OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

There are still no FDA-approved autologous chimeric antigen receptor (CAR) T-cell therapies available for solid tumors, with many constructs to date showing minimal efficacy.

 Comparatively, there are 7 commercial anti-CD19 and anti–B-cell maturation antigen (BCMA) CAR T-cell products currently available for the treatment of patients with hematologic malignancies, with dozens of others in active development.

 Challenges faced in the development of CAR T-cell agents for solid tumors include selecting appropriate target antigens while mitigating antigen escape, ensuring adequate CAR T-cell expansion, augmenting localization of the CAR T cells to tumor sites, minimizing exhaustion of CAR T cells in the setting of an immunosuppressive tumor microenvironment, and prolonging persistence of CAR T cells.

 Recent clinical trials, including those of anti-CLDN18.2 CAR T-cell therapies for patients with CLDN18.2-expressing gastrointestinal cancers and anti-GD2 CAR T-cell agents for patients with neuroblastoma, have provided reasons for optimism that some of these challenges are being overcome.

As we plan for a future when solid tumor CAR T-cell therapy becomes available, we should be mindful of lessons learned from the introduction of CAR T-cell agents for hematologic malignancies. The first lesson is to recognize that timely access to therapy can be a significant barrier. Unsurprisingly, delays in access to anti-CD19 and anti-BCMA CAR T-cell agents have been shown to worsen survival, as patients who are waiting for treatment may die from their cancer.

 The impact of delays on patient outcomes will likely be more detrimental in solid tumors, as there are typically fewer options for effective systemic therapy to maintain disease control compared with hematologic malignancies.

Psychosocial factors including geography and socioeconomic status are potential barriers to timely access.

CAR T-cell therapy is typically only available at tertiary academic centers; many patients live a significant distance away and also need referrals. The need to travel, stay an extended period away from home, and have a caregiver as well as associated financial costs may prevent patients with disadvantages from receiving CAR T-cell therapy. Although insurance coverage can be a limitation, patients with private insurance may have longer “decision to vein” time than those with government insurance.

 Analyses from patients receiving anti-CD19 CAR T cells highlight the effect of disparities: patients with disadvantages may experience shorter survival

 and are less likely to receive CAR T-cell therapy.

Production capacity can also contribute to delays in receiving CAR T-cell therapy.

 The rollouts of idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti) were hampered by limited numbers of manufacturing slots, forcing patients onto waiting lists at multiple institutions and leading to difficult decisions about which patients to allocate slots to.

 Manufacturing-related delays could be a much bigger challenge for solid tumors than hematologic malignancies on the basis of sheer number of patients alone. In 2024, it was estimated there were more than 2 million new cases of cancer, of which less than 10% were myeloma, lymphoma, or leukemia.

 Additionally, a certain percentage of CAR T-cell products will not conform to FDA requirements, leading to “out-of-specification” designations and a need to recollect and/or remanufacture or to proceed on a research basis using an expanded access protocol.

 Either choice will lead to a delay in cell therapy infusion, and it is critical to inform patients considering CAR T-cell therapy about this possibility.

Another lesson is the importance of being cognizant and transparent about risks of CAR T-cell therapy. Although the risk of CAR T-cell toxicity such as cytokine release syndrome and immunoeffector cell (IEC)–associated neurotoxicity syndrome may be associated with increased tumor burden at the time of infusion, there are other risks as well.

 These other risks are not trivial: findings from a meta-analysis of real-world and clinical trial data estimated a CAR T-cell treatment–related mortality up to 15% depending on the product used.

 Years after the initial commercial approvals of CAR T-cell agents, we are still learning about potential CAR T-cell–related toxicities such as secondary primary malignancies, IEC-associated hemophagocytic syndrome and colitis, and parkinsonism.

 Infection has been the primary driver of morbidity and mortality in CAR T-cell therapy so far, requiring providers to be vigilant about using appropriate antimicrobial prophylaxis, growth factors, and intravenous immunoglobulin as needed.

 Although infection and other toxicities such as IEC-associated hematotoxicity may be less common if the CAR T-cell target does not reside in the bone marrow or lymphoid compartments, there will likely be hitherto undescribed emerging toxicities given the use of new targets that will have different off-tumor specificity.

The final lesson is that even an effective CAR T-cell construct for a specific solid tumor will not be effective for all patients with that disease. It remains important to continue development of other forms of systemic therapy, including medical and cellular immunotherapy. For example, bispecific antibodies and antibody-drug conjugates can be effective in treating lymphoma or myeloma even when a CAR T-cell therapy directed toward the same target is not.

 Fortunately, in 2024, the FDA approved 2 other types of adoptive T-cell therapies for solid tumors: lifileucel (Amtagvi), a tumor-infiltrating lymphocyte therapy for metastatic or unresectable melanoma, and afamitresgene autoleucel (Tecelra), a T-cell receptor cell therapy for advanced synovial sarcoma and myxoid round liposarcoma. Several bispecific antibodies for solid tumors have recently been approved as well.

When CAR T-cell therapies are approved for solid tumors, a greatly increased number of patients will become eligible. We can use our experience with CAR T-cell therapy thus far to refine our current approaches and incorporate promising new techniques in order to make sure the maximum number of patients benefit. The most important step will continue to be ensuring that our patients are adequately informed and prepared for this new landscape (

Zhubin Gahvari, MD, MS, is an assistant professor in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health, the University of Wisconsin Carbone Cancer Center in Madison. 

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Articles

CAR T-cell therapies for solid tumors face significant challenges, including target antigen selection, CAR T-cell expansion, and overcoming the immunosuppressive tumor microenvironment. While hematologic malignancies have seen success with CAR T-cell therapies, solid tumors lag behind. Barriers such as timely access, production capacity, and psychosocial factors hinder therapy availability. Toxicities, including cytokine release syndrome and secondary malignancies, remain concerns. Despite these challenges, recent FDA approvals of adoptive T-cell therapies and bispecific antibodies for solid tumors offer hope. Continued development of systemic therapies is crucial for comprehensive cancer treatment.

As we plan for a future with solid tumor CAR T-cell therapy, we should be mindful of lessons learned from CAR T-cell agents for hematologic malignancies.

CAR T-Cell Therapy for Solid Tumors: Leveraging Lessons From Hematologic Malignancies

In patients with renal cell carcinoma (RCC), clonal neoantigen load (CNL) was significantly associated with exceptional responses to PD-1/PD-L1 and CTLA-4 combination therapy and tertiary lymphoid structure (TLS) formation was associated with these exceptional responses to PD-1/PD-L1 and VEGF inhibitor combination treatment, according to findings from a retrospective study published in 

“Treatment [for patients with RCC] has evolved greatly over the past couple of years with immune checkpoint inhibitors in combination with VEGF tyrosine kinase inhibitors, [which] have been serving as the cornerstone of therapy,” Renee Maria Saliby, MD, MSc, a senior author of the study and a postdoctoral research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts, said in an interview with 

. “[However], kidney cancer has challenged everything we know in terms of biomarkers, and a lot of work has been done in terms of biomarkers for response vs progressive disease. Patients want deep, durable responses, so we decided to look at these patients who had a deep, durable response and called them exceptional responders. [We wanted] to understand the genomic and transcriptomic mechanisms that were underlying these responses.”

Saliby and her coauthors utilized whole-exome and RNA sequencing to examine genomic features associated with exceptional response to immunotherapy-based combinations in patients with clear cell RCC. An exceptional response was defined as a complete response (CR) with a progression-free survival (PFS) of at least 1 year, a partial response (PR) with at least 50% tumor shrinkage and a PFS of at least 2 years, or any PR with a PFS of at least 3 years. Investigators also defined an intermediate response as any CR or PR that was not an exceptional response.

Tumor specimens were obtained from patients with available tumor sequencing data enrolled in the phase 3 JAVELIN Renal 101 (NCT02684006) and CheckMate 214 (NCT02231749) trials. CheckMate 214 enrolled patients with previously untreated advanced or metastatic RCC to evaluate the combination of the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy), with primary end points around efficacy in patients classified as intermediate or poor risk based on International Metastatic RCC Database Consortium (IMDC) risk-stratifying criteria.

 The JAVELIN Renal 101 trial evaluated the PD-L1 inhibitor avelumab (Bavencio) plus the VEGF inhibitor axitinib (Inlyta) for the first-line treatment of patients with advanced RCC.

 Data from the CheckMate 214 and JAVELIN Renal 101 studies supported the FDA approvals of the regimens in their patient populations in April 2018 and May 2019, respectively.

To validate these response classifications outside clinical trials, investigators used the IMDC registry to evaluate the baseline characteristics and outcomes of a real-world population of exceptional responders who received immunotherapy-based regimens.

Patients included from CheckMate 214 trial (n = 550) had a median age of 62 years (IQR, 55-68). Most patients were male (75%) and had IMDC intermediate-risk disease (59%). Overall, these patients achieved a CR rate of 11% and a PR rate of 29%.

Patients included from JAVELIN Renal 101 (n = 434) had a median age of 62 years (IQR, 55-67). Most were male (71%), had disease without sarcomatoid features (89%), and had IMDC intermediate-risk disease (62%). The overall CR and PR rates were 3.9% and 50%, respectively (Figure).

Investigators evaluated the association of previously described tumor-intrinsic biomarkers with exceptional response, including total somatic tumor mutational burden (TMB), frameshift TMB, weighted genome instability index (wGII), intratumoral heterogeneity, and germline human leukocyte antigen (HLA) class I evolutionary divergence. Additionally, they defined CNL as the total number of neoantigens arising from clonal mutations and examined it as a determinant of response to immunotherapy-based combinations.

CNL and TLS Display Association to Exceptional Response to Therapy

Findings from the analysis demonstrated that patients treated with the immunotherapy doublet in CheckMate 214 who experienced an exceptional response, an intermediate response, or disease progression all had similar TMB, frameshift insertions or deletions, mean HLA class I evolutionary divergence, wGII, tumor purity and ploidy, and loss of heterozygosity. Data from patients who received doublet therapy in JAVELIN Renal 101 also showed no correlation with exceptional response and TMB, frameshift insertions or deletions, mean HLA class I evolutionary divergence, wGII, tumor purity and ploidy, and loss of heterozygosity.

However, patients treated in CheckMate 214 who experienced an exceptional response displayed a significantly higher CNL compared with those in the intermediate response and progressive disease groups. Comparatively, patients who experienced an exceptional response in the sunitinib malate (Sutent) arm of the study did not have a significantly higher CNL vs the intermediate response or progressive disease groups.

Findings from a univariate Cox regression analysis showed that patients in CheckMate 214 with a higher CNL who received the doublet also had improved PFS. When patients were stratified into CNL-high (≥ 75th percentile) and CNL-low (< 25th percentile) subgroups, those who received the doublet in the CNL-high group experienced a median PFS of 16.99 months compared with 5.82 months in the CNL-low group.

In the JAVELIN Renal 101 cohort, investigators performed a transcriptomic analysis to identify pathways and immune cell populations associated with exceptional response in patients who received combination therapy. Patients with an exceptional response were found to have a higher expression of pathways associated with adaptive immunity, including B-cell receptor pathways. Patients with exceptional responses also had tumors that were highly infiltrated with plasma and memory B cells.

Investigators then examined the T-cell–inflamed gene expression profile, a mechanism that mediates immune response. Patients with an exceptional response to immunotherapy/VEGF inhibitor treatment had a significantly increased T-cell–inflamed signature compared with those who experienced progressive disease. Additionally, the plasma and memory B cells associated with exceptional responses were determined by investigators to be associated with TLS formation.

Patients with an exceptional response to doublet therapy in JAVELIN Renal 101 had higher scores of Meylan, Cabrita, and Xu TLS signatures compared with those who experienced an intermediate response. The same trend of higher scores of Meylan, Cabrita, and Xu TLS signatures was observed in patients with an exceptional response vs those who experienced disease progression. These TLS signatures were not favorably associated with exceptional response among patients who received sunitinib.

Additional findings showed that patients who experienced an exceptional response to doublet therapy and had a TLS-low signature upregulated metabolism-related pathways, including those related to peroxisome, xenobiotic metabolism, bile acid metabolism, adipogenesis, fatty acid metabolism, oxidative phosphorylation, cholesterol homeostasis, and heme metabolism.

“[These results] showed that these elements could be used as biomarkers in the future to help select the patients who would benefit the most from these therapies and to reduce toxicities and [unnecessary] treatment for those who do not benefit,” Saliby explained. “These findings could also help us think about potential therapeutic avenues. We are going to keep using immune checkpoint inhibitors, and we [will be able to] optimize patient responses to these [agents] by targeting mechanisms [such as] CNL and TLS.”

Notably, findings from a biomarker analysis of the phase 3 KEYNOTE-426 study (NCT02853331) of pembrolizumab (Keytruda) plus axitinib vs sunitinib in patients with treatment-naive advanced RCC also demonstrated an association between a higher T-cell–inflamed gene expression profile and response to treatment. Data from the analysis presented during the 2024 American Society of Clinical Oncology Annual Meeting showed that patients with an 18-gene T-cell–inflamed gene expression profile who received the combination achieved an overall response rate, PFS, and overall survival benefit compared with those who did not display this genetic profile.

“The most important next step is to validate [our] results in different cohorts to [ensure] that they are reproducible and not just findings we see in one cohort, which happens a lot in kidney cancer; that’s why we don’t have clear biomarkers yet,” Saliby said. “Ideally, we want to design a trial similar to the [phase 2] OPTIC RCC study [NCT05361720] that would be prospective and [allow us] to stratify patients depending on their initial biomarkers. Patients would then receive one combination or the other. If these [data] are validated, they would be important to our understanding of how we can create [agent] mechanisms and potentiate better immune environments for patients.”

Jammihal T, Saliby RM, Labaki C, et al. Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma. Nat Cancer. Published online January 9, 2025. doi:10.1038/s43018-024-00896-w

FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. Updated April 16, 2018. Accessed February 4, 2025. bit.ly/3WNh0fY

FDA approves avelumab plus axitinib for renal cell carcinoma. FDA. Updated May 15, 2019. Accessed February 4, 2025. bit.ly/4jZ08gD

Rini BI, Plimack ER, Stus V, et al. Biomarker analysis of the phase 3 KEYNOTE-426 study of pembrolizumab (P) plus axitinib (A) versus sunitinib (S) for advanced renal cell carcinoma (RCC). J Clin Oncol. 2024;42(suppl 16):4505. doi:10.1200/JCO.2024.42.16_suppl.4505

A retrospective study explored the genomic and transcriptomic mechanisms underlying exceptional responses to immunotherapy in renal cell carcinoma (RCC). Clonal neoantigen load (CNL) was linked to exceptional responses to PD-1/PD-L1 and CTLA-4 therapies, while tertiary lymphoid structure (TLS) formation was associated with responses to PD-1/PD-L1 and VEGF inhibitor combinations. The study highlighted the potential of CNL and TLS as biomarkers for predicting treatment efficacy and optimizing patient outcomes. Further validation in diverse cohorts is necessary to establish these findings as reliable biomarkers for RCC treatment.

Clonal neoantigen load was significantly associated with promising responses to PD-1/PD-L1 and CTLA-4 combination therapy in RCC.

Immunogenomic Properties Predict Exceptional Responses to Immune Checkpoint Inhibition in RCC

Putting an emphasis on immunohistochemistry (IHC) staining is top of mind as fam-trastuzumab deruxtecan-nxki (Enhertu, T-DXd) sits alongside tisotumab vedotin-tftv (Tivdak) as options in the second-line cervical cancer setting. Unlike the tissue factor–directed antibody-drug conjugate (ADC), the HER2-targeted ADC does not hold an all-comer indication and is only applicable for a select few patients. Notably, following the 2024 approval of tisotumab vedotin for patients with recurrent or metastatic cervical cancer who experienced disease progression on or after chemotherapy, version 1.2025 of the NCCN Clinical Practice Guidelines in Oncology adjusted the preferred regimen recommendation for the agent from category 2A to category 1.

“The landscape for gynecologic malignancies has been exploding, and it’s been very exciting [with] the advent of ADCs and [their] incorporation into standard therapies. What’s on the horizon is also [intriguing],” Ritu Salani, MD, MBA, a gynecologic oncologist and the director of the Division of Gynecologic Oncology at UCLA Health in Los Angeles, California, said in an interview with 

Salani and colleagues will shed light on the latest strategies, changes in the treatment of cervical cancer, and more at the 

 International Symposium on Ovarian Cancer and Other Gynecologic Malignancies, which she is cochairing.

“A challenge I’m looking forward to discussing with my colleagues is [therapeutic] sequencing in cancers, not just in cervical cancer but also in endometrial cancer, especially as immunotherapy has disrupted some of the earlier lines of therapy in a good way,” she noted. “We’ve seen improvements in survival, but we’re not curing all patients. Understanding which patients may benefit most from immunotherapy in the frontline vs second-line setting [and if] there [are] other combinations or agents that may be even more compelling to use in these settings are the most exciting areas.”

NCCN Updates Seem to Solidify Immunotherapy's Frontline Role

Although pembrolizumab (Keytruda) and atezolizumab (Tecentriq) are both listed in the NCCN guidelines as preferred regimens for use in combination with chemotherapy with or without bevacizumab (Avastin) in the first-line setting for cervical cancer, the pembrolizumab regimen is the only one holding an FDA approval.

“There have been 2 large studies that have looked at the role of checkpoint inhibitors in addition to chemotherapy for patients with metastatic or recurrent cervical cancer. Only the incorporation of pembrolizumab with chemotherapy with or without bevacizumab is FDA approved in the US—atezolizumab with bevacizumab and chemotherapy was also studied but is not on label in the US,” Salani explained. “But both studies [evaluating these regimens] showed a significant impact in both PFS and OS. Incorporation of [them for] select patients is critical, and it should be the standard.”

The combination of pembrolizumab plus chemotherapy with or without bevacizumab has been FDA approved since 2021, and the final OS analy- sis of the phase 3 trial that supported the approval, KEYNOTE-826 (NCT03635567), showed that patients with persistent, recurrent, or first-line metastatic cervical cancer (n = 617) had a meaningful improvement in OS with the combination vs chemotherapy with or without bevacizumab.4,5 The median OS was 26.4 months vs 16.8 months (HR, 0.63; 95% CI, 0.52-0.77), respectively.

 Additional data from the phase 3 BEATcc trial (NCT03556839) revealed that adding atezolizumab to bevacizumab and chemotherapy in the frontline yielded a high median OS.6 Interim analysis data from this trial showed that the median OS was 32.1 months (95% CI, 25.3-36.8) among those treated with the atezolizumab combination (n = 206) vs 22.8 months (95% CI, 20.3-28.0) with bevacizumab and chemotherapy alone (n = 204; HR, 0.68; 95% CI, 0.52-0.88; 

“Since those studies have been conducted, we had the advent of immunotherapy being incorporated into chemoradiation for patients [whom] you may consider to have high-risk locally advanced cervical cancer,” Salani said. “Therefore, some patients may already be experienced with check- point inhibitors by the time their cancer recurs. Understanding the role of checkpoint inhibitor therapy after checkpoint inhibitor therapy remains a needs gap for us because we have not encountered that yet. Whether we should use immunotherapy again, if it should be a different combination, or if we should avoid it is still something that’s unclear at this time.”

Following encouraging data showing that tisotumab vedotin yielded significantly improved efficacy vs chemotherapy in patients with recurrent or metastatic cervical cancer who received 1 or 2 prior systemic regimens, the ADC has become a standard of care.

 In the phase 3 innovaTV 301 trial (NCT04697628), patients who received tisotumab vedotin (n = 253) achieved a median overall survival (OS) of 11.5 months (95% CI, 9.8-14.9) vs 9.5 months (95% CI, 7.9-10.7) in the chemotherapy arm (n = 249; HR, 0.70; 95% CI, 0.54-0.89; 

 = .004) at a median follow-up of 10.8 months (95% CI, 10.3-11.6).

 The 12-month OS rates were 48.7% (95% CI, 41.0%-55.8%) vs 35.3% (95% CI, 28.0%-42.7%), respectively.

Patients also had a 33% lower risk of disease progression or death in the tisotumab vedotin arm vs the chemotherapy arm as the median progression-free survival (PFS) was 4.2 months (95% CI, 4.0-4.4) compared with 2.9 months (95% CI, 2.6-3.1), respectively (HR, 0.67; 95% CI, 0.54-0.82; 

 < .001). Furthermore, the confirmed objective response rate (ORR) was 17.8% (95% CI, 13.3%-23.1%) among patients treated with the ADC vs 5.2% (95% CI, 2.8%-8.8%) among those treated with chemotherapy (OR, 4.0; 95% CI, 2.1-7.6). As assessed by the investigator, the median duration of response (DOR) was 5.3 months (95% CI, 4.2-8.3) in the tisotumab vedotin arm compared with 5.7 months (95% CI, 2.8-not reached) in the chemotherapy arm. The most common grade 3 or higher adverse effects (AEs) experienced in the tisotumab vedotin arm vs the chemotherapy arm in innovaTV 301 were anemia (8.4% vs 27.6%, respectively), urinary tract infection (4.4% vs 7.1%), and neutropenia (3.6% vs 13.4%). Patients also experienced serious AEs during treatment (32.8% vs 39.3%), and fatal AEs occurred in 4 and 5 patients, respectively.

“Currently, tisotumab vedotin is the second- line therapy after patients have experienced recurrence on first-line platinum-based therapy with or without immunotherapy, and most patients will have received immunotherapy,” Salani said. “HER2 is an exciting target, [and] it’s not highly prevalent in cervical cancer, so if you find it, it is a good target—we’re talking about [IHC] 2+ or 3+ expression. Both tisotumab vedotin and T-DXd could be used in a patient, and how you sequence them may be based on access, patient understanding, and the expression rates because very few patients will be candidates for HER2-[targeted therapies] with cervical cancer.”

Data on T-DXd that supported the April 2024 pan-tumor accelerated approval of the ADC for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment showed that patients with cervical cancer (n = 10) achieved an ORR of 70.0% (95% CI, 34.8%-93.3%).

 This was the highest ORR recorded among the follow- ing groups of patients examined with colorectal (46.9%), bladder (37.0%), biliary tract (45.5%), non–small cell (52.9%), endometrial (56.3%), ovarian (66.7%), salivary gland (66.7%), and pancreatic (0.0%) cancers (

). Notably, the DOR range was 7.2+ to 25.0+ months in patients with cervical cancer, and the recommended T-DXd dose for this indication is 5.4 mg/kg given every 3 weeks.

“Sequencing continues to be an interesting challenge, and understanding which therapies may have the best response, but also the longest duration, is key. It makes good sense to use T-DXd in patients with HER2 3+ expression because we’re seeing provocative response rates and impressive durations of response [in this population and] it’s not typical to see that. [However,] tisotumab vedotin has an all-comers indication,” Salani noted.

Looking to the future, Salani added, “There are some exciting trials in the cervical cancer space that should be on everybody’s radar, particularly with TROP2 ADCs, which are being looked at in the second line for patients after receipt of platinum-based chemotherapy with immunotherapy whether it’s with radiation or with chemotherapy. Continuing to look at opportunities to improve the landscape is critical.”

One study showed that TROP2 was expressed in 98.5% of cervical cancer samples (n = 66/67), demonstrating the potential promise for targeting TROP2 in cervical cancer.

 TROP2-directed ADCs under investigation in this setting include sacituzumab govitecan-hziy (Trodelvy), which is being evaluated in those with recurrent or persistent disease in a phase 2 trial (NCT05838521).

FDA approves tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. April 29, 2024. Accessed February 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer

NCCN. Clinical Practice Guidelines in Oncology. Cervical cancer, version 2.2025. Accessed February 4, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf

International Symposium on Ovarian Cancer and Other Gynecologic Malignancies. Physicians’ Education Resource, LLC. Accessed February 4, 2025. https://www.gotoper.com/courses/international-symposium-on-ovarian-cancer-and-other-gynecologic-malignancies

FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. FDA. October 13, 2021. Accessed February 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-combination-first-line-treatment-cervical-cancer#:~:text=On%20October%2013,2021,%20the,by%20an%20FDA-approved%20test

Monk BJ, Colombo N, Tewari KS, et al; KEYNOTE-826 Investigators. First-line pembrolizumab + chemotherapy versus placebo + chemotherapy for persistent, recurrent, or metastatic cervical cancer: final overall survival results of KEYNOTE-826. 

. 2023;41(36):5505-5511. doi:10.1200/JCO.23.00914

Oaknin A, Gladieff L, Martínez-García J, et al; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. 

. 2024;403(10421):31-43. doi:10.1016/S0140-6736(23)02405-4

Vergote I, González-Martín A, Fujiwara K, et al; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. 

. 2024;391(1):44-55. doi:10.1056/NEJMoa2313811

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed February 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2

Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2025. Accessed February 4, 2025. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true

Mallmann MR, Tamir S, Alfter K, Ratiu D, Quaas A, Domroese CM. Expression of potential antibody-drug conjugate targets in cervical cancer. 

. 2024;16(9):1787. doi:10.3390/cancers16091787

A study of sacituzumab govitecan (IMMU-132) in patients with recurrent or persistent cervical cancer. ClinicalTrials.gov. Updated December 17, 2024. Accessed February 4, 2025. https://clinicaltrials.gov/study/NCT05838521

Recent advancements in cervical cancer treatment emphasize the role of antibody-drug conjugates (ADCs) and immunotherapy. Tisotumab vedotin has become a standard second-line therapy, showing improved efficacy over chemotherapy. Pembrolizumab, combined with chemotherapy, is FDA-approved for first-line treatment, demonstrating significant survival benefits. The potential of HER2-targeted therapies like T-DXd is being explored, although HER2 expression is rare in cervical cancer. Future research is focusing on TROP2-directed ADCs, which show promise due to high TROP2 expression in cervical cancer samples.

IHC staining is top of mind for the use of ADCs in cervical cancer management; however, the specific indications for each agent must be considered.

Second-Line Sequencing May Hinge on IHC Staining in Cervical Cancer

The treatment paradigm of relapsed/refractory (R/R) follicular lymphoma has undergone a drastic transformation in recent years with the FDA approval of lenalidomide (Revlimid) plus rituximab (Rituxan) offering a platform for investigators to build additional combination regimens in the second-line setting. 

In the third line of treatment and beyond, chimeric antigen receptor (CAR) T-cell agents such as axicabta- gene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi) have transformed the landscape by providing sustained disease control, offering patients multiple effective treatment options.

“What we’ve seen [with recent developments] are the number of options that patients with follicular lymphoma now have. So many of these options are not relying on chemotherapy; they’re relying on immunotherapy or other targeted mechanisms, and I believe that is going to be the way forward for follicular lymphoma,” Laurie H. Sehn, MD, MPH, said. “Many [new] options are moving forward with randomized trials
in the second-line setting, [as well as] the frontline setting. I
believe we will be replacing chemotherapy at some point and
these immunotherapy options are going to offer patients choices
in an earlier setting. It is going to be confusing for a while moving forward [and] there is not going to be 1 answer for every patient.”

OncologyLive was onsite at the 2024 American Society of Hematology
(ASH) Annual Meeting and Exposition to film a Peer Exchange that
featured commentary from experts in the field of follicular lymphoma. The
panelists provided their view on the impact of the data updates that were
shared during the meeting, weighed in on how these data will affect treatment options and therapeutic sequencing strategies, and looked ahead to the future of treatment for patients with R/R follicular lymphoma.

Lenalidomide Plus Rituximab Provides the Basis for Second-Line Therapy

For patients with high-risk, R/R follicular lymphoma, there is currently no definitive standard of care.

 The combination of lenalidomide and rituximab is an FDA-approved option; the regimen received approval for this patient population from the agency in May 2019, based on findings from the phase 3 AUGMENT (NCT01938001) and MAGNIFY (NCT01996865) studies.

 Since this approval, investigators have been evaluating the addition of other agents to lenalidomide and rituximab with the hope of achieving even greater efficacy for these patients.

One such study, the phase 3 inMIND trial (NCT04680052), was a double-blind, placebo-controlled, multicenter study that enrolled adult patients with grade I to IIIA follicular lymphoma or marginal zone lymphoma (MZL) who received at least 1 prior line of therapy, including an anti-CD20 monoclonal antibody.

Patients were randomly assigned 1:1 to receive tafasi- tamab-cxix (Monjuvi) in combination with lenalidomide and rituximab or placebo plus lenalidomide and rituximab. The primary end point was progression-free survival (PFS); overall survival (OS) and PET-complete response (CR) rate in the fluorodeoxy- glucose (FDG)-avid population represented key secondary end points.

At a median follow-up of 14.1 months, the median investigator-assessed PFS in the investigational arm (n=273) was 22.4 months (95% CI, 19.2-not evaluable [NE]) compared with 13.9 months (95% CI, 11.5-16.4) in the placebo arm (n=275; HR, 0.43; 95% CI, 0.32-0.58; 

<.0001). Among patients who were FDG-avid in the tafasitamab (n=251) and placebo (n=254) arms, the PET-CR rates were 49.4% (95% CI, 43.1%-55.8%) and 39.8% (95% CI, 33.7%- 46.1%), respectively (OR, 1.5; 95% CI, 1.04-2.13; nominal 

“This is the first time we’ve combined a CD19[- directed] monoclonal antibody with a CD20[-directed] monoclonal antibody; [these data] improve upon the standard that we’ve been using with lenalidomide and rituximab in the second-line setting for follicular lymphoma,” Cyrus M. Khan, MD, commented. “Any improvement that prolongs the duration of response [DOR] and delays [therapy] in the third line is great. Toxicity wise, it’s [tolerable]. [Additionally], we always add rituximab to anything we do in follicular lymphoma later and we never exactly know what the response will be for [a given] patient. In the case that there is a detriment where rituximab isn’t as efficacious, at least you’re also blocking CD19 and getting the benefit there.”

In the phase 1/2 EPCORE NHL-2 trial (NCT04663347), investigators combined lenalido- mide and rituximab with the CD20- and CD3-directed bispecific antibody epcoritamab-bysp (Epkinly) in patients with R/R, grade I to IIIA, stage II to IV, CD20-positive follicular lymphoma who received
at least 1 prior treatment including an anti-CD20 antibody.

Recent advancements in the treatment of relapsed/refractory follicular lymphoma have significantly expanded therapeutic options, particularly with the introduction of lenalidomide plus rituximab and CAR T-cell therapies. These developments emphasize a shift from traditional chemotherapy to immunotherapy and targeted treatments. The combination of lenalidomide and rituximab serves as a foundation for second-line therapy, while CAR T-cell agents like axi-cel, tisa-cel, and liso-cel offer promising outcomes in later lines. Ongoing trials and data updates continue to refine treatment strategies and improve patient outcomes.

OncologyLive was onsite at the 2024 ASH Annual Meeting to film a Peer Exchange featuring expert commentary on follicular lymphoma.

Vol. 26 No. 3 | Oncology Live®

CAR T-Cell Therapy for Solid Tumors: Leveraging Lessons From Hematologic Malignancies

Immunogenomic Properties Predict Exceptional Responses to Immune Checkpoint Inhibition in RCC

Second-Line Sequencing May Hinge on IHC Staining in Cervical Cancer

Chemotherapy-Free Combos Lead the Way in R/R Follicular Lymphoma

Ethical Considerations in the Conduct of Clinical Cancer Research Always a Timely Topic

Cardio-Oncology Investigations Begin to Uncover More Links Between CVD and Breast Cancer