Durable improvements were seen with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) compared to treatment with single-agent ipilimumab in patients with previously untreated advanced melanoma, according to a 6.5-year follow-up of the CheckMate-067 trial presented at the 2021 ASCO Annual Meeting.

The long-term data showed that the median OS with the combination was 72.1 months (95% CI, 38.2–not reached) and 36.9 months with nivolumab alone (95% CI, 28.2-58.7), compared with 19.9 months with ipilimumab alone (95% CI, 16.8-24.6). This is reportedly the longest median OS in a phase 3 clinical trial of advanced melanoma.

Additionally, the 6.5-year progression-free survival (PFS) rate was 34% with nivolumab and ipilimumab and the median PFS was 11.5 months. The rates were 29% and 7% with nivolumab and ipilimumab as single agents, respectively; the median PFS was 6.9 months and 2.9 months, respectively.

“The sustained OS and PFS benefit shown with nivolumab-based treatment, particularly the nivolumab plus ipilimumab combination, has changed the way we look at long-term efficacy outcomes for patients with advanced melanoma,” Jedd D. Wolchok, MD, PhD, FASCO, lead author and chief of the Immuno-Oncology Service, Human Oncology and Pathogenesis Program, at Memorial Sloan Kettering Cancer Center, stated in a press release.2 “These new results from the CheckMate-067 trial, with nearly half of patients treated with the nivolumab and ipilimumab combination surviving to 6.5 years, confirm the durable, sustained benefit of the combination in patients with advanced melanoma.”

In 2015, the FDA approved the combination of nivolumab and ipilimumab for the treatment of patients with metastatic melanoma, based on earlier findings from CheckMate-067. Nivolumab is also approved for use as a single agent in this patient population.

In the double-blind, phase 3 CheckMate-067 study, investigators randomized patients with previously untreated unresectable advanced (stage III or IV) melanoma 1:1:1 to receive the combination of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks (n = 314), nivolumab alone at 3 mg/kg every 2 weeks plus placebo (n = 316), or ipilimumab alone at 3 mg/kg every 3 weeks for 4 doses plus placebo (n = 315). Treatment was administered until disease progression or unacceptable toxicity.

Patients were stratified by PD-L1 status, 

 mutational status, and metastasis stage.

The co-primary end points of the trial were PFS and OS; secondary end points included objective response rate, descriptive efficacy assessments, and safety.

At the 6.5-year analysis, 49% of patients were alive and in follow-up. Of this percentage, 77% of patients who were treated with nivolumab plus ipilimumab were reported to be off of therapy and did not receive subsequent systemic treatment. Sixty-nine percent of those on nivolumab alone, and 43% of those on single-agent ipilimumab also have been off of treatment and did not require subsequent systemic therapy.

The clinical benefit was sustained and observed with both nivolumab/ipilimumab and nivolumab alone across relevant key subgroups, which included those with 

 wild-type tumors, and patients with baseline liver metastases.

 wild-type melanoma, the OS rate was 46% in those who received the combination, 42% for nivolumab alone, and 22% for ipilimumab alone. In those with liver metastases, the OS rates were 38%, 31%, and 22% for the combination, nivolumab monotherapy, and ipilimumab monotherapy, respectively.

In the combination arm, as well as in the single-agent nivolumab arm, the median duration of response (DOR) has still not yet been reached; the median DOR was 19.2 months for those on the ipilimumab arm.

Regarding safety, the profile of nivolumab and ipilimumab combined was found to be consistent with prior data of the regimen and no new safety signals were observed. No additional treatment-related deaths had occurred since the 5-year analysis of CheckMate-067.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 59% of patients on the nivolumab/ipilimumab arm, in 24% on the nivolumab-alone arm, and in 28% of patients on the ipilimumab arm.

“These results build upon our decade-long legacy in treating melanoma, which began when the average life expectancy following a diagnosis of metastatic melanoma was roughly six months and less than 10% of patients survived beyond five years,” stated Gina Fusaro, development lead, melanoma, Bristol Myers Squibb.

 “With some of the longest follow-up with immunotherapies to date, Opdivo and Yervoy have consistently demonstrated durable, long-term survival benefits for patients diagnosed with advanced melanoma.”

Previously, 5-year follow-up findings from CheckMate-067, which were published in the 

, showed that the median OS with nivolumab/ipilimumab was not reached and was 36.9 months with nivolumab alone, compared with 19.9 months with ipilimumab alone (HR, 0.52 for nivolumab/ipilimumab vs ipilimumab; HR, 0.63 for nivolumab vs ipilimumab). The median follow-up was 60 months.

At 5 years, the OS rate was 52% with nivolumab plus ipilimumab, 44% with nivolumab alone, and 26% with ipilimumab alone.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9506. doi:10.1200/JCO.2021.39.15_suppl.9506

Six-and-a-half-year outcomes for Opdivo (nivolumab) in combination with Yervoy (ipilimumab) continue to demonstrate durable long-term survival benefits in patients with advanced melanoma. News release. Bristol Myers Squibb. May 19, 2021. Accessed June 6, 2021. https://bit.ly/3pnRufC

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836

Articles

Nivolumab with or without ipilimumab improved survival over ipilimumab alone in patients with previously untreated advanced melanoma. 

Melanoma Outcomes Are Improved With Nivolumab Alone or With Ipilimumab

The phase 3 IMpower133 trial (NCT02763579), which examined atezolizumab (Tecentriq) plus platinum-based chemotherapy and etoposide in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) helped lay the foundation for the exploration of other novel immunotherapy combinations, according to Ravi Salgia, MD, PhD.

In the phase 3 CASPIAN trial (NCT03043872), investigators examined the use of first-line durvalumab (Imfinzi) plus the same chemotherapy backbone in patients with ES-SCLC.

 The combination yielded a durable improvement in overall survival, but the addition of tremelimumab (formerly ticilimumab; CP-675,206) did not appear to elicit any further statistically significant improvement.

Now, a phase 1 study (NCT04560972) will further build off of the IMpower133 regimen by examining the safety of the novel agent LB-100 in combination with carboplatin, etoposide, and atezolizumab in patients with untreated ES-SCLC.

Further exploration of immunotherapy regimens will be necessary, Salgia said.

“It is important for us to realize that the tumor mutational burden for SCLC is very high,” Salgia said. “We need to be able to [consider whether] immunotherapy [may] work even better [when used] in combination with chemotherapy or other therapeutic strategies.”

® during an Institutional Perspective in Cancer webinar on lung cancer, Salgia, a medical oncologist and Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope, discussed pivotal trials that have shaken up the small cell lung cancer treatment paradigm, novel immunotherapy regimens under investigation, and next steps for research.

®: What is your approach for selecting treatment for patients with limited-stage SCLC [LS-SCLC] vs ES-SCLC?

: SCLC is a difficult disease to treat. We have come a long way in terms of thinking about [the disease] and we know that there are 2 varieties of [the disease] that we consider in terms of the staging: LS-SCLC and ES-SCLC. For [patients with] LS-SCLC, we still [administer] chemotherapy and radiation therapy [with consideration] for prophylactic cranial radiation. For those with [ES-SCLC], we are changing the paradigm. Currently, we are using chemotherapy with immunotherapy. After the first line of therapy fails, [we have a] second-line option, which is lurbinectedin [Zepzelca]. Of course, we really try to emphasize [enrollment to] clinical trials, as well.

Starting in the frontline setting, how are you applying the findings from the pivotal phase 3 IMpower133 trial to clinical practice?

Results have [demonstrated] that platinum-based chemotherapy with etoposide in combination with atezolizumab does [yield] better survival. That is revolutionary for us and we are using that [agent] in our clinical practice. It is important to realize that the severity of the adverse effects were not worse than [what was reported in] the chemotherapy arm.

An ongoing study that is open at City of Hope is building off of the success seen with the IMpower133 regimen. Could you highlight this research and its potential implications?

For ES-SCLC, we are using carboplatin and etoposide with atezolizumab, as an example. However, we know patients can recur and relapse, so we wanted to make that better. In our laboratory, we had discovered that the PP2A pathway in SCLC is very important. We can inhibit that pathway with a drug called LB-100. We are using a backbone of the IMpower133 regimen—carboplatin and etoposide with atezolizumab—and combining it with LB-100. We are going to be publishing [these data] relatively soon. It is important to realize it is a phase 1 study, but we are quite hopeful that this [research] will [result in] revolutionary breakthroughs.

Does LB-100 have a safety profile that makes it amenable for use in a 4-drug combination?

The initial LB-100 study [that examined the] drug by itself was done here, at City of Hope, and that [research] was published by Vincent Chung, MD, and colleagues. The safety profile [of LB-100] was really good. [However], we do not know yet [what this will look like] in combination [with other agents] because this is a phase 1 study. Once we start the study, we are very much hoping that the toxicity is no different than [what we saw in] the IMpower133 study.

What has been learned from the phase 3 CASPIAN trial? How do you select which patients should receive this regimen vs the IMpower133 regimen in practice?

The CASPIAN study also gives us another [option] for our patients. Instead of utilizing atezolizumab, we utilize durvalumab. The study looked at durvalumab [plus platinum/etoposide and] with tremelimumab [vs platinum/etoposide alone]. However, the issue became that the [the addition of tremelimumab] did not [provide more benefit] than durvalumab [with platinum/etoposide]. We are using a platinum-based backbone, with etoposide and durvalumab. The difference is that in the context of the maintenance study, durvalumab was given once a month [while] atezolizumab was given once every 3 weeks. At the same time, we use it in our practice either way. I do believe [the decision] is really dependent on [factors like] tolerability. Both of the regimens are very reasonable.

In February 2021, the FDA approved trilaciclib (Cosela) to reduce chemotherapy-induced bone marrow suppression in adult patients with ES-SCLC who were receiving certain chemotherapy agents. How did this decision impact the paradigm?

Growth factor support has been always important for SCLC, especially [because of] the cytotoxic therapies that we give [to our patients]. We have used granulocyte colony-stimulating factor, and now, we have another option [in the form of] this new CDK4/6 inhibitor.

It was nice to see that [that the agent] did not affect the survival [of the patients who received it] in a negative way. We are very happy with that and [we will] be utilizing that [option] in our clinical practice. The more choices we have, the better it is for patients.

Shifting to the second-line setting, in June 2020, lurbinectedin was also approved by the FDA for use in patients with metastatic SCLC following progression on a platinum-based chemotherapy. How does the agent compare with standard topotecan?

We know that in the first-line setting of SCLC, many of our patients relapse and/or recur. [Therefore], it is important to have [options in the] second-line setting. We have always said that clinical trials are incredibly important and lurbinectedin provides a potential [option] beyond topotecan. As we know, topotecan has been approved as a second-line therapy; however, lurbinectedin seems to be better tolerated and is showing [good] efficacy. [Moreover], topotecan is given on days 1 through 5, whereas [lurbinectedin] is really much easier to give. Having another choice makes a huge difference in practice.

How would you approach choosing between the 2 options?

Lurbinectedin is probably going to become the standard of choice; it has been in our practice. It is because of convenience—instead of days 1 through 5, it is [administered every] 21 days—as well as tolerability. I do think it has a huge role for us, and we will continue to utilize it. It [will be] important for us to explore this [agent] in the first-line setting [and learn] how we can overcome resistance in the second line.

The indication for pembrolizumab (Keytruda) in patients with metastatic SCLC who experienced disease progression on or after platinum-based chemotherapy and at least 1 prior line of treatment was recently withdrawn by the FDA. How do you foresee this impacting the use of the agent in this disease?

We has been excited about the approval of pembrolizumab, but it has since been withdrawn by the FDA, and very reasonably so— the end points [of the confirmatory trial] have not been met. If it does not help our patients, it is not worth it. [It begs the question], is pembrolizumab important? It could be very important in terms of early-stage disease, in the first-line setting, [and] in combination in other settings. We do not [currently] know and, clearly, we need to do more clinical trials.

Bispecific antibodies are going to be important, as well as bispecific T-cell engagers. Potentially even CAR T-cell therapies will be significant. All of those [options] will lead to significant advances in SCLC. Can one use immunotherapeutics with small molecule inhibitors? Can one [leverage] the genomics or alterations in SCLC [to improve outcomes]? That is to be determined, and that is where we need to [focus our] attention in [terms of] clinical trials.

Lung cancer is still a very tough disease to treat. We have some therapeutics that have revolutionized our way of thinking, but it is not good enough; we need to do better. We need to continue to [conduct] clinical trials [and encourage enrollment] so we can make a difference. It is important to do research in, and fund research [for], SCLC as we have done for non–small cell lung cancer, [where] many of the codes are being broken. We need to break the code even better for SCLC.

Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. 

. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8

LB-100, carboplatin, etoposide, and atezolizumab for the treatment of untreated extensive-stage small cell lung cancer. ClinicalTrials.gov. Updated March 15, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04560972

This article was originally published on OncLive as, "

Future of SCLC Treatment Lies in Innovative Immunotherapy Combos

New immunotherapy combinations are being explored in the small cell lung cancer space.

Next Up in SCLC: Immunotherapy Combinations

The optimal treatment of patients with early-stage and locally advanced non–small cell lung cancer (NSCLC) in 2021 consists of multidisciplinary management, 

 gene testing, and consolidation treatment with durvalumab (Imfinzi) in addition to clear pathways that enable the successful delivery of such care to all patients, explained Jacob Sands, MD.

“We’ve discussed all these best ways to treat patients based upon the data that we have, and one element of this in the real world that then becomes a challenge is the logistics,” said Sands. “One of the things within our health care system and within our hospital systems to start really recognizing more and doing a better job of is how to help make [high level care] feasible for everybody.”

®, Sands, a physician at Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School, discussed current approaches to the treatment of patients with early-stage and locally advanced NSCLC.

®: How would you define the multidisciplinary treatment of patients with early-stage NSCLC?

: In early-stage disease, treatment can involve a few different things. Often patients end up with surgically resectable disease, so there’s surgery, and then there’s the postoperative pathology that we look at, which really defines what we do after surgery. That pathology gives us a lot more information. If the size [of the tumor] is greater than 4 cm, particularly if there are lymph nodes involved, we are talking about adjuvant chemotherapy in the case of NSCLC. In the case of small cell lung cancer, we really give adjuvant chemotherapy to anybody.

What is your optimal approach to molecular testing?

In early-stage disease, when we’re talking about something that has been resected and there’s no evidence of disease, those individuals often end up getting adjuvant chemotherapy. If [the tumor is] greater than 4 cm, if there’s any lymph node involvement, that becomes a stage in which adjuvant chemotherapy is important.

As far as genomic testing, we have the recent ADAURA publication that showed a substantial improvement in [disease-]free survival. The overall survival data are going to [require] more [time to mature], but [the results] led to [the] approval [of osimertinib in the adjuvant setting]. Now [the results of] 

 testing, in particular, on the pathology of these patients [is important]. 

As far as doing genomic testing for other potential targets, the data are really compelling [in the metastatic setting] and given how osimertinib [Tagrisso] works for patients with 

 mutations, what about alectinib [Alecensa] for patients with 

 fusions, or some of these other really effective targeted therapies that we use as a standard of care in stage IV disease? Should we be using those agents in earlier-stage disease as well? Those [questions] have led to a number of other trials that are ongoing and now getting started.

Would you say that, if not for standard practice, but for clinical trials, that next-generation sequencing should be ordered rather than a single-gene panel for

Right now, we really don’t have a number of different approved therapies. In the earlier-stage setting, we just have osimertinib right now as an approved adjuvant therapy. It is really important for those patients to also be offered chemotherapy, assuming that they qualify for it. In the ADAURA publication, I was a little surprised by the number of people that actually didn’t get chemotherapy, so it’s important to highlight that these patients should get offered adjuvant chemotherapy, and then, if appropriate, osimertinib.

We don’t really have other approved therapies, so testing for 

 alone right now as far as what you’re clinically going to do is meaningful. Other agents we don’t really have a defined role for, but consideration of enrollment to these various other trials, I would really encourage. In that sense, getting genomic testing to drive enrollment to some of these other studies is really compelling.

What is the role of postoperative radiation in treatment?

For patients who get surgical resection and have N2 mediastinal node involvement, there is really kind of a question now about radiation. There was a recent trial that was negative for inclusion of postoperative radiation. That being said, there are still patients where I would expect postoperative radiation to provide some potential benefits. This is really a population that requires interaction with radiation oncologists and discussion about each individual case, and whether you think that someone is going to really benefit from radiation in that setting.

What are your thoughts on immunotherapy entering the early-stage treatment paradigm?

We have seen great results with immunotherapy in metastatic disease. We have seen also really impressive results after chemoradiation. Now the question is: In resectable disease, do these checkpoint inhibitors have a potential role to play? There are multiple studies that are being done or have enrolled [to that end]. These are studies that enroll after chemotherapy, but a study that is currently open within the ALCHEMIST portfolio is a study called ACCIO. This is a study I’m running, and I would love for people to enroll and to be aware of this. It’s a 3-arm study [that is enrolling patients] after surgical resection, an R0 resection, who are 

 negative, wild-type. Patients need PD-L1 testing for stratification, but all-comers with any level of PD-L1 can enroll, and all [patients with] NSCLC can enroll, [be it] squamous [or] nonsquamous [histology].

The [treatment arms will consist of] standard chemotherapy, followed by observation standard of care vs chemotherapy, followed by pembrolizumab [Keytruda] in a sequential arm, and then the third arm consists of concurrent chemotherapy plus pembrolizumab. Both the sequential and the concurrent arm [will administer] the same duration [of pembrolizumab], which is 1 year, just [at] different starting [points]. This trial is currently open throughout the country, and we certainly welcome enrollment.

Shifting to the stage III setting, what are some of the best practices for ensuring that patients receive durvalumab after concurrent chemoradiation?

The PACIFIC data have really showed pretty impressive and durable results in patients who get chemotherapy plus radiation with curative intent. Specifically, concurrent chemoradiation followed by durvalumab. I was a little skeptical at first [based on] the initial data that were reported. There was separation of curves, the progression-free survival was statistically significant, [but] at the time, I thought maybe some of the people who were in the control arm later on at recurrence [would] end up getting immunotherapy and [the curves] might even out.

[However,] we’ve really seen impressive separation of the curves that has persisted, and the longer these data mature, the more impressive [the data look] to me. In the control arm of the study, there was a pretty good number of patients who at recurrence did end up getting immunotherapy, so we really have a fair comparator arm, which is an important thing to look into.

Not in all of the immunotherapy trials did the control arm later on get immunotherapy in the appropriate setting, but [those in the PACIFIC trial] did, so this is a very fair comparison that had a good standard-of-care control arm. The responses have really been impressive as the data mature. For everybody that gets concurrent chemoradiation for stage III unresectable disease, I then put them on durvalumab for 1 year. We can use [every-4-week] dosing, which is a little better than the initial [every-2-week] week dosing and is easier for patients.

Also, in PACIFIC, those who got durvalumab earlier seemed to do better. That being said, I suspect that those [were] patients who tolerated their prior treatment and had better prognosis. Specifically, individuals who got chemoradiation and recovered immediately and didn’t really have any problems who were then able to start durvalumab earlier. I don’t necessarily take that [to mean that] people have to immediately start durvalumab earlier.

That being said, I want to start it about 4 weeks after, get that scan, making sure that there’s no new disease, and then start durvalumab. However, if somebody is really struggling to recover, for whatever reason, I don’t really stress pushing back or not immediately starting durvalumab after that. That’s probably still okay [to do].

On durvalumab there are people that then end up with adverse effects [AEs] from the treatment. Thankfully, most people getting these checkpoint inhibitors generally do really well, so AEs are somewhat limited. But I certainly have patients that have had AEs, and pneumonitis is always the tough one. Someone with pneumonitis [should be] started on steroids and make sure that they recover. I have patients restart [durvalumab] if it wasn’t a really severe pneumonitis. If [the pneumonitis] recovers well—when I start prednisone, once we complete the taper, and if they’re doing well off of steroids—I do restart durvalumab. In some cases, that’s worked out. In other cases, I’ve had patients who had pneumonitis again, so I haven’t been able to get everybody through 1 year of therapy. We do as much as we can. If patients are having really significant AEs, then we stop at that time.

In the trial, we did see that not everybody was able to complete the full year [of durvalumab], but those who were able to complete the full year had really impressive outcomes. If you’re more than a year out from finishing the chemoradiation, your prognosis is better in that setting as well, so I would expect those numbers to look better, but the results are actually really impressive. I try to get as much of [durvalumab] in as I can over the course of that year. If we have to start a little bit later than I want to start the therapy, that’s fine. I don’t stress about that. If there are AEs that really don’t allow for further treatment, then we stop at that time. However, getting durvalumab is very meaningful [for those patients].

What are some important resources regarding the management of immune-related adverse effects?

I really benefit from being at a center with so many specialists. I’m able to draw in specialists who really focus on some of these specific AEs. When AEs come up on some of these checkpoint inhibitors, whether it be durvalumab after chemoradiation, or any of the others in any setting, there are guidelines on how to manage them, which is important. Thankfully, most people really tolerate the therapy well, but when there are AEs, we really need to make sure that we’re managing them appropriately. Checking the guidelines on how to do that [is important]. There are publications on this, there are the National Comprehensive Cancer Network guidelines on how to manage these AEs, and it’s important to look at those.

For patients who do complete the full year of durvalumab, is there ever a situation where you would continue it?

As far as whether or not to continue treatment after 1 year, I really wouldn’t. A percentage of these patients are cured of their disease. The trouble is, we can’t define and identify prospectively who’s cured and who’s not. That is an area of important research. We know that a percentage of patients are, and the data that we have doesn’t really support doing any treatment beyond 1 year, so I would stop the treatment at 1 year and then monitor patients closely at that time going forward.

Does PD-L1 status affect whether you recommend durvalumab to patients who do not progress on concurrent chemoradiation?

As far as giving durvalumab after concurrent chemoradiation, PD-L1 expression really isn’t something that drives my decision making. If I have somebody who never smoked where I have a high suspicion of them having an 

 mutation, for example, then I’d look for that and that then becomes harder to know. We know that these checkpoint inhibitors aren’t as effective in general in people who never smoke and have an 

 mutation. At the same time, I do worry a little bit about somebody being on a checkpoint inhibitor and then having recurrence of disease where we would then use osimertinib because we know that the culmination of osimertinib and durvalumab leads to a higher incidence of pneumonitis. What to do in that setting is a little less clear. The PACIFIC trial did enroll patients that fit this population, although there wasn’t a big population of them. Based on the study results, everyone would get durvalumab. If you’re looking at that subpopulation, that’s where I still kind of have a question about whether or not to add durvalumab in that setting. 

What are some treatment barriers that may prevent patients from receiving optimal care that you would like to see addressed?

Within different communities, [treatment] really looks different. There are some communities where the patient is able to take time off work or is retired or is really financially stable and able to come in at any time and get their treatment at any time. There are other communities where patients are having [to organize their treatment] in the middle of trying to hold everything else together, and those are entirely different situations. When we’re talking about these data, and the different drugs and the different curves, it’s without the challenges of real life, but that’s not how it is for everybody.

There are communities where it’s going to take more coordination and more resources to help people get in [for optimal care]. I have some patients who having to navigate the public transportation system to come in and get chemotherapy and get home is a challenge. Having nurse navigation and having some of these other resources is something that’s overwhelmingly important within our health care system to really provide this very high level of care to everybody throughout society and is clearly something we need to address much better within our health care system and within the country.

An expert gives an overview of recent advancements in the lung cancer space.

Lung Cancer Advancements Highlight the Need for Multidisciplinary Care

Chronic immune-related adverse effects (irAE) arising from adjuvant anti–PD-1 therapy in patients with high-risk melanoma are more common than previously recognized, and often persisted with longer follow-up, according to findings from a multicenter cohort study published in 

Chronic irAEs, which are defined as those that persist after 12 weeks of anti–PD-1 discontinuation, occurred in 43.2% of patients enrolled to the trial (n = 167/387). Although the majority of these chronic irAEs were grades 1 or 2 (96.4%; n = 161/167), most of the effects persisted until last available follow-up (85.6%; n = 143/167).

“It is certainly important to recognize that anti–PD-1 therapy, regardless of this study and others, certainly does improve outcomes for patients with melanoma and is something that I will certainly still be offering my patients” lead study author Douglas Johnson, MD, MSCI, an associate professor of Medicine at Vanderbilt University Medical Center, and clinical director of Melanoma at Vanderbilt-Ingram Cancer Center, told 

. “There is a subset of patients with stage III melanoma who have a very low risk of recurrence, and for those patients, [these data] may make us reevaluate how to [treat] them, and perhaps [revisit] how [we] make risk/benefit determinations in those settings.”

Moreover, irAEs such as endocrinopathies (83.0%; n = 73/88), arthritis (48.9%; n = 22/45), xerostomia (52.9%; n = 9/17), neurotoxicities (73.3%; n = 11/15) and ocular effects (62.5%; n = 5/8), were the most likely to become chronic, while effects impacting visceral organs like the liver, colon, lungs, and kidneys, had much lower rates of becoming chronic.

“We tend to think of specific organs that are being affected by these toxicities,” Johnson said. “The big ones that come to mind are the colon, the lungs, and the liver, but the toxicities in those organs seem to really get better; it was toxicities in the smaller organs that seemed to more commonly develop into chronic [effects].”

Adjuvant therapy with anti–PD-1 agents has been found to result in improved relapse-free survival (RFS) in patients with resected, advanced-stage melanoma. However, the long-term effects of this treatment approach remain uncharacterized. To address this knowledge gap, investigators launched this retrospective, multicenter cohort study to determine the incidence, length, spectrum and associations of chronic irAEs that arise from adjuvant anti–PD-1 treatment in patients with stage III and IV melanoma. The study was conducted from 2015 to 2020 at 8 medical centers across the United States and Australia.

The median age for patients enrolled on the study was 63 years (range, 17-88) and the majority were male (60.7%; n = 235/387). Additionally, 74.9% (n = 290) had preexisting comorbidities, 85.8% (n = 332) had cutaneous primary sites, and 51.2% (n = 198) had 

 wild-type variants. Moreover, 33.1% (n = 128) of patients had resected stage IIIB melanoma, while 39.5% (n = 153) had resected stage IIIC disease. Around 84% (n = 326) of patients had received prior treatment with nivolumab (Opdivo), and 15.8% (n = 61) of patients received pembrolizumab (Keytruda), with a median treatment duration of 306 days (range, 1-1049).

Reasons for treatment discontinuation included therapy completion for 50% (n = 193), irAEs for 25.3% (n = 98) of patients, and disease progression for 20.9% (n = 81) of patients. Moreover, median RFS and overall survival had not been reached. At a median follow-up of 529 days, the majority of patients (93%) were alive. Notably, patients with observed acute and chronic irAEs were found to have superior RFS compared with those who did not experience irAEs.

Of all 387 patients included on the trial, 69.0% (n = 279) experienced acute irAEs; 44.2% (n = 171) of these effects were grade 2 or higher, while 13.4% (n = 52) were grades 3 to 5 in severity. Two patients died from irAEs; 1 patient had myocarditis, while the other had Guillain-Barré–like syndrome.

The most common acute irAEs observed were dermatitis/pruritus (25.8%), thyroiditis/hypothyroid (16.3%), arthralgias (10.6%), colitis/diarrhea (9.8%), hepatitis (6.2%), pneumonitis (4.4%), and xerostomia (4.1%). About 28% of patients required treatment with glucocorticoids; 55.0% needed this for grade 2 irAEs, while 45.0% needed them for grade 3 to 5 effects.

In those who developed chronic irAEs, systemic glucocorticoids were needed in 32.9% (n = 55) of patients. The most common chronic irAEs observed were hypothyroidism (14.0%), arthralgias (5.7%), dermatitis/ pruritus (6.6%), adrenal insufficiency (3.1%), and xerostomia (2.3%).

Age and gender were not found to be linked with the development of chronic irAEs (63.0 years vs 63.0 years in those who did not develop chronic irAEs, 

 = .31, respectively). Moreover, the median time of onset of acute irAEs was not determined to be associated with chronicity (

 = .95). With the exception of endocrinopathies, those who were given glucocorticoids for acute effects did not go on to develop chronic effects more often than those who did not receive the agents (

The investigators concluded that the risks of chronic irAEs should be integrated into treatment decision-making for this patient population.

“In terms of future directions, we might potentially be able to intervene early and identify these effects before they established themselves to become chronic,” Johnson noted.

Patrinely JR, Johnson R, Lawless AR, et al. Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma. 

. Published online March 25, 2021. doi:10.1001/jamaoncol.2021.0051

Chronic immune-related adverse effects arising from adjuvant anti–PD-1 therapy in patients with high-risk melanoma are more common than previously recognized, and often persisted with longer follow-up.

Chronic Immune-Related Adverse Events Are Common in Certain Melanoma Subgroups

The introduction of immunotherapy to the treatment paradigms of esophageal and gastric cancers has been an exciting advance, said Namrata (Neena) Vijayvergia, MD, who added that although agents, such as nivolumab (Opdivo), are not yet approved by the FDA in the adjuvant or metastatic settings, they should be considered for use based on National Comprehensive Cancer Network (NCCN) recommendations.

“Experts put out these guidelines for a reason,” said Vijayvergia. “There are phase 3 data supporting [the use of immunotherapy in esophageal and gastric cancers].”

On January 20, 2021, the FDA granted a priority review to a supplemental biologics license application (BLA) for adjuvant nivolumab (Opdivo) in patients with resected esophageal or gastroesophageal junction (GEJ) cancer following neoadjuvant chemoradiation treatment.

Also, on January 20, 2021, the FDA granted a priority review to a supplemental BLA for nivolumab in combination with a fluoropyrimidine- and platinum-containing chemotherapy for use in patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma.

® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Vijayvergia, assistant chief of Gastrointestinal Medical Oncology, assistant professor in the Department of Hematology/Oncology, and medical director of Medical Oncology at Fox Chase Cancer Center Partners, of Fox Chase Cancer Center, discussed the emerging role of immunotherapy in resectable and metastatic esophageal and gastric cancers, as well as key nuances that could complicate these agents’ utility in clinical practice.

®:How do the results of the CheckMate-577 trial support the use of nivolumab as adjuvant treatment for patients with esophageal cancer?

:The CheckMate-577 study was very exciting in terms of adjuvant therapy for patients with esophageal cancer. [The results support the use of] adjuvant therapy with nivolumab [for these patients].

[CheckMate-577] compared nivolumab with placebo in patients who had treatment for their esophagus cancer and, at the time of surgery, did not have a complete pathological response. Giving those patients nivolumab in the adjuvant setting for up to 1 year led to an improvement in progression-free survival [PFS]. The disease-free survival was 22 months for the nivolumab group compared with 11 months for the placebo group. The curves started separating at around 3 months, and at around 6 months, they separated further. The separation continued for a long time, which is a really exciting finding. [Nivolumab] is something that is going to hopefully get [FDA] approval in [the adjuvant] setting soon. Interestingly, this study included patients with squamous and adenocarcinoma, so [adjuvant nivolumab] works for both [patient populations].

Should chemoimmunotherapy be considered for patients with metastatic esophageal cancer?

In [the metastatic] setting, esophageal and gastric cancer are differentiated from each other.

There are new data [regarding] the role of adding immunotherapy with pembrolizumab [Keytruda] to chemotherapy for patients with esophageal cancer. The KEYNOTE-590 trial [enrolled] patients with locally advanced and unresectable metastatic esophageal adenocarcinoma or squamous cell carcinoma. Patients were randomized to receive chemotherapy, which was cisplatin and 5-fluorouracil, with pembrolizumab or placebo. The primary end point was overall survival [OS] and PFS.

Interestingly, in this study, most patients, not just those who had a CPS greater than 10, benefited from the addition of pembrolizumab to chemotherapy with a hazard ratio [HR] of 0.73. Obviously, the extent of benefit improved in patients who had squamous cell carcinomas, as well as those who had PD-L1 [expression] greater than 10%.

What data support the use of immunotherapy in metastatic gastric cancer?

In terms of gastric cancer, we had the CheckMate-649 study that was presented at [the 2020] ESMO [Virtual Congress] that suggested the addition of nivolumab to chemotherapy in patients with a CPS greater than 5 was associated with an improvement in OS and response rate. The OS was 11 months [with chemotherapy alone] vs 14 months [with nivolumab/chemotherapy], favoring the combination arm. The study’s primary end point was to look at patients with a CPS of greater than 5 for PD-L1 [expression], but when [the investigators] looked at the entire population, the benefit was maintained [with nivolumab] in all patients. However, that was not the primary end point. The outcome of the study was that adding nivolumab to oxaliplatin-based chemotherapy was beneficial in patients who have a CPS greater than 5.

Apart from [CheckMate-649], there were 2 other studies that complicated the picture a little bit. There was the ATTRACTION-4 trial, as well as the KEYNOTE-062 trial, which had suggested that the benefit of immunotherapy was not that [significant]. In the KEYNOTE-062 trial, some benefit [was observed] in PFS, but not much in OS, meaning there wasn’t much benefit to adding pembrolizumab to chemotherapy.

However, in patients who had a CPS greater than 10, pembrolizumab alone was very effective. Unfortunately, this was not a primary end point of the study and this was more of a secondary analysis. Hence, we cannot take [pembrolizumab monotherapy] to the frontline [setting], but it is beneficial. In patients who are frail and cannot get chemotherapy [but] have a CPS greater than 10, using single-agent pembrolizumab is absolutely reasonable and should be considered.

What could explain the conflicting results observed in the KEYNOTE-062, ATTRACTION-4, and CheckMate-649 trials?

Trying to understand why one [immunotherapy] worked and one didn’t is a little confusing, but patient selection is very important. Interestingly enough, if we look [at the data] and compare these 3 trials, the KEYNOTE-062 trial compared with the ATTRACTION-4 trial and the CheckMate-649 trial used a cisplatin-based regimen rather than oxaliplatin. [The discrepancy] could be that the chemotherapy backbone was different.

Second, the primary study population in ATTRACTION-4 included all-comers, and only 16% of patients were PD-L1 selected. In CheckMate-649, 60% of patients had a CPS greater than 5, so [the population] was more selected for PD-L1 positivity [compared with ATTRACTION-4]. In the KEYNOTE-062 trial, only 36% of patients had a CPS greater than 10.

Also, the [study] locations [were different]. The ATTRACTION-4 trial was done in Asia, [whereas] the KEYNOTE-062 and CheckMate-649 studies were done worldwide.

There were a lot of differences in these studies and people are attributing [the conflicting results] to the chemotherapy backbone in the KEYNOTE-062 trial vs the nivolumab studies. Also, the higher enrichment of PD-L1 in the CheckMate-649 study [may have contributed] to the overall benefit; 82% of patients had a CPS greater than 1 and 60% had a CPS greater than 5 in that study.

Having seen these data, do you adhere to the NCCN guidelines that recommend immunotherapy?

Absolutely. Even though these agents are not approved by the FDA, they are under review by the FDA. The NCCN guidelines recommend nivolumab as a category 1 indication in the adjuvant setting for [patients with] esophagus cancer. For patients with gastric cancer who are HER2 negative and have a CPS greater than 5, adding nivolumab [to chemotherapy] is recommended. Similarly, adding immunotherapy for patients with esophageal cancer [is recommended].

Could there be any overlap between biomarkers such as PD-L1 and microsatellite instability status that could be used identify a specific population of patients that benefit most from immunotherapy?

Interestingly, the KEYNOTE-062 trial tried to do this testing. In the study, about 5% of patients in the pembrolizumab alone–arm were MSI-high [(MSI-H) vs], about 7% in the chemotherapy-alone arm, and about 8% in the pembrolizumab plus chemotherapy arm. A very interesting finding showed that there was a collection of MSI-H tumors that were enriched for PD-L1. If we look at the benefits of therapy in those patients, there is a clear benefit to pembrolizumab plus chemotherapy vs chemotherapy alone. The HRs were in the range of 0.2 to 0.3, [representing] very significant benefit in that area. Patients with MSI-H disease tend to enrich PD-L1 scoring.

There are some data in early-stage disease that patients with MSI-H disease may not respond very well to chemotherapy. That would even extend into the metastatic setting too, but we will see. At this point in time, I would definitely recommend pembrolizumab with or without chemotherapy for patients who are MSI-H.

Beyond immunotherapy, what other advances appear promising in gastric cancer?

There is also a lot of excitement around HER2-directed therapy. A study that was presented during the [2021 Gastrointestinal Cancers Symposium evaluated] 

-altered gastric cancer. [The data showed that] the addition of an FGFR inhibitor to FOLFOX chemotherapy improved outcomes.

Therefore, not only is immunotherapy buzzing in this space, a lot of targeted therapy options [are emerging]. Data with ZW25 [zanidatamab] were presented during the [2021 Gastrointestinal Cancers Symposium]. At the same time, [fam-trastuzumab deruxtecan-nxki (Enhertu)] was approved for second- and third-line HER2-positive gastric cancer.

testing become a standard marker to test for in practice?

 testing] is available, but we typically didn’t test for it because there were no therapies suggesting benefit until now. We’re still awaiting the phase 3 study to [reveal] more data, but it is something we can all work toward easily to figure how to [best identify 

US Food and Drug Administration accepts for priority review application for Opdivo® (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer. News release. Bristol Myers Squibb. January 20, 2021. Accessed March 12, 2021. http://bit.ly/3qDi6bT.

US Food and Drug Administration accepts for priority review application for Opdivo® (nivolumab) combined with chemotherapy as first-line treatment in metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma. News release. Bristol Myers Squibb. January 20, 2021. Accessed March 12, 2021. http://bit.ly/3a4b6OL.

Immunotherapy Makes Waves in Gastroesophageal and Gastric Cancers

Namrata (Neena) Vijayvergia, MD, discusses the emerging role of immunotherapy in resectable and metastatic esophageal and gastric cancers, as well as key nuances that could complicate these agents’ utility in clinical practice.

Immunotherapy Enters Gastroesophageal and Gastric Cancers

Immunotherapy has yielded impressive survival benefits when used as a frontline treatment for patients with non–small cell lung cancer (NSCLC); however, with its increasing up-front use, the issue of resistance to checkpoint inhibition has become more pronounced, according to Edgardo Santos, MD, FACP.

“Immunotherapy is generally very effective, very well tolerated, and most importantly, it improves overall survival [OS],” Santos said. “For patients who fail immunotherapy up front, it is very difficult for them to switch to a regular cytotoxic drug. As such, we are focusing right now on trying to overcome resistance to immunotherapy.”

®, during an Institutional Perspectives in Cancer webinar on Lung Cancer, Santos, a founding member of the Florida Precision Oncology Care, medical director of research services, and associate professor at Florida Atlantic University, discussed advances made with immunotherapy regimens in the first-line treatment of patients with metastatic NSCLC and areas of active investigation.

®: The phase 3 KEYNOTE-189 (NCT02578680) trial is one of the most pivotal trials examining immunotherapy in patients with stage IV disease. How did this trial set the stage for future efforts?

: KEYNOTE-189 was a landmark [trial] in NSCLC. In a subsequent follow-up of more than 23 months, the study still demonstrated positive results, with clinical meaningful outcomes, including OS and progression-free survival [PFS]. The combination of pembrolizumab [Keytruda] plus chemotherapy of either cisplatin or carboplatin, followed by maintenance therapy [comprised of] pembrolizumab and pemetrexed, was very well tolerated. [Additionally,] all the primary end points [of the trial] were positive.

A dual-immunotherapy approach was examined in the phase 3 CheckMate-227 trial (NCT02477826). Could you speak to the significance of this research?

After KEYNOTE-189, which showed that the addition of immunotherapy to chemotherapy improves OS, several clinical trials have shown clinical meaningful outcomes for our patients with stage IV lung cancer. CheckMate-227 [examined] the combination of nivolumab [Opdivo], which is a checkpoint inhibitor, and ipilimumab [Yervoy], another checkpoint inhibitor that focuses on the CTLA-4 pathway. For the first time, we have a combination of checkpoint inhibitors with no chemotherapy involved and improved OS over chemotherapy. Now, we have this option for patients who do not want to receive any chemotherapy whatsoever; we can offer them just pure immunotherapy.

for use in the frontline treatment of patients with metastatic NSCLC and PD-L1 positivity. Could you expand on how this regulatory decision impacted the paradigm?

Prior to CheckMate-227, we could only use immunotherapy alone if a patient had PD-L1 expression above 50% in the tumor. When we see a patient with lung cancer, we do a biopsy to test for PD-L1. Depending on the expression, we have different indications by the National Comprehensive Cancer Network to decide what we can do [in terms of treatment]. For those patients who have an expression of PD-L1 above 50%, we can use immunotherapy alone. However, for patients with a PD-L1 expression below 50%, we would have to combine with chemotherapy. Now, [because of] CheckMate-227, we can use immunotherapy alone in patients with a PD-L1 expression below 50%.

Then, in the phase 3 CheckMate-9LA trial (NCT03215706), chemotherapy was added to nivolumab/ipilimumab. What was the objective of this research?

The idea here was to achieve better outcomes. In this study, the primary end point was OS, and the trial demonstrated positive results for OS and for PFS. Importantly, by adding chemotherapy to the nivolumab/ipilimumab combination, when you stratify all patients by PD-L1 [expression], which is the best biomarker that we have for immunotherapy, this combination was positive for all the subgroups [analyzed].

The other thing worth mentioning is that the chemotherapy given in this study was very short. Instead of the classic set of 4 to 6 cycles of a platinum-based doublet that we [generally] use for patients with stage IV disease, in this study, we use 2 cycles. As such, the patient receives nivolumab/ipilimumab plus 2 cycles of chemotherapy, and then after those 2 cycles [of chemotherapy] are done, the patient will continue with nivolumab/ipilimumab alone.

Also, during the study, if a patient had adenocarcinoma or squamous cell carcinoma, the appropriate chemotherapy was assigned based on their histology. We know that histology matters for the type of chemotherapy we use.

What should be known about the safety of the chemoimmunotherapy approach?

The cycles of chemotherapy [in CheckMate-9LA] were given once every 3 weeks, so there is 3 weeks off in between cycles 1 and 2. No red flags were reported, and no added toxicities were observed beyond what we already knew [to be common] from nivolumab and ipilimumab, which is important to emphasize.

What are some other ongoing trials of interest that are further examining novel approaches with checkpoint inhibitors?

Several studies are coming up. One phase 3 study is looking at another checkpoint inhibitor called sintilimab [Tyvyt], [which] seems to be effective. The caveat is that we are waiting for the OS data [with this approach]. This study was done in the first-line treatment of [patients with] stage IV lung cancer. Cemiplimab-rwlc [Libtayo] is another checkpoint inhibitor [of interest]. The agent showcased] strikingly positive results, with a long-term median OS [observed in] patients with a PD-L1 expression above 50%.

What are some future directions for research?

What is more important is what we are doing in this space when a patient [progresses] on up-front immunotherapy. What we are doing now is looking to use, perhaps, another checkpoint inhibitor in combination with another pathway to overcome the resistance of the tumor to immunotherapy.

This interview was conducted prior to the February 22, 2021 FDA approval of cemiplimab for use in the frontline treatment of patients with advanced NSCLC with a PD-L1 expression level of 50% or higher.

Santos Spotlights Success With Checkpoint Inhibition in Frontline Metastatic NSCLC

Edgardo Santos, MD, FACP, discusses advances made with immunotherapy regimens in the first-line treatment of patients with metastatic non–small cell lung cancer and areas of active investigation.

Checkpoint Inhibitors in Lung Cancer: The Progress Continues

Six indications for immune checkpoint inhibitors (ICIs) granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) will hold a special 3-day public hearing on April 27 to 29 to allow expert commentary and patient testimony about the drugs, which are being used to treat triple-negative breast cancer (TNBC), metastatic urothelial carcinoma (mUC), gastric cancers, and hepatocellular carcinoma (HCC), the agency said Thursday. Based on the testimony, ODAC will consider whether the approvals should be withdrawn and whether additional trials should be conducted.1

The hearings will involve 2 indications for atezolizumab (Tecentriq), 3 for pembrolizumab (Keytruda), and 1 for nivolumab (Opdivo). Specifically, these indications will be reviewed:

Atezolizumab―in combination with nab-paclitaxel (Abraxane) for the treatment of patients with PD-L1–positive unresectable locally advanced or metastatic TNBC; and as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy

Pembrolizumab—as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy; for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that express PD-L1 and has progressed after 2 or more prior lines of therapy; and for patients with HCC previously treated with sorafenib (Nexavar)

Nivolumab—as a single agent for patients with HCC who previously received sorafenib

The FDA announced the hearings after a flurry of ICI indications were voluntarily withdrawn by pharmaceutical companies, starting in December 2020, as part of what the FDA described as an industry-wide evaluation of accelerated approvals in oncology “in which confirmatory trials did not confirm clinical benefit.”1

As part of the voluntary withdrawals, Bristol Myers Squibb and Merck said they will discontinue indications for nivolumab and pembrolizumab, respectively, for patients with metastatic small cell lung cancer whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy; AstraZeneca will withdraw an indication for durvalumab (Imfinzi) for patients with locally advanced or mUC that has progressed after chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy; and Genentech will halt an indication for atezolizumab for patients with mUC previously treated with platinum-based chemotherapy.

Under the accelerated approval program, drugs are able to gain indications more quickly than through a regular approval timeline based on a surrogate end point. Pharmaceutical companies are then required to conduct a trial that confirms a clinical benefit; if the study is successful, the FDA grants regular approval status.2

The FDA’s Oncology Center of Excellence, which reviews and expedites the development of cancer drugs, requested the April hearings. The center is headed by Richard Pazdur, MD, a 2019 Giants of Cancer Care® award winner for Community Outreach who also is serving as acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” Pazdur said in a statement.1 “The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn.”

The hearings will give oncology experts outside of the FDA and patients with cancer an opportunity to describe their experiences with the drugs, said Pazdur. “After this advisory meeting, our staff will consider the committee’s comments and will make final decisions regarding continuing approval of each indication,” he said.

Six indications for immune checkpoint inhibitors granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway.

Immuno-Oncology

Melanoma Outcomes Are Improved With Nivolumab Alone or With Ipilimumab

Next Up in SCLC: Immunotherapy Combinations

Lung Cancer Advancements Highlight the Need for Multidisciplinary Care

Chronic Immune-Related Adverse Events Are Common in Certain Melanoma Subgroups

Immunotherapy Enters Gastroesophageal and Gastric Cancers

Checkpoint Inhibitors in Lung Cancer: The Progress Continues

FDA to Reassess Accelerated Immunotherapy Approvals

Immunotherapy Only Gets Better in NSCLC

Pembrolizumab-Ipilimumab Combo Boosts Toxicity, Not Survival in NSCLC

Immunotherapy May Highlight Neoadjuvant Treatment's Use in Lung Cancer