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

Articles

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

Next Up in SCLC: Immunotherapy Combinations

The EGFR TKI osimertinib (Tagrisso) has shaken up the treatment paradigm of advanced non–small cell lung cancer (NSCLC), and now the agent is under exploration in earlier-stage settings in an effort to further prevent recurrence and prolong survival, according to Edward S. Kim, MD, who added that the key to reaching patients earlier is to test for biomarkers earlier.

“In the early-stage setting, it is devastating when [patients experience] recurrence. Hopefully, [with osimertinib,] we can do something about it and treat them. Too many times, because of the nihilism that has built up over the years, we are just waiting for the recurrence to occur,” Kim said. “I hope we get to a point where recurrence is less common, and we are treating more patients with earlier-stage disease. Our paradigm has changed. We will continue to study other drugs and targets in these settings, as well.”

 during an Institutional Perspectives in Cancer webinar on lung cancer, Kim, physician-in-chief of City of Hope Orange County and vice physician-in-chief of City of Hope National Medical Center, highlighted the impact of osimertinib in the treatment of patients with 

-mutant NSCLC, next steps with the agent, and the importance of early genetic testing to provide personalized care.

: How has the emergence of osimertinib impacted the management of patients with

 has really been one of the pioneering biomarker pathways in lung cancer. Osimertinib is the preferred drug because it has very strong efficacy and a [favorable] safety profile. The newer-generation drugs penetrate the brain and the central nervous system much more predictably than older-generation agents; this has changed the paradigm of how we approach patients who have initially been diagnosed with brain metastases. If they are stable, then we do not jump right to radiation. Instead, we treat them [with these drugs] if they have a mutation and watch them in case we need the radiation. [However,] it is great to see even our radiation colleagues embrace these data.

What are some areas of focus in the realm of

Throughout our investigations, we have also found other mutations in 

; some are sensitizing, some are resistant, and some we are not sure about yet. We are developing drugs [to target] these specific mutations, which is exciting. That is what we dream [to do with] cancer [treatment]: identify a marker in the tumor that is unique to an individual and finding a [targeted] therapy that [that is efficacious and] will not cause many adverse effects [AEs].

 moving into the earlier-stage setting; this [development,] indeed, follows what we have seen in the breast cancer paradigm. You have drugs that [are initially used in the] metastatic [setting], like tamoxifen, that are now moving into the earlier-stage setting. [Patients] can take [these agents] for several years and [they are effective]. We are seeing that now with osimertinib, [which is under examination] in the early-stage setting, in patients who have stage IB through IIIA [disease].

 mutations. If you find one, then after you finish the surgery and/or give chemotherapy, [you can] then treat the patient with osimertinib for 3 years; this has been shown to greatly improve disease-free survival [DFS]. We are still waiting for overall survival [OS] data [with this approach]. However, the trial [that examined this strategy] was unblinded early because of its effectiveness, and patients are still being treated.

[Treatment has] really cascaded in the direction [where] we want to reach patients earlier—especially those who have curable disease or curative intent disease. [We want to] try to keep disease away as long as possible. I am really happy that biomarkers have made it into the clinic. I urge everyone out there to test [for] biomarkers. Ensure that you are testing for these before you initiate any treatment. It does not matter if you are using smaller panels or larger panels; just ensure that you are getting that information and utilizing it to inform decisions.

Looking more closely at the use of osimertinib in the adjuvant setting, how did the agent perform in the phase 3 ADAURA trial (NCT02511106)? What does this information mean for practice?

The primary end point of ADAURA was DFS, specifically in [patients with] stage II and IIIA [disease], although the trial did enroll [those with] IB through IIIA [disease]. DFS was the first reported outcome because you get those outcomes earlier. Data were revealed early because of the effectiveness [of the agent]; this [runs] parallel to what happened with tamoxifen.

The hazard ratios for DFS were unprecedented. We had not seen that magnitude [of benefit] in lung cancer [previously], although we should; this is a curative intent population. We are asking patients to take a drug for up to 3 years and need to show that there is some benefit. Some would say we need to wait for OS and, of course, our due diligence has to be to wait for [those data].

However, you have to ask yourself, if this was a friend or family member, and they had gone through lung cancer resection, would you prescribe them osimertinib if they have an 

 mutation? My answer is a very clear yes. I do believe that DFS is an important end point, and it is one that we use quite often in earlier stages [of disease]. If you consider any patient who has had early-stage breast cancer and they get a recurrence, it is just devastating.

How are the AEs associated with osimertinib being managed? Are there any challenges to using this agent in the clinic?

What has been really helpful is that osimertinib was first approved [for use] in the advanced metastatic setting. Clinicians gathered quite a bit of experience with not only this drug, but also with drugs that were similar in class. We all remember using gefitinib [Iressa], erlotinib [Tarceva], afatinib [Gilotrif], and now, we have osimertinib. There is a comfort level [with these agents]. Again, the parallels [to what has been seen in the] breast cancer [paradigm] are there. Tamoxifen was first used in the metastatic setting and [people felt comfortable] dealing with those AEs.

On the whole, osimertinib has a very [safe] toxicity profile, when considering other classes of drugs [that are used] in the metastatic setting. Upon conducting the study and reporting out, we really did not see any new safety [signals]. As we consider primary end points and focus on the [patients with] stage II and IIIA disease, even in the total analysis of [those with] IB through IIIA [disease], we saw a benefit across the board. [Osimertinib] is [an agent] that people are comfortable with and we [have] quite a bit of experience [with its use].

Research Efforts Focus on Reducing Recurrence in Early-Stage EGFR-Mutant NSCLC

Edward S. Kim, MD, highlights the impact of osimertinib in the treatment of patients with EGFR-mutant non–small cell lung cancer, next steps with the agent, and the importance of early genetic testing to provide personalized care.

Reduce Recurrence in Early-Stage NSCLC

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

Lurbinectedin (Zepzelca) has demonstrated impressive activity and tumor reduction in patients with small cell lung cancer (SCLC), and its addition to the treatment arsenal represents a promising development in a field with limited available options, according to Wade T. Iams, MD. However, questions pertaining to its clinical application remain.

“We finally have a new option for patients with relapsed SCLC,” Iams said. “We saw an [encouraging] overall response rate in these patients treated with lurbinectedin with a significant reduction in tumors, which compares favorably with previously available chemotherapy options.”

lurbinectedin for the treatment of patients with metastatic SCLC

 with disease progression after platinum-based chemotherapy. The regulatory decision was based on data from a phase 2 basket trial (NCT02454972), which showed that patients treated with the agent experienced an overall response rate (ORR) of 35.2%,1 and 65% of those enrolled in the study experienced a reduction in tumor size.2

Additionally, in July 2020, the agent was added to the 

Clinical Practice Guidelines in Oncology by the National Comprehensive Cancer Network (NCCN)

 for the second-line treatment of patients with SCLC.

® during an Institutional Perspective in Cancer webinar on Lung Cancer, Iams, and assistant professor of medicine for the Division of Hematology/Oncology at Vanderbilt-Ingram Cancer Center, discussed the efficacy and safety of lurbinectedin in patients with SCLC, the impact of its approval on the paradigm, and remaining questions regarding its use.

®: What was the significance of the accelerated FDA approval of lurbinectedin? How has it impacted clinical practice?

: Lurbinectedin was only the second FDA-approved agent for patients with relapsed SCLC. The only previous option was topotecan. As such, this has been a significant development for patients who haven't seen many developments for decades. We're excited about more options for these patients in the clinic. This was great progress for the field.

What is known about the mechanism of action of lurbinectedin? What makes it unique from other agents?

Lurbinectedin is a transcription factor inhibitor that acts by blocking RNA polymerase at the site of active transcription. In the sense that it is a broad cytotoxic agent, we would place it in a category of more traditional cytotoxic chemotherapy. However, [lurbinectedin] differs from other cytotoxic chemotherapy agents [because of its] administration schedule. We're hopeful that the transcription factor profiles that are inhibited by lurbinectedin can potentially be more specific for SCLC, although that's under investigation.

A really intriguing dynamic, to me, is [whether there is] specificity of this agent for subtypes of SCLC, which is where the preclinical science in [this disease] is moving. [We’re] defining for subtypes by transcription factor profiles and [determining] what relationship this new agent may have to each subtype is a really intriguing [area of focus].

What should be known about the safety profile of this agent when used as a monotherapy?

When used as monotherapy, which is the FDA-approved application, the most common adverse effect [AE] observed was fatigue in a slight majority of patients. The vast majority [of patients] were not hospitalized; it was not a severe AE.

The big toxicity to be aware of is neutropenia, but I took that all the way to rate of febrile neutropenia, which typically guides our use of primary prophylactic growth factor for these patients. In the COVID-19 era, we've had ASCO recommendations to lower the threshold to use of primary prophylaxis growth factor down to 10% rates. Now, when we look at the monotherapy lurbinectedin data, [we see a] less than 10% rate of febrile neutropenia. Although, there is a much higher rate of grade 3 neutropenia without febrile neutropenia [with the agent]. Distinguishing between those 2 is a big component of looking at these toxicities.

Patients did have more expected nausea, vomiting, and diarrhea. There was only 1 hospitalization, or grade 3 or higher toxicity, for a gastrointestinal event, and that was 1 episode of diarrhea. [Additionally], only 1 skin toxicity of grade 3 or higher [was observed], and less than 10% of patients had transaminase elevation of grade 3 or higher. No hospitalizations for acute kidney injury [occurred], although some creatinine elevation was observed. [However,] when we put that next to other chemotherapy toxicities [that we see], I would certainly describe it as very well tolerated.

How do you feel this agent fits into the treatment landscape? What are some questions that still need to be sorted out?

The big question when we look at the clinical application of lurbinectedin for patients with relapsed SCLC is, how do we feel about the time since they received their last platinum chemotherapy? The way that the study breaks down results is by 3 months since last platinum, or more than 3 months since last platinum.

The way that our NCCN guidelines break down that timeline is 6 months since last platinum chemotherapy vs 6 months after last platinum chemotherapy. The reason I harp on that point is because we know that reusing that platinum chemotherapy is more effective, particularly if patients have had 6 months since their last platinum. However, some folks also use that 3-month threshold clinically.

The application of lurbinectedin is a bit stronger compared with the other options [available] for patients who have relapsed in less than 3 months. When we get to the [patients who are] platinum sensitive, relapsed 3 months or even 6 months or later, I think there's more of a question about do you reinstitute that platinum that they had the first time around? That may be dependent on adverse effects and tolerance of that individual patient the first time they received it. Or do we use lurbinectedin? Lurbinectedin, again, is FDA approved for any of those scenarios, and it is an NCCN guidelines option for any of those scenarios, but it is a wrinkle, clinically, in the platinum-sensitive setting.

In the phase 3 ATLANTIS trial (NCT02566993), lurbinectedin was paired with doxorubicin; the trial failed to meet its primary end point of overall survival (OS). What should be taken away from these findings?

That is the key question in the field. I would reserve my comments until we see more comprehensive data from this trial. All we've seen is that the primary end point was OS, and it was not met. To reiterate the structure of the trial, [it was] a 1:1 randomization of lurbinectedin plus doxorubicin compared with dealer's choice of cyclophosphamide/doxorubicin/vincristine or topotecan. Lurbinectedin was given at a lower dose than [it had been] in the monotherapy trial. All we know is that [the study] did not meet its primary end point. I'd like to see the full data set before we can fully interpret [what these data mean for the field].

Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. 

. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1

Paz-Ares LG, Perez JMT, Besse B, et al. Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial. 

 2019;37(suppl 15):8506. doi:10.1200/JCO.2019.37.15_suppl.8506

Lurbinectedin Makes a Splash in Second-Line SCLC.

Wade T. Iams, MD, discusses the efficacy and safety of lurbinectedin in patients with small cell lung cancer, the impact of its approval on the paradigm, and remaining questions regarding its use.

Lurbinectedin Shows Promise in Small Cell Lung Cancer Treatment

First-line treatment with camrelizumab, an investigational PD-1 inhibitor, plus chemotherapy induced robust and durable clinical responses in patients with advanced squamous non–small cell lung cancer (NSCLC), according to findings from the phase 3 CameL-sq trial that were presented during the 2021 European Lung Cancer Virtual Congress.

The median progression-free survival (PFS) was 8.5 months (95% CI, 6.9-10.4) with camrelizumab plus chemotherapy compared with 4.9 months (95% CI, 4.2-5.5) with placebo plus chemotherapy per a blinded independent review committee (BIRC; HR, 0.37; 95% CI, 0.29-0.47; 

 < .0001), meeting the primary end point of the study.

Moreover, PFS by BIRC favored the camrelizumab-based regimen vs the placebo-based regimen irrespective of age, sex, ECOG performance status (PS), smoking history, disease stage, presence of liver or brain metastases at enrollment, and PD-L1 status by tumor proportion score (TPS).

“These findings support camrelizumab plus paclitaxel and carboplatin as standard first-line treatment for [patients with] advanced squamous non–small cell lung cancer,” said Caicun Zhou, MD, PhD, lead study author and director of the Department of Oncology at Shanghai Pulmonary Hospital, affiliated with Tongji University School of Medicine in Shanghai, China, in a virtual presentation of the data.

As monotherapy, camrelizumab has shown antitumor activity in patients with previously treated advanced NSCLC. Additionally, interim findings from the phase 3 CameL trial showed that at a median follow-up of 11.9 months, the median PFS was 11.3 months with camrelizumab plus chemotherapy vs 8.3 months with placebo plus chemotherapy in patients with chemotherapy-naïve advanced nonsquamous NSCLC (HR, 0.60; 95% CI, 0.45-0.79; 

The findings from the CameL trial established camrelizumab plus chemotherapy as a standard frontline option for Chinese patients with advanced nonsquamous NSCLC who do not harbor 

The CameL-sq study aimed to establish camrelizumab as a standard frontline option for patients with advanced squamous cell disease.

In the study, 390 patients were randomized 1:1 to the camrelizumab- or placebo-based regimens. Patients in the camrelizumab group (n = 193) received 200 mg of camrelizumab plus carboplatin at an area under the curve (AUC) of 5 and 175 mg/m2 of paclitaxel in 3-week cycles for 4 to 6 cycles followed by 200 mg of camrelizumab given every 3 weeks until progressive disease or unacceptable toxicity.

Patients treated in the placebo group (n = 196) received placebo plus carboplatin and paclitaxel at the same dose as the camrelizumab group, followed by placebo until disease progression or unacceptable toxicity. Patients receiving placebo were allowed to cross over to 200 mg of camrelizumab if they experienced progressive disease with placebo per BIRC.

Eligible patients had pathologically confirmed stage IIIB to IV squamous NSCLC, no prior systemic treatment, and an ECOG PS of 0 or 1.

Patients were stratified by sex, smoking history (≥400 cigarette-years vs <400 cigarette-years vs never-smokers), and the presence of liver or brain metastases at enrollment (both sites vs 1 site vs none).

PFS per BIRC served as the study’s primary end point, with overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety as key secondary end points.

Of the patients in the camrelizumab group, 126 discontinued treatment because of disease progression (n = 77), adverse effects (AEs; n = 23), withdrawn consent (n = 14), death (n = 6), investigator decision (n = 4), and other reasons (n = 2); 67 patients are receiving ongoing treatment. In the placebo group, 186 patients discontinued treatment because of disease progression (n = 161), withdrawn consent (n = 11), AEs (n = 5), death (n = 5), lost to follow-up (n = 1), investigator decision (n = 1), new antitumor therapy (n = 1), and other reasons (n = 1); 10 patients are receiving ongoing treatment.

Baseline patient characteristics were well-balanced between arms. The median patient age was 64 years in the camrelizumab arm vs 62 years in the placebo arm, and the majority of patients were male in both arms. Most patients were smokers, had an ECOG PS of 1, and had stage IV disease.

Additionally, 13.0% of patients receiving camrelizumab had liver or brain metastases upon enrollment compared with 11.2% of patients receiving placebo.

In the camrelizumab arm, 47.2% of patients had less than 1% PD-L1 TPS expression, 30.1% had 1% to 49% expression, 19.2% had 50% or greater expression, and 3.6% were not evaluable. These rates were 49.5%, 25.0%, 22.4%, and 3.1%, respectively, in the placebo arm.

Secondary end point analyses revealed that the median OS was not reached (NR) with camrelizumab/chemotherapy (95% CI, 18.4-NR) compared with 14.5 months (95% CI, 13.2-16.6) with placebo/chemotherapy (HR, 0.55; 95% CI, 0.40-0.75; 

In all subgroups beside female patients (HR, 1.06; 95% CI, 0.21-5.26), median OS favored the camrelizumab regimen compared with the placebo regimen.

The ORR by BIRC was 64.8% (95% CI, 57.6%-71.5%) with camrelizumab/chemotherapy vs 36.7% (95% CI, 30.0%-43.9%) with placebo/chemotherapy. In the experimental arm, 7.8% of patients achieved a complete response (CR), 57.0% achieved a partial response (PR), 23.3% had stable disease (SD), 7.8% had progressive disease, and 4.1% were not evaluable. In the placebo arm, 1.5% of patients achieved a CR, 35.2% achieved a PR, 46.4% had SD, 14.8% had progressive disease, and 2.0% were not evaluable.

The DCR was 88.1% with the addition of camrelizumab (95% CI, 82.7%-92.3%) vs 83.2% with placebo (95% CI, 77.2%-88.1%). The median DOR was 13.1 months (95% CI, 9.3-15.7) vs 4.4 months (95% CI, 4.2-4.9), respectively.

Patients received camrelizumab for a median of 12 cycles (range, 1-32) and placebo for median of 7 cycles (range, 1-26). In both arms, patients received a median of 5 cycles (range, 1-6) of paclitaxel and carboplatin.

All patients (100%) on the camrelizumab regimen vs 99.5% of patients on the placebo regimen experienced any-grade treatment-emergent AEs (TEAEs); 80.3% vs 75.0% of patients reported grade 3 or 4 TEAEs, respectively.Additionally, 10.4% of patients in the camrelizumab group compared with 13.8% of patients in the placebo group died from TEAEs.

Similarly, all patients (100%) on the camrelizumab regimen vs 99.5% of patients on the placebo regimen experienced any-grade treatment-related AEs (TRAEs); 73.6% vs 71.4% of patients reported grade 3 or 4 TRAEs, respectively. Additionally, 3.1% of patients receiving camrelizumab compared with 1.5% of patients received placebo died from TRAEs.

Immune-related AEs (irAEs) were reported in 76.7% of patients on camrelizumab compared with 20.4% of patients on placebo.

Common TRAEs included hematologic events, such as decreased white blood cell, neutrophil, and platelet counts and anemia, and non-hematologic events, such as alopecia, hypoesthesia, asthenia, decreased appetite, nausea, increased alanine aminotransferase and aspartate aminotransferase, and extremity pain.

Common irAEs included reactive capillary endothelial proliferation, endocrinopathy, skin adverse reactions, pneumonitis, hepatitis, colitis, and hematologic toxicity.

Zhou C, Ren S, Chen J, et al. Camrelizumab or placebo plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-sq): a randomized, double-blind, multicenter, phase 3 trial. Presented at: European Lung Cancer Congress; March 25-27, 2021; Virtual. Abstract 96O.

Zhou C, Chen G, Huang Y, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. 

 2021;9(3):305-314. doi:10.1016/S2213-2600(20)30365-9

Camrelizumab Plus Chemo Prolongs PFS in Advanced Squamous NSCLC

First-line treatment with camrelizumab, an investigational PD-1 inhibitor, plus chemotherapy induced robust and durable clinical responses in patients with advanced squamous non–small cell lung cancer.

Investigational Combo Improves PFS in NSCLC Subset

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

The role of comprehensive genomic testing in patients with cholangiocarcinoma has become more pronounced as more is learned about the biology of the disease and as more agents are being developed to target associated alterations, according to Daniel Lin, MD, MS.

“What we've seen in many gastrointestinal cancers, and biliary cancer is a good example, is the key role that comprehensive genomic testing can play for patients [in that it can be used] to guide their treatment [decisions] and to expand their options,” Lin said.

Fifteen to 20% of all patients with biliary tract cancers have tumors that harbor 

 mutations, while 10% to 15% of tumors harbor 

 In recent years, many options targeting these alterations have emerged in the pipeline and impacted the outcomes of these patients.

For example, ivosidenib (Tibsovo) resulted in improved progression-free survival (PFS; HR, 0.37; 95% CI, 0.25-0.54) and overall survival (OS) after adjustment for crossover (HR, 0.49; 95% CI, 0.34-0.70) in previously treated patients with 

-mutated cholangiocarcinoma, according to data from the pivotal phase 3 ClarIDHy trial (NCT02989857).

For previously treated patients with cholangiocarcinoma and 

 fusions or rearrangements, infigratinib elicited an overall response rate of 23.1%, with a median duration of response of 5.0 months and a median PFS of 7.3 months.

 “For patients who have been previously exposed to chemotherapy who harbor this alteration, this is another clinically meaningful therapy,” noted Lin. Other FGFR inhibitors under exploration includepemigatinib (Pemazyre) and futibatinib.

® during an Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Lin, a medical oncologist and assistant professor at the Sidney Kimmel Cancer Center of Jefferson Health, discussed pivotal trials examining important targeted agents for patients with cholangiocarcinoma and the importance of comprehensive genomic testing to guide treatment decisions.

®: How would you say findings from the phase 3 ClarIDHy trial have impacted clinical practice?

Daniel Lin, MD, MS, discusses pivotal trials examining important targeted agents for patients with cholangiocarcinoma and the importance of comprehensive genomic testing to guide treatment decisions.

Lung Cancer

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Investigational Combo Improves PFS in NSCLC Subset

Checkpoint Inhibitors in Lung Cancer: The Progress Continues

Genomic Testing Leads Change in Cholangiocarcinoma Landscape

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