Megan Hollasch joined MJH Life Sciences in 2022 following graduation from the University of Massachusetts Amherst with majors in Communication and English, and a specialization in Literature as History. She produces and edits original content for the print publication 

, aiding in all aspects of the publication process, as well as content for OncLive.com.

Anbalcabtagene autoleucel (anbal-cel) exhibited encouraging efficacy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to findings from a phase 1 trial (NCT04836507) presented at the 2022 European Hematology Association Congress (EHA).

Anbal-cel is a novel autologous CD19 CAR T-cell agent that has been knocked down for PD-1 and TIGIT. In preclinical studies, it was suggested that the elimination of CD19-positive cells in vitro and in vivoachieved better results with anbal-cel compared with conventional CD19 CAR T cells.

Eleven patients were assigned to received one of 3 dose levels: 2 × 10

 cells/kg (dose level 3). The overall response rate (ORR) in the total population (n=11) was 82%, all of which were complete responses (CRs). Notably, patients treated at dose level 3 (n=4) all achieved CRs.

“In recent years, we are looking at the very impressive outcome of the CAR T-cell therapy in relapsed or refractory large B-cell lymphomas, but we are not curing every patient,” Won Seog Kim, MD, PhD, said. “Still 40% to 50% of the patients treated with CAR T cells are getting some relapse or disease progression.”

, Kim, a professor in the Division of Hematology-Oncology at Samsung Medical Center in Seoul, South Korea, discussed the potential clinical role of anbal-cel in relapsed/refractory DLBCL and the continued evolution of CAR T-cell therapy.

What differentiates anbal-cel from other CAR T-cell agents?

A major reason for CAR T-cell failure is CD19 loss. The other is ingestion of the infused CAR T cell, mainly caused by immune checkpoint protein overexpression, [such as] PD-1.

In anbal-cel cells, we are putting in 2 small hairpin RNA structures into the construct to reduce the expression of TIGIT and PD-1. We are expecting [to]sustain the efficacy of CAR T cells with this strategy.

What was notable concerning the findings of the trial?

The primary end point was safety. The secondary end points were ORR, the CR rate, and duration of response. In the safety aspect, we confirmed it is quite safe. Grade 3 or 4 toxicities were quite uncommon. We had very manageable cytokine release syndrome and neurotoxicity is quite rare compared with other [agents].

The efficacy was quite impressive; there was an 82% CR rate, and all patients experienced tumor shrinkage. It is a quite promising CAR T-cell [therapy].

What are the next steps for this research?

An issue in the CAR T-cell setup is that [that] it is too expensive. To overcome that, the allogenic CAR T-cell [agents] and allogenic natural killer cells are actively developing. Maybe in the future with that kind of approach we can reduce the cost very significantly. I think we can make many different kinds of CAR T cells in the future quite soon and I’m expecting an overcome this very terrible disease.

What would you like your colleagues to take away from this research?

In the CAR T-cell sessions during the EHA [Congress] this year we saw that there are several different ways of approaching the failure of CAR T cells. Our strategy putting in the immune checkpoint level blocking CAR T [cells].

There are many ways to overcome the [common] CAR T-cell failures. In our case, we successfully prevented the exhaustion of CAR T cells through decreased expression of new checkpoint proteins. That is 1 way but there are many other reasons for CAR T-cell failure, like intrinsic T-cell issues or the microenvironment. That will be our next step; how can we overcome these kind of resistance mechanisms?

Kim WS, Kim SJ, Yoon SE, et al. Phase 1/2 study of anbalcabtagene autoleucel novel anti-CD19 CAR-T therapy with dual silencing of PD-1 and TIGIT in relapsed or refractory large B-cell lymphoma. Presented at: European Hematology Association Congress 2022; June 9-12, 2022; Vienna, Austria. Accessed August 16, 2022. bit.ly/3Qzssqz

Articles

Won Seog Kim, MD, PhD, discusses the potential clinical role of Anbalcabtagene autoleucel in relapsed/refractory diffuse large B-cell lymphoma and the continued evolution of CAR T-cell therapy.

Anbalcabtagene Autoleucel Shows Promise in Relapsed/Refractory LBCL

The FDA has granted accelerated approval to the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for adult and pediatric patients 6 years or older with unresectable or metastatic 

 V600E–mutant solid tumors. Patients must have been disease progression following prior treatment and have no satisfactory treatment options. The safety and efficacy of the combination were evaluated in 131 adult patients from open-label, multiple cohort trials ROAR (NCT02034110) and NCI-MATCH (NCT02465060) and 36 pediatric patients from the CTMT212X2101 trial (NCT02124772).

The studies included 24 tumor types. Individuals in ROAR had high-grade glioma (HGG), biliary tract cancer, low-grade glioma (LGG), adenocarcinoma of small intestine, gastrointestinal stromal tumor, and anaplastic thyroid cancer. NCI-MATCH Subprotocol H included patients with 

 V600E–positive solid tumors (excluding melanoma, thyroid cancer, and colorectal cancer [CRC]), and the pediatric trial included patients with refractory or recurrent LGG or HGG.

The objective response rate (ORR) was 41% among the 131 adult patients (95% CI, 33%-50%). Among the highest representative tumor types, ORR was 46% (95% CI, 31%-61%) for biliary tract cancer, 33% (95% CI, 20%-48%) for HGG (combined adult and pediatric) and 50% (95% CI, 23%-77%) for LGG (combined adult and pediatric). Among all pediatric patients, the ORR was 25% (95% CI, 12%-42%) with 78% of patients have a response lasting at least 6 months and 44% of responders having a response lasting at least 24 months.

“This is a known [combination] that’s already been approved [by the FDA] for 3 different indications, the [adverse] effects are known and managed by oncologists, and we know that 

 V600E are actionable across these 3 tumor types [melanoma, non–small cell lung cancer (NSCLC), anaplastic thyroid cancers],” Vivek Subbiah, MD, said. “This important tissue agnostic approval across solid tumors provides access to patients with rare malignancies.”

, Subbiah, an associate professor and clinical medical director of the Clinical Center for Targeted Therapy in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston discussed the significance of the approval and future directions for tumor agnostic drug development.

What is the significance of the FDA approval of the combination in this population and how do you see it affecting current practice patterns?

The FDA granted accelerated approval to dabrafenib, which is a BRAF inhibitor, in combination with trametinib, which is a MEK inhibitor, for the treatment of adult and pediatric patients [age] 6 years [or older] with unresectable metastatic solid tumors that harbor the 

 V600E mutation who have followed and progressed following prior treatment and have no satisfactory alternative treatment. The BRAF and MEK inhibitor combination is approved for melanoma, NSCLC, and anaplastic thyroid cancer. The lack of clinical benefit in BRAF inhibition and 

 V600E-mutated CRC had prevented its tissue agnostic developing.

The MAP kinase pathway was first implicated in the pathogenesis of melanoma and since then, we have 3 different combinations that have shown activity and are FDA approved in melanoma specifically harboring 

 V600E mutations. The main challenge is [targeted] 

 V600E mutations [across] all malignancies. We reviewed case reports, outcomes of patients with BRAF-mutated nonmelanoma malignancies [and saw that] 

 V600E mutations are prevalent across multiple nonmelanoma malignancies [with] more than 20 different tumor types harboring this mutation. They lead to oncogene addiction across all these tumor types and are clinically actionable in a broad variety and range of other and pediatric nonmelanoma malignancies. CRC remained an exception.

Please put the efficacy data in context, especially for some of the rare tumor types.

We put together 3 different clinical trials and the safety and efficacy were evaluated in 131 adult patients from open label, multi-cohort studies. The trials were the ROAR study, which is a rare oncology agnostic research study, the NCI-MATCH study, and a pediatric study. The pediatric study was supported by the COMBI-d and COMBI-v studies in melanoma and lung cancer which have been described extensively in literature and the product labeling.

The main study was a ROAR basket study which enrolled patients with 

 V600E mutations across multiple tumor types such as LGG, HGG, biliary tract cancer, carcinoma of the small intestine, gastrointestinal stromal tumor, and anaplastic thyroid cancer. Part C and D of the pediatric study enrolled patients with 

 V600E refractory or recurrent LGG and HGG. Based on the data of clinical benefit and the area of unmet need, the combination [of dabrafenib and trametinib] received additional agnostic approval across all solid tumors, with the exception of CRC, harboring 

What are the implications on routine diagnostics?

I think the combination of dabrafenib and trametinib demonstrates meaningful efficacy in multiple 

-mutant tumor types, including some patients with rare cancers who have no alternative treatment options. Physicians should consider a 

 test as a routine diagnostic test step that could enable this new treatment option for patients with many solid tumors. Specifically, we need comprehensive next-generation sequencing in patients with solid tumors so that patients can benefit from 

Based on this approval, and others in the past, do you believe that the field of oncology is headed toward more tumor agnostic approvals? Or will it be used as a tool for rarer subsets?

I think it’s going to be a combination of both, think there will be more tissue agnostic approvals, especially for targets that share biomarkers across different tumor indications. We see these biomarkers in rare cancers more than common cancers. We are learning [about these] are new approvals, new targets, and new medications.

The first ever tissue agnostic agent that was approved was immunotherapy, pembrolizumab [Keytruda], for [patients with] mismatch repair deficient [dMMR] microsatellite instability-high tumors. The second drug was larotrectinib [Vitrakvi] for antifusion paths to solid tumors. The third drug was entrectinib [Rozlyrek], and subsequently pembrolizumab also received approval for [patients with high] tumor mutation burden. More recently, dostarlimab-gxly [Jemperli] was approved in a histology agnostic manner for patients with dMMR and there is a VHL-targeted agent also approved with a tissue agnostic indication.

 V600E, has been a specific target for the past decade, but for patients beyond melanoma, lung cancer, or anaplastic thyroid cancer, those harboring 

 mutations did not have any approved therapy, especially patients with CRC, HGGs, or LGGs. This approval will provide access for these patients.

Is there anything else that you would like to add?

My personal belief is universal genomic testing is needed to move our needle against cancer. I think the more comprehensive tests we do in patients the earlier in the disease course, more patients will benefit from these therapies.

FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with 

 V600E mutation. FDA. June 23, 2022. Accessed July 26, 2022. bit.ly/3cIz4E6

Vivek Subbiah, MD, discusses the significance of the approval of dabrafenib plus trametinib for adult and pediatric patients 6 years or older with unresectable or metastatic BRAF V600E–mutant solid tumors and highlights future directions for tumor agnostic drug development.

Tumor Agnostic Approval Targets BRAF V600E–Mutant Disease

Widening disparities in genetically informed cancer care prompted investigators to conduct a study of germline testing (GT) rates among racially diverse groups of men with prostate cancer, which highlighted the importance of GT in prostate cancer treatment.

A retrospective analysis of patients used the 14-gene prostate cancer panel to evaluate 427 men: African American (n = 237; 56%) and White (n = 190; 44%). The overall pathogenic/likely pathogenic (P/LP) variant rate was 8.2%.

Lower P/PL variant rates were reported among African American men (5.91%) vs White men (11.05%; 

 = .05). Further, rates of variants of uncertain significance (VUS) were 25.32% vs 16.32%, respectively 

02). Multiple VUSs were reported among 5.1% and 0.53% individuals, respectively (

“The idea is to not shy away from identifying the disparities. I think in the past there has been a stigma, but we can't solve the problem by not looking at it” said Carrie Horton, MS, CGC. “It’s been exciting to see Ambry [Genetics] rally behind a lot of health disparity research and I hope it can motivate other groups to do the same thing.”

, Horton, a senior clinical research specialist who designs and conducts studies at Ambry Genetics, discussed how the findings of the retrospective analysis of genetic testing in prostate cancer care will guide future research and influence the steps community oncologists can take to increase testing rates.

What was the catalyst for this investigation?

This specific study came about when the lead principal investigator Veda Giri, MD, a medical oncologist at Thomas Jefferson University Hospital, approached [Ambry Genetics]. She had seen a paper that we had done previously looking at the genetic testing results in individuals with prostate cancer, but it wasn’t selected for any one race or ethnicity. Since African Americans are more likely to develop and die of prostate cancer, there’s a real area of opportunity for targeted therapeutics in that group. Therefore the need for accurate genetic testing is even more important.

[Giri] came to us and wanted to see if we could use our existing data set and design a protocol with the intent to evaluate disparities between African American males with prostate cancer and White males. In doing that, we enriched our cohort for African Americans so that our sample was about equal. In most of the past studies looking at genetic testing in prostate cancer, identifying these disparities was a byproduct and not the whole focus of the study; there were a lot of inconsistencies [such as] the genes tested, not every [individual] had prostate cancer, or only 10% of the population was African American and 90% were other ethnicities. This study was specifically to evaluate the differences we’re seeing in genetic testing results in African Americans compared with White males.

We were excited to be able to help Giri with this because we have such a huge data set which is one of the benefits of working with Ambry [Genetics]; we can leverage that volume to find meaningful results.

What methods were used throughout the study?

We had our existing data set results of genetic testing in White males with prostate cancer from 2016 to 2017 and [all individuals] had the same multigene panel test—a 14-gene panel targeted for hereditary prostate cancer. We had the population needed for White individuals but wanted to make sure that we enriched for African Americans as well, so we expanded our timeline and our recruitment for African Americans through 2020.

We also looked at personal history and reviewed the clinic notes that were provided, [such as] pathology [reports] to see if there were any differences in when [individuals] were being sent for testing. [For example,] we wanted to see if African Americans were being sent only when they were extremely high risk but didn’t find a huge difference in who was being sent for testing in terms of the severity of the presentation. However, we saw a stark difference in the positive and VUS rates, where White individuals were almost twice as likely to have a positive result compared with African Americans. The VUS rate was half in White individuals compared with African Americans.

Was there anything particularly surprising in the findings?

There’s been precedent that we see a higher VUS rate in underrepresented populations across most genetic testing indications. However, one thing that was fairly novel [in this study] was that we found approximately half the positive findings in genes exclusive to White individuals. We need to improve our interpretation of the existing variants, and the fact that half the genes were exclusive to White individuals signals to me that perhaps there’s some room to improve our gene discovery.

We may not have found all the predisposition risk genes for prostate cancer in African Americans yet; there’s 2 genes where the positive rate is driven by a single mutation in White individuals. So, maybe there is a gene that has a mutation in an underrepresented group, and we just haven’t been able to find it because that’s not who has historically been presented for testing.

What effect can these data have for the testing moving forward?

What action steps would you like to relay to your colleagues to take to help address these disparities?

There’s a shift now into focusing on identifying disparities and when we set out to shine a spotlight on the inequities, it allows us to figure out what’s really going on and provides an opportunity to improve and mitigate those disparities. I’m hoping this helps motivate [individuals] to revisit the idea of gene discovery in diverse populations and to come up with new ways for varying interpretation that are agnostic of race and ethnicity, that don’t rely on volume in order to accurately interpret variants. The more accurate we can get a test, especially in the hereditary prostate cancer space, the more opportunities there are for targeted medicine for PARP inhibitors such as olaparib [Lynparza].

It’s a multi-level [issue]. At the base level, we must] try to come up with better ways to engage underrepresented communities in genetic testing. We’ve seen studies that showed that underrepresented groups are preferred for genetic testing and adopt genetic testing at lower rates. [Solutions may include] looking more at genetic testing recruitment through nontraditional settings, such as health fairs or community gatherings. We first need to get [individuals] in the door to even get their result.

A more diverse population improves the accuracy that we can interpret the results with both in reference population databases, but also in the clinical and research cohorts. For laboratorians, I would encourage them to look at health disparities and what to do to circumvent existing gaps in evidence. For example, there are newer ways to derive functional evidence that does not rely on the accumulation of observing a variant multiple times.

Giri VN, Hartman R, Pritzlaff M, Horton C, Keith SW. Germline variant spectrum among African American men undergoing prostate cancer germline testing: need for equity in genetic testing. 

. 2022;6(1):e2200234. doi:10.1200/PO.22.00234

Carrie Horton, MS, CGC, discusses how the findings from a retrospective analysis of germline testing rates among racially diverse groups of men with prostate cancer will guide future research and influence the steps community oncologists can take to increase testing rates.

Retrospective Analysis Highlights Disparities in Germline Testing in Prostate Cancer

Results of the phase 2 CRESTONE study (NCT04383210) have demonstrated the tolerable safety profile and efficacy of seribantumab for the treatment adult patients with metastatic solid or locally advanced tumors harboring the rare 

 fusions. Initial findings were presented at the 2022 American Society of Clinical Oncology Annual Meeting.

In CRESTONE, the investigator-assessed objective response rate (ORR) with seribantumab for cohort 1 (n = 12) was 33% with 2 partial responses (PR) and 2 complete responses (CR). Among the patients in cohort 1, 11 had non–small cell lung cancer (NSCLC). The ORR for these patients was 36% and included 2 PRs and 2 CRs.

 fusions are found in 0.2% of all solid tumors and the oncolytic drivers associated overactivation of HER3. Seribantumab, an anti-HER3 monoclonal antibody, demonstrated preclinical activity 

Yasir Y. Elamin, MD, an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas said, “[The data] are an important finding, but we must be conscious that the numbers are limited. This analysis was only done on 12 patients so I would like to see more numbers.”

, Elamin discussed how the early data support further investigation of seribantumab, which is especially important as there are no current approved targeted therapies for patients with 

Please describe the background on NRG1 fusions and solid tumors and the practice for detecting these fusions.

 gene with another partner gene. They are very rare, and the overall [incidence] is 0.2% in all solid tumors, but they are enriched in adenocarcinoma for lung which is also rare to begin with. It’s also enriched in 

 wild-type adenocarcinoma of the pancreas.

The NRG1 protein binds to the healthy protein on the surface of the cancer cell, activating downstream signaling, so it does activate the PI3K pathway, the MAPK pathway, and so forth. Given how rare this fusion is, it’s [recently] become a focus of extensive clinical research and preclinical research. What we can tell based on some limited retrospective studies is that patients with 

 fusions may not be very responsive to chemotherapy or immunotherapy. Therefore, the treatment options in the metastatic setting are limited.

 fusion would be to use an RNA-based sequencing platform because the intronic region in the fused gene is quite large, so, it is much easier to detect.

What makes seribantumab unique from other agents in this space?

There are [other] pan-ERBB inhibitors, such as tyrosine kinase inhibitors, which would inhibit the entire HER family. One of them that’s already commercially available is afatinib (Gilotrif), although it is not approved specifically for 

Seribantumab is a fully humanized monoclonal antibody that binds to HER3 on the cell surface and it essentially competes with 

. By doing that, it prevents the diagonalization of HER3 and other HER family members and it will suppress the activation of downstream signaling. Monoclonal antibodies target HER3 and HER2 when they treat 

What inspired the launch of the CRESTONE study? And what are the key objectives of the research?

The overall goal of the study is to provide patients with 

 fusion–positive tumors with treatment options. We don’t have any FDA-approved targeted drugs for patients with 

 fusions and the promise of targeted therapy has been well established across solid tumors. These therapies are typically effective, have less adverse event [AE], and patients treated with targeted therapy, in most cases, have better quality of life.

The primary end point of the phase 2 portion of the study is to establish the ORR in 3 different cohorts. The first cohort [includes] patients with 

 fusions who were not treated with HER3 targeted therapy or pan-ERBB targeted therapy, and who have their 

 fusions centrally confirmed. Then there is a second cohort for patients who have been treated in the past with HER3 targeted therapy, or a pan-ERBB inhibitor. And finally, cohort 3 [includes] patients who don’t fit in cohort 1 and cohort 2, and these are mostly patients who lack the EGF-like domain of the 

There are a number of secondary end points including safety, progression-free survival, duration of response, and so forth. The key thing is that all patients with 

What were the efficacy findings reported with this agent?

The efficacy that was reported was from cohort 1, which is, again, focused on patients who had no prior ERBB-directed [therapy]. The number of [patients and] what was reported was small, but the data are very encouraging. In this cohort, the efficacy [data included] 12 patients, and 4 of these 12 patients had response [for a] response rate of 33% and of these 2 were complete responses and 2 partial responses. If you look specifically at patients who [had] NCSLC, the overall response rate was 36%. The disease control rate in patients in cohort 1 was 92%.

I think it’s an important finding, but we must be conscious that the numbers are limited. The critical question here is around the efficacy: Is the drug going to be active in all fusion partners? Based on the initial data that we have seen, it [appears] that the fusion partner does not impact the efficacy in a negative way.

Generally speaking, the agent was safe and that is evident because we did not see any patients who discontinued service [because of] an AE. The vast majority of AEs were grade 1 or grade 2.

[The data] reinforce the utmost importance of genetic testing, especially in the context of lung cancer. I think it is important to do genetic testing, because it does impact clinical decision, outcomes, and survival. For 

you could miss it if you use the DNA-based [next-generation sequencing]. If you used an RNA -based test, I think that would be the gold standard way of detecting this.

These data that we’ve seen warrant further clinical development of this drug in solid tumors with an 

fusion. We need more targeted therapies for patients and the promise of targeted therapy is real.

Carrizosa DR, Burkard ME, Elamin YY, et al. CRESTONE: initial efficacy and safety of seribantumab in solid tumors harboring 

. 2022;40(suppl 16):3006. doi:10.1200/JCO.2022.40.16_suppl.3006

Results of the phase 2 CRESTONE study have demonstrated the tolerable safety profile and efficacy of seribantumab for the treatment adult patients with metastatic solid or locally advanced tumors harboring the rare NRG1 fusions. 

CRESTONE Data Signal Positive Start to Treat Rare NRG1 Fusions in Solid Tumors 

A 5-year analysis of the CheckMate 227 trial (NCT02477826) further supported the use of nivolumab (Opdivo) and ipilimumab (Yervoy) to treat metastatic non–small cell lung cancer (NSCLC) regardless of tumor PD-L1 expression level, according to Julie R. Brahmer, MD, MSc.

Data presented during the 2022 American Society of Clinical Oncology Annual Meeting showed a 5-year overall survival (OS) rate was 24% with the combination (n = 396) vs 14% with chemotherapy alone (n = 397) among patients with high PD-L1 expression (≥ 1%). For those with low PD-L1 expression (< 1%), the 5-year OS rates were 19% vs 7%, respectively, for nivolumab/ipilimumab (n = 187) vs chemotherapy (n = 186). At 5 years, the hazard ratio was 0.77 for OS.

“Regardless of PD-L1 expression level, responses were maintained for greater than 5 years in more than 40% of those who responded [to treatment with nivolumab/ipilimumab]," Brahmer said. “The majority [of patients] remain treatment free for more than 3 years after treatment discontinuation.”

, Brahmer discussed how the data may affect the treatment landscape for NSCLC and the quality-of-life outcomes reported with nivolumab and ipilimumab. Brahmer is codirector of the Upper Aerodigestive Department and a professor of oncology at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. Brahmer is also the codirector of the Cancer Immunology Program and the director of thoracic oncology.

Please describe the rationale for investigating this drug combination and what sets it apart from different combinations in the space.

For CheckMate 227 we evaluated nivolumab and ipilimumab, which is a combination of checkpoint inhibitors. This is the first nonchemotherapy combination for patients with metastatic NSCLC in the first-line treatment setting.

For patients on this trial, they were treated up to 2 years and then [therapy was stopped] and followed thereafter. That’s where we get a lot of our long-term data. We know that this trial led to the approval of nivolumab and ipilimumab in patients with PD-L1–positive disease based on improvements in OS response rate and progression-free survival.

Also, it does have compendia listing for patients with PD-L1 negative disease. [Although] the trial was not statistically designed to answer this question, in patients [with PD-L1–negative disease] nivolumab and ipilimumab did trend [toward] improvements in OS in that patient subgroup.

What methodologies were leveraged in the 5-year analysis?

For the 5-year OS update, we also looked at treatment-free interval. This was defined as the time from the last dose of therapy to the subsequent systemic therapy or death.

This was a chance to look at this type of output in patients who stopped therapy and how long were they off their peak. When most [individuals] are on chemotherapy, they need to remain on some type of therapy, where patients on immunotherapy can stop treatment and not need any further therapy for a very long time. That was what we wanted to look at.

What were the top takeaways from the data shared at the 2022 ASCO meeting?

The data at ASCO this year were a 5-year [updated for] OS in patients with PD-L1–positive disease treated with nivolumab and ipilimumab. The 5-year OS [rate] was 24%; the hazard ratio remained 0.77 in patients with [PD-L1–]positive disease compared with chemotherapy where the 5-year OS [rate] was 14%. It was quite exciting to see that there seems to be a plateau from the 4-year survival to the 5-year survival.

The median overall survival is [approximately] 17 months in the nivolumab and ipilimumab arm compared with [approximately] 14.9 months in the chemotherapy arm for patients with PD-L1–positive disease. We are seeing a plateau for these patients. This is exciting, nearly almost a doubling of 5-year OS compared with chemotherapy and most of these [patients receiving] chemotherapy, at least some of them, go on to receive second-line immunotherapy.

We also showed a plateau of progression-free survival, and the median duration of response was over 2 years in the nivolumab and ipilimumab arm: 5-year duration of response of 28% in nivolumab and ipilimumab compared with only 3% in the chemotherapy arm. Again, [this] just shows the power of immunotherapy to control disease for quite some time.

In patients with PD-L1–negative disease, the 5-year OS [rate] in patients treated with nivolumab and ipilimumab was approximately 19%. Again, median survival [was] very similar to the PD-L1–positive [population] at 17.4 months. In the chemotherapy arm, the 5-year survival [rate] in the PD-L1–negative group was 75%; the hazard ratio remained quite significant at 0.65, but again, this [trial] was not designed to statistically compare the arms. From a clinical standpoint, this is important.

Progression-free survival was [approximately] 10% in the [PD-L1–negative] patient group treated with nivolumab and ipilimumab and again, an amazing [median] duration of response, 19.4 months, [was also reported, with] response at 5-years of approximately 21%. Very similar to PD-L1–positive disease.

I think these efficacy outcomes that we’re seeing at 5 years is amazing to report in patients with metastatic disease. We want to increase or that tail of the curve even further, but this is a great next step.

[In terms of] quality of life, we were able to show that patients had a very similar quality of life compared with the [general] US population. This again was great to be able to show. From a treatment status [perspective], for most patients, approximately 66%, who were treated with nivolumab and ipilimumab [who had] PD-L1–positive had not received subsequent therapy [at 5 years].

[For patients with] PD-L1–negative [disease] that was very similar for 5-year survivors [who received] nivolumab and ipilimumab; 64% of patients did not require any subsequent treatment. If you look at the treatment-free interval for 5-year survivors, patients who did not require further therapy beyond 3 years was approximately 66%. Again, [although] these numbers are relatively small, the percentage of patients [who] didn’t require further therapy beyond 3- ears, now they’re 5 years and beyond. It is pretty telling that this type of treatment can control their disease for a very long time. 

[These data are] important for patients and [provide information clinicians] need to prescribe nivolumab and ipilimumab for this patient population. Obviously, we want to compare these [data] with chemotherapy and single-agent immunotherapy, or even the combination of nivolumab and ipilimumab with chemotherapy based on the CheckMate 9LA study [NCT03215706]. This is when we really need the 5-year survival [data] from these studies across the board.

What is the significance of these data for clinical practice?

[Going forward] we must think about long-term cancer survivorship programs in order to help these patients and figure out what’s the best way to follow them after they finish therapy. And [we must examine if] there are other issues that we need to be looking at long term.

Most of us are starting to use the word “cure.” But cure in patients with metastatic disease that they can do well for an extremely long time and may not ever have this cancer come back.

Again, that is completely different than where we were 5 years ago, when we were barely saying that word for patients with advanced disease. This is changing the outlook for patients; if they do well and have a great response, they can do well for a long period of time, even off therapy. You can’t tell me this does not affect someone's quality of life and change and improve hope for our patients.

For my colleagues, I would recommend considering nivolumab and ipilimumab as a treatment choice. We need to figure out how best to parse out who should receive what from single-agent immunotherapy, combination immunotherapy, and if we need chemotherapy at all. Over time, we will have studies and technology that gets us to that point.

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):9025. doi:10.1200/JCO.2022.40.17_suppl.LBA9025

Julie R. Brahmer, MD, MSc, discusses how data from the CheckMate 227 trial may affect the treatment landscape for NSCLC and notes the quality-of-life outcomes reported with nivolumab and ipilimumab.

Megan Hollasch

Articles

Anbalcabtagene Autoleucel Shows Promise in Relapsed/Refractory LBCL

Tumor Agnostic Approval Targets BRAF V600E–Mutant Disease

Retrospective Analysis Highlights Disparities in Germline Testing in Prostate Cancer

CRESTONE Data Signal Positive Start to Treat Rare NRG1 Fusions in Solid Tumors

Brahmer Discusses Influence of 5-Year Nivolumab and Ipilimumab OS Data in Metastatic NSCLC