A 5-year analysis of the CheckMate 227 trial (NCT02477826) revealed that combination nivolumab (Opdivo) plus ipilimumab (Yervoy) yielded durable long-term benefit among patients with metastatic non–small cell lung cancer (mNSCLC).

The findings, which were presented at the 

, demonstrated a 5-year rate of overall survival (OS) was 24% in patients who received nivolumab/ipilimumab who had PD-L1 expression of at least 1%, and 19% in those with PD-L1 expression less than 1%, vs 14% and 7%, respectively, in patients who received chemotherapy. The immunotherapy combination also had a significantly higher duration of response (DOR) of 24.5 months for those with positive PD-L1 expression and 19.4 months for those with negative PD-L1 expression versus 6.7 months and 4.8 months with chemotherapy, respectively.

“Nivolumab and ipilimumab led to increased 5-year survivorship among these 5-year survivors and regardless of PD-L1 expression level,” Julie R. Brahmer, MD, director of the thoracic oncology program and professor of oncology at Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, said in her presentation. “Responses were maintained for greater than 5 years in over 40% of those who responded.”

The phase 3 CheckMate 227 stratified patients with stage IV or recurrent NSCLC who had no prior systemic therapy and were negative for 

 alterations by positive or negative PD-L1 expression. In the PD-L1-positive subgroup, 1189 patients were randomized 1:1:1 to receive nivolumab/ipilimumab, nivolumab alone, or up to 4 cycles of chemotherapy. In the PD-L1-negative subgroup, 550 patients were randomized 1:1:1 to receive nivolumab/ipilimumab, chemotherapy, or nivolumab plus chemotherapy.

Chemotherapy consisted of pemetrexed plus cisplatin or carboplatin every 3 weeks for patients with nonsquamous disease or gemcitabine plus cisplatin or carboplatin every 3 weeks for patients with squamous disease.

The primary end points were OS for the PD-L1–positive population and progression-free survival (PFS) in patients with a high tumor mutational burden. The OS was previously reported at a minimum follow-up of 29.3 months with a median of 17.1 months for nivolumab/ipilimumab versus 14.9 months with chemotherapy, with 2-year OS rates of 40.0% and 32.8%, respectively.2 With the 5-year analysis, OS benefit continued to be observed with a hazard ratio of 0.77 favoring nivolumab/ipilimumab (95% CI, 0.66-0.91).

With all patients having stopped receiving immunotherapy for at least 3 years, the efficacy versus chemotherapy has persisted in patients regardless of positive or negative PD-L1 expression.Combined 5-year OS, PFS, and DOR rates were 22%, 11%, and 27%, respectively, for those who received nivolumab/ipilimumab versus 12%, 2%, and 3% for chemotherapy.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 for PD-L1–negative patients who received immunotherapy, versus 9.5 months and 24.9 months respectively for those who received chemotherapy. The median duration of response was not reached (52.6-NA) for PD-L1–positive patients and 59.4 months (18.0-NA) for PD-L1–negative patients, compared with 12.4 (5.6-24.4) and 15.2 (2.7-NA) for those who received chemotherapy.

“In patients that survived 5 years, improved outcomes were universally observed with nivolumab and ipilimumab versus chemotherapy irrespective of PD-L1 expression,” said Brahmer in her presentation. “The majority of patients treated with nivolumab and ipilimumab did not receive subsequent therapy, with approximately two-thirds of patients remaining treatment free 3 years after discontinuing treatment.”

In contrast, among those who received chemotherapy and survived for 5 years, only 22% of PD-L1–positive patients and 17% of PD-L1–negative patients received no subsequent systemic therapy.

No new safety signals were seen in this analysis. Quality of life (QOL) was measured by an EQ-5D assessment, which showed that 5-year survivors who received nivolumab/ipilimumab reported a QOL similar to the general United States population of 79.3, significantly above the lung cancer norm of 68.0.

“These long-term results from CheckMate 227 further support nivolumab and ipilimumab as an effective first-line treatment for patients with mNSCLC regardless of tumor PD-L1 expression level,” Brahmer concluded.

1. Brahmer JR, Lee JS, Ciuleanu TE, et al. Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. J Clin Oncol. 2022;40(suppl 17):LBA9025. doi:10.1200/JCO.2022.40.17_suppl.LBA9025

2. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. 

. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

Articles

Frontline nivolumab and ipilimumab combination therapy was associated with increased 5-year survivorship in patients with metastatic non–small cell lung cancer—regardless of PD-L1 expression. 

5-Year Survival Data Showcases Long-Term Benefit With Nivolumab/Ipilimumab-Treated Metastatic NSCLC

Patients with solid tumors experienced promising initial responses with the CAR T-cell therapy BNT211. Furthermore, the treatment yielded tolerable safety results, according to data from a phase 1 trial (NCT04503278) that were presented at the 2022 AACR Annual Meeting.

The trial of BNT211, consisting of a Claudin-6 (CLDN6)-targeting CAR T-cell product plus the CAR T-cell cell-amplifying RNA vaccine (CARVac), had an overall response rate (ORR) of 43% and an acceptable safety profile in 14 patients with relapsed/refractory testicular cancer, ovarian cancer, or other solid tumors.

“We found robust engraftment of CAR T cells in all patients, which translated into a very encouraging clinical benefit with an ORR of 43% and a disease control rate of 86%. CARVac really supports the T-cell engraftment and also mediates expansion,” John Haanen, MD, PhD, director of the Center for Cellular Therapy at the Netherlands Cancer Institute and professor of translational immunotherapy of cancer at Leiden University, said during his presentation.

CAR T-cell therapy has demonstrated limited success in patients with solid tumors. CLDN6 was identified as a tumor-specific antigen expressed in solid tumors but silenced in adult healthy tissue during organogenesis, leading to the development of a second-generation CAR T-cell product with high affinity and specificity for CLDN6. In addition, CARVac encoded with CLDN6 has previously been demonstrated to promote expression and persistence of CLDN6 CAR T cells.

In part 1 of the study, patients received 1 course of lymphodepletion (LD) followed by dose escalation of CAR T cells to assess dose-limiting toxicities (DLTs) and determine a recommended phase 2 dose. In the second part, patients received a dose escalation of CAR T cells and CARVac starting on day 4. There were 2 dose levels in each part. Doses were increased every 3 weeks and CARVac was administered every 6 weeks.

As of March 10, 2022, 3 cohorts with a total of 16 patients were treated, and 1 more cohort is ongoing. The patient population included 8 patients with testicular cancer, 4 with ovarian cancer, and 4 with other solid tumor types.

Robust CAR T-cell engraftment was seen in all patients across dose levels and in both parts. At an assessment 6 weeks following infusion, 14 of 16 patients were evaluable. There were 6 partial responses (PR), 5 with stable disease (SD) with shrinkage of target lesions, and 1 with SD alone. At 12 weeks, patients with a PR showed a deepening of response including 1 complete response (CR), though investigators observed disease progression in 5 patients who had previously had SD or PR.

“These early responses unfortunately don’t appear to be as durable as we would have hoped because only 1 patient in the analysis set had a response past 18 weeks and that was the CR,” Vincent K. Lam, MD, assistant professor of oncology and director of the Esophageal Cancer Research Program at Johns Hopkins University, said during the conference presentation. “We do note, though, that there’s another patient with ongoing PR at about 6 weeks and we await further follow-up.”

The patient with CR had failed 6 previous lines of treatment for testicular cancer. His remission included a lowered level of alpha-fetoprotein that has lasted for 6 months. This patient’s CAR T cells persisted for 150 days and had a dominant phenotype of effector memory cells re-expressing CD45RA, while other patients had a phenotype of effector memory cells negative for CCR7 and CD45RA.

Two cases of DLTs were observed, 1 in each arm. In the monotherapy arm, prolonged cytopenia was observed after LD in a patient with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplant, leading to the creation of a cohort who would receive reduced or no LD. Hemophagocytic lymphohistiocytosis occurred in a patient with ovarian cancer in the CARVac arm before CARVac was started. Both toxicities were managed successfully.

Grade 3 or higher adverse events were mainly caused by LD or were asymptomatic enzyme elevations. Manageable grade 1 or 2 cytokine release syndrome occurred in 8 patients, 7 of whom were in the CARVac arm and 70% of whom were treated with the higher dose level. These patients showed an increase in interleukin-6 and elevated lipase but were confirmed to not have pancreatitis.

According to Lam, “CARVac appears safe in combination with CLDN6 CAR T, but CAR T persistence does not appear to be consistently enhanced yet.” He suggested that more optimal timing, dose, and duration of CARVac could maximize its effectiveness in mediating CAR T cell persistence.

Though these data are preliminary, and the study population is small, it suggests a future role for CAR T cells in solid tumors including testicular and ovarian cancer as well as CLDN6’s potential as a targetable biomarker.

“The infusion of CLDN6 CAR T, alone or in combination with CARVac, is safe and holds promise for patients with CLDN6-positive cancers,” Haanen stated in a press release.

“CLDN6 was never targeted before with cellular therapy, but in our study, this approach is already showing efficacy that may be better than the data from other CAR T trials in solid tumors.”

Haanen JB, Mackensen A, Koenecke C, et al. CT002 - BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT002.

Reinhard K, Rengstl B, Oehm P, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. 

. 2020;367(6476):446-453. doi:10.1126/science.aay5967

New CAR T-cell Therapy for Solid Tumors Was Safe and Showed Early Efficacy. American Association for Cancer Research. Published April 10, 2022. Accessed April 11, 2022. https://bit.ly/3KrcZFY

Findings from a phase 1 trial evaluating CAR T-cell therapy in patients with solid tumors showed promising clinical benefit with the treatment strategy.  

Investigators Inch Closer to Unlocking CAR T-Cell Therapy Potential in Solid Tumors

Researchers believe that key biomarkers, including mismatch repair deficiency (dMMR), microsatellite instability (MSI),

mutations, may be quite useful in directing treatment decisions in endometrial cancer. However, more research is needed to properly understand how these mutations might affect patient outcomes, according to Casey M. Cosgrove, MD.

For example, Cosgrove added that dMMR or MSI status and increased tumor mutational burden are more clearly defined for use in clinical practice, but it is still unclear whether a patient with a tumor that harbors a 

“[We] must continue to integrate the right biomarkers that we have information for into clinical practice,” Cosgrove said. “Certainly, it is easy to order a lot of testing, but if we do not have a clear game plan with what we are going to do with that testing, then we [could] harm our patients. [We need to practice some] caution when we are discussing biomarkers and new technologies with any cancer types.”

® during the 2022 SGO Winter Meeting, Cosgrove, an assistant professor in the Department of Gynecologic Oncology at The Ohio State University College of Medicine, discussed the current state of biomarkers in the realm of endometrial cancer and how they may be optimally leveraged for prognostic and predictive purposes.

®: What is the interest in biomarkers for endometrial cancers?

 We know that with many different types of cancers, we’re starting to look at a more specialized approach as to how we can better take care of our patients, and endometrial cancer certainly has many opportunities where we can identify molecular markers or things that we can’t see under the microscope to help guide the best way to treat these patients.

We can use biomarkers to treat patients, to guide which trial metric to use, [or] which type of treatment we want to use. But we can also use biomarkers to tell us which patients should be treated, or maybe even which patients should not be treated. It’s an incredibly exciting area of research for endometrial cancer because it allows us to home in on their individual types of cancers and treat them with the most individualized approach.

What is the current landscape of endometrial cancer?

One of the things that needs to be highlighted about endometrial cancer is it's one of the few cancers that is getting worse. We have more patients dying of endometrial cancer now than we did last year, and that's a travesty. Endometrial cancer is aligning itself to overtake ovarian cancer to become the deadliest gynecologic cancer in the United States in the near future. We need our researchers and clinicians to be aligned with what patients that are having poor outcomes are seeing.

What biomarkers are most relevant to endometrial cancer and what role do they play?

With biomarkers in endometrial cancer, there are 2 fundamental questions. The first question is, ‘Who should we be treating?’ Several studies have looked at the best ways that we can predict whether patients' cancers will come back or not.

Classically, we have been guided by [disease] stages or the histology, as well as several other features. However, now, we are starting to appreciate that we can use molecular signatures to tell us whether these cancers are at higher or lower risk for recurrence.

There have been reports from our group, as well as others, that have looked at different markers that have predicted higher-risk cancers; this can include 

 or genomic alterations, and several other mutations that we have noted. If we identify patients who have some of those higher-risk features, they may derive benefit from receiving extra treatment. Another marker, [referred to as] 

, is needed to help the DNA repair itself; this allows for the immune system, without any additional treatment, to fight cancer cells better. We see that those patients [with 

A question that we have also been asking is, ‘Can we 

 treat these patients, even if they traditionally would have had higher-risk features?’ [Specifically regarding] biomarkers, [we want [to see whether] we [can] work smarter, and not necessarily harder. Can we target therapies that are based off molecular signatures?

Perhaps the one that we have the most research and the most experience with is deficiencies in MMR proteins or MSI within endometrial cancers; these markers predict response for immunotherapies. As such, when we look at an endometrial cancer that has 1 of these markers, perhaps we should jump right to immunotherapy as opposed to going through our classical chemotherapy algorithms. We also know that MMR and MSI status can also be an important prognostic biomarker because these patients seem to also have poor outcomes.

As such, taken collectively, a patient that has a dMMR tumor or MSI-high tumor may benefit from receiving more aggressive treatment and a [potentially] smarter [approach] with immunotherapy as opposed to traditional chemotherapy.

What are the most significant potential areas for improving care?

Several ongoing clinical trials are trying to refine the way that we take care of a patient with endometrial cancer. What I hope that we can see through all these trials is that we have some easily applied clinical markers that are going to directly impact our decision making. The ProMisE [Proactive Molecular Risk Classifier for Endometrial Cancer system] from the University of British Columbia, which establishes endometrial cancer into 4 different molecular groups, has the most traction right now throughout the gynecologic oncology community.1 This is testing for dMMR, 

 [positivity], and grouping endometrial cancers into 1 of 4 groups.

Depending on which group [patients] fall into, then the next question will be, ‘What is the best treatment for those individuals?’ This has been evaluated through several trials. There is a lot of excitement [in this area] and we hope to get some answers over the next couple of years. The endometrial cancer [setting] has a lot of opportunity for growth in patient care, and we, as clinicians, are going to have to start integrating a lot of this information quickly as it becomes available.

With the improvements in technology, we are going to be getting more information for each cancer type in the future than we have ever had before. Assimilating that information into the clinical setting [may represent] a major barrier for patients and clinicians alike. [That being said], hopefully, we will have some standardized protocols that [can help] us to [select] the [best] way to care for each individual patient.

What studies are further exploring biomarkers in the endometrial setting? Which ones are you most excited about?

The RAINBO [trials] are very exciting because not only are [the investigators] using the molecular classifications to determine the risk for recurrence and the aggressiveness of treatment, but they are also integrating novel treatment strategies for the different molecular groups. As suh, I might identify that a patient is at higher risk, and I know what [treatments are] available, but I can [consider adding] more targeted therapies because of that molecular class, and I can treat them more aggressively and with a smarter therapy.

One of the things that is most notable is the vast amount of ongoing research that we have in the area right now; this also highlights the vast number of [unanswered] questions right now. One potential concern is that physicians may start integrating little pieces of this information into their clinical practice, without having a full tool belt available for what they need to be doing [with respect to] what are the right tests [to use] and the right treatments that might be available.

How do the National Comprehensive Cancer Network (NCCN) guidelines align with this new biomarker research?

Within the past 1 or 2 years, the NCCN guidelines have started incorporating the algorithms for molecular classification with endometrial cancer.2 Traditionally, we have broken endometrial cancers into type 1 and type 2, with type 1 being a less aggressive type of [disease], and type 2 being more aggressive. In 2013, the Cancer Genome Atlas [TCGA] broke endometrial cancer [down further,] into 4 important groups with differing risk of recurrence and differing molecular features.3 Recent research has tried to integrate those in the clinical setting because TCGA uses technologies that we cannot apply to the bedside. By utilizing newer technologies, we are able to start integrating some of their findings into clinical care.

The NCCN has started to appreciate that, and [currently uses] the algorithm for breaking endometrial cancers into 1 of 4 molecular groups, as opposed to the 2 groups that we had traditionally [used]. We also see a greater emphasis on what we can do with that information in the NCCN guidelines. For instance, 1 of the most important molecular groups is the MSI or dMMR group. Not only is this an important prognostic biomarker, but it is also a predictive biomarker for the use of immunotherapy—that has been highlighted in the more recent editions of the NCCN guidelines, where they say if [a patient] recurs [and has] MSI-high disease or dMMR, then immunotherapy is very appropriate.

The other thing that the NCCN guidelines highlight is that even in the absence of having a biomarker, patients can receive immunotherapy with the combination of lenvatinib [Lenvima] and pembrolizumab [Keytruda]. As such, sometimes having a negative biomarker can be just as informative for guiding treatment.

What is your take-home message to your colleagues working in this space?

One of the most important concepts to understand is that we do not have all the answers quite yet; we are still working on it. As we get more information, [we may identify other biomarkers] to look for. It is hard to cherry pick 1 or 2 things that [we] can utilize [for all patients]. The question is whether we need to have a whole grouping of testing to make the right decision for our patients.

Right now, we are [in] a situation where there are clearly defined biomarkers that can be utilized in a clinical setting, like dMMR or MSI status and increased tumor mutational burden, but we still have unclear knowledge whether a patient with a tumor with, [for instance], a 

 mutation, can safely forego treatment. If you hear that these tumors have no recurrences, [we want to know] why we are treating them with chemotherapy and radiation, which have high toxicities. However, at the same time, we have not clearly proven that withholding treatment [in these patients] is not compromising outcomes.

[It is also important to note] our reliance on classic pathologic findings, histology, and stage, and [reflect on] how we integrate that into our patient care algorithms. Once we start getting more molecular data, how do we integrate the old and new data? What do we do if we have conflicting information? This could cause problems in the future if we do not adequately study these questions.

Kommoss S, McConechy MK, Kommoss F, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. 

 2018;29(5):1180-1188. doi:10.1093/annonc/mdy058

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Uterine Cancers, version 1.2022. Accessed January 24, 2022. 

Levine D, Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma [published correction appears in 

. 2013;497(7447):67-73. doi:10.1038/nature12113

This article was originally published on OncLive as “Leveraging Biomarkers in Endometrial Cancer Requires Careful Integration, More Research”

An expert from the Ohio State University Comprehensive Cancer Center discusses whether predictive biomarkers hold the potential to change endometrial prognoses. 

Jonah Feldman

Articles

5-Year Survival Data Showcases Long-Term Benefit With Nivolumab/Ipilimumab-Treated Metastatic NSCLC

Investigators Inch Closer to Unlocking CAR T-Cell Therapy Potential in Solid Tumors

More Research Is Needed to Utilize Biomarkers in Endometrial Cancer