.1200/JCO.22.01989
3. Makharadze T, Gogishvili M, Melkadze T, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in advanced NSCLC: 2-year follow-up from the phase 3 EMPOWER-Lung 3 Part 2 trial. J Thorac Oncol. 2023;18(6):755-768. doi:10.1016/j.jtho.2023.03.008
4. Socinski MA, Nishio M, Jotte RM, et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 2021;16(11):1909-1924. doi:10.1016/j.jtho.2021.07.009
5. Reck M, Ciuleanu TE, Schenker M, et al. Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial. Eur J Cancer. 2024;211:114296. doi:10.1016/j.ejca.2024.114296
6. Schild SE, Wang X, Bestvina CM, et al. Alliance A082002 -a randomized phase II/III trial of modern immunotherapy-based systemic therapy with or without SBRT for PD-L1-negative, advanced non-small cell lung cancer. Clin Lung Cancer. 2022;23(5):e317-e320. doi:10.1016/j.cllc.2022.04.004