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The decision to omit radiation therapy for patients with favorable characteristics is at the center of many studies seeking to evaluate which groups of patients could be eligible for therapy omission, such as older women with early-stage hormone receptor–positive, node-negative disease after breast-conserving surgery, according to Reshma Jagsi, MD, DPhil. Accordingly, it is important to keep in mind that advances in radiation therapy continue to occur, with data from several key trials and studies having been presented over the course of 2023.

Studies diving into regional nodal irradiation and disparities encompass those that are currently underway, of which Jagsi detailed new research findings in an interview with 

. Jagsi is the Lawrence W. Davis Professor and chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia.

Searching for Disparities and Ways to Counteract Them

Jagsi and fellow investigators examined cardiac radiation doses in a large cohort of patients with breast cancer, as previous research has not explored the implications of dose disparities or looked at cardiac radiation doses by race.

“When you take a deep breath in, you push your heart out of the way of the radiation beam—it’s the best way to get away from a normal tissue. It’s not hard to have someone hold their breath reproducibly during treatment and yet we now have evidence that the access to that simple, important advance is not equitable in our society,” Jagsi said. “This gives us ideas of ways that we can intervene at every level, no matter where we come in [during] the treatment continuum.”

In the study, when investigators generated laterality- and fractionation-specific models of mean heart dose among patients (n = 8750) who received whole breast therapy from 2012 to 2018 and generated patient- and facility-level models to estimate race-specific cardiac doses, they found that depending on laterality and fractionation, Asian and Black women received higher cardiac doses than White women. Compared with findings among White women, there was an estimated excess of up to 2.6 cardiac events and 1.3 deaths per 1000 Black women and 0.7 cardiac events and 0.3 deaths per 1000 Asian women as a result of cardiac dose disparities.

The study also demonstrated that when controlling for radiation technique, including deep inspiration breath hold, the dose disparity for Black women was reduced by 30%. However, among patients treated with conventional fractionation for left-sided disease, 14% of Black patients received deep inspiration breath hold compared with approximately 30% to 45% of Asian and White patients.

“African American patients are receiving care in centers that don’t have access to breath hold devices,” Jagsi explained. “If your hospital doesn’t buy you the equipment that you need [as a radiation oncologist,] that’s problematic; and if you’re serving an underserved community, and you face the challenge of being under-resourced that is a societal problem.”

An additional factor that may have influenced cardiac dose levels in the study was intensity-modulated radiotherapy (IMRT), which was associated with an increased cardiac dose and used in Black patients more often—70.1% of Black women received IMRT compared with 35.8% of Asian women and 42.1% of White women. Facility-level practice variation was also found to produce cardiac dose disparities.

Further, investigators of another study noted that shorter courses of radiation therapy may aid in reducing disparities as African American patients are 48% more likely to have radiation therapy omitted during treatment, 40% less likely to complete radiation therapy, and significantly more likely to experience radiation treatment delays than White patients.

 Level 1 evidence has also indicated that treatment with standard fractionation and hypofractionated regimens results in equivalent outcomes and adverse effect profiles. As overall treatment time with hypofractionation is reduced by 30% to 40%, acute toxicities are in turn reduced.

“We finally have a more efficient way of delivering radiation that creates less toxicity, and we’re less likely to use it in the patients we know are more likely to have acute toxicity and more likely to have financial toxicity. It’s shocking and it also gives us a little window into something that is entirely within the control of a treating radiation oncologist. Offering hypofractionated courses is something that we have direct control over and can help improve the equity of cancer care,” Jagsi said.

De-Escalation/Omission Approaches in Favorable Subgroups Requires Careful Examination

In addition to being mindful of disparities, omission of radiation in certain patient populations also is top of mind, with data from many studies presented throughout 2023 exploring the de-escalation as well as omission of radiation for patients with favorable characteristics. Jagsi noted that careful consideration of these recent data is warranted because meaningful advances in radiation treatment delivery have also occurred.

“PRIME II [ISRCTN95889329] is the best trial to point to because it was a randomized trial whose data showed there is a benefit from radiation treatment for pretty much any group of patients, even [those with] highly favorable select [characteristics]. But in some subgroups of patients, the risk of recurrence even without radiation is reasonably low enough that some women might want to choose to omit radiation.”

Ten-year outcomes of the phase 2 PRIME II trial revealed that local recurrence rates increased when radiation therapy was omitted vs given for patients 65 years or older with node-negative, hormone receptor–positive, T1 or T2 primary breast cancer who received breast-conserving surgery with clear excision margins and adjuvant endocrine therapy.

 However, no significant impact was observed regarding breast cancer–specific survival or overall survival (OS) rates.

“We now would feel comfortable offering patients, if they’re 65 and older, the option of omitting radiation treatment with the caveat that the risk of recurrence at 10 years is approximately 10% without radiation and only 1% or 2% with radiation, even in that highly selected subgroup of patients,” Jagsi explained.

The cumulative incidence of local recurrence among patients who did not receive radiotherapy (n = 668) was 9.5% (95% CI, 6.8%-12.3%) compared with 0.9% (95% CI, 0.1%-1.7%) for those who did receive radiotherapy (n = 658). Ten-year distant recurrence–free survival rates were 1.6% (95% CI, 0.4%-2.8%) vs 3.0% (95% CI, 1.4%-4.5%), respectively, and the breast cancer–specific survival rate was 97.4% (95% CI, 96.0%-98.8%) for patients who did not receive radiotherapy compared with 97.9% (95% CI, 96.5%-99.2%) for those who did. The 10-year OS rates were 80.8% (95% CI, 77.2%-84.3%) vs 80.7% (95% CI, 76.9%-84.3%), respectively (

“Many patients can also avail themselves of the advances of ultrahypofractionated whole breast radiation, which has somewhat shorter follow-up, as well as accelerated partial breast irradiation, which has good long-term follow-up. We can probably get treatment done in 5 fractions [with either approach],” Jagsi noted.

In addition to PRIME II, data from the IDEA study (NCT02400190) revealed that the 5-year OS and breast cancer–specific survival rates were 100% among postmenopausal patients (n = 186) who omitted radiotherapy treatment and received at least 5 years of endocrine therapy.

 Patients who were prospectively enrolled were 50 to 69 years old and had estrogen receptor–positive, progesterone receptor–positive, HER2-negative, pT1N0 unifocal invasive breast cancer with margins of 2 mm or greater after breast-conserving surgery and an Oncotype DX 21–gene recurrence score of 18 or less. Further, the 5-year rate of freedom from any recurrence was 99% (95% CI, 96%-100%).

Study authors, led by Jagsi herself, noted that due to the low risk of recurrence observed under these circumstances in IDEA, long-term follow-up of the study in conjunction with additional studies will aid in determining whether initial radiotherapy treatment is avoidable in a broader group of patients than guidelines currently recommend.

“But we have to be very careful when presenting these results to patients to make sure they understand both the risks and the benefits of radiation treatment,” Jagsi noted on study findings on the omission of radiotherapy. “Radiation [oncology] is the only specialty that has a ‘danger: radiation’ sign that comes immediately to mind when you think about the treatment modality that we use. Patients are scared of radiation, and we don’t want patients who don’t fall into these favorable groups where there’s clearly a substantial benefit from radiation to be scared about radiation. Nor do we want patients who are in patient populations where there is some benefit from radiation treatment to dismiss that benefit without understanding the current experience of radiation treatment.”

A portion of radiation treatment that has remained under debate, according to Jagsi, includes regional nodal irradiation, which encompasses areas that are typically left undissected. As many patients receive sentinel lymph node biopsy alone, levels 1 and 2 of the axilla as well as level 3 (the infraclavicular region), the supraclavicular region, and the internal mammary nodal region—may be included.

“These are areas where there has been long-standing debate over whether our treatment fields should encompass those areas—there is not zero toxicity from encompassing those regions; there is a slight increase, for example, in the rates of radiation pneumonitis or lymphedema that come from including those regional nodal basins. However, when we treat with radiation, we are not only trying to prevent local regional recurrence, which of course can be morbid, but also the persistence of an isolated reservoir of disease that might remain after surgery and systemic therapy that could serve as a source for distant metastases. Regional nodal irradiation may be particularly important in improving overall disease control because of that latter mechanism,” Jagsi said.

Pointing to a landmark publication from November 2023, Jagsi noted that a metanalysis from the Early Breast Cancer Trialists’ Collaborative Group examining 8 modern trials from 1989 to 2008 found that regional nodal irradiation significantly reduced recurrence in 12,167 patients (rate ratio [RR], 0.88; 95% CI, 0.81-0.95; 

). Mortality was also significantly reduced with radiotherapy (RR, 0.87; 95% CI, 0.80-0.94; 

 = .0010) with no significant effect on non–breast cancer mortality observed (RR, 0.97; 0.84-1.11;

 = .63); this resulted in a significant reduction in all-cause mortality (RR, 0.90; 0.84-0.96; 

Although regional nodal radiotherapy significantly reduced the rates of breast cancer mortality and all-cause mortality in trials completed following the 1980s, it did not in those prior to the 1980s which could be a result of radiotherapy improvements, according to the study authors.

“Data from studies [such as this one] emphasized the potential for long-term gains from relatively minor adaptations of our radiation treatment fields,” Jagsi said. “We’ve learned a lot about patient selection [and] how to administer treatment more efficiently with lower doses to normal tissues. That’s a key takeaway from this regional nodal irradiation meta-analysis—we have made truly meaningful advances, and we have seen transformation of the most worrisome potential complications of radiation therapy as a result. 2023 was quite a year for radiation oncology and for breast cancer [with so many key analyses and trial data published].”

Unpacking Burgeoning Advances in Radiation Oncology at The Miami Breast Cancer Conference

Discussions centered around disparities, the new American Society for Radiation Oncology (ASTRO) guidelines, and more will be among those of interest at the Miami Breast Cancer Conference

 “I am excited about this year’s Miami Breast Cancer Conference because it’s the first time that radiation oncology has had its own full track,” Jagsi, who is cochairing the conference, said. Topics such as “Radiation Therapy for Oligometastases” and “Considerations in Concurrent Use of Radiation Therapy and Systemic Agents” will also be highlighted at the conference.

The new ASTRO guidelines that now recommend partial breast rather than whole breast irradiation for patients with favorable characteristics and early-stage node-negative invasive disease or ductal carcinoma in situ will also be discussed.

 The guidelines, which were based on a systemic literature and comparative effectiveness evidence review, mark the first ASTRO recommendations for partial breast radiation since 2017. The review conducted by the Agency for Healthcare Research and Quality found comparable outcomes for partial breast and whole breast radiation.

“The wonderful thing about the Miami Breast meeting is that the world experts who led these trials and initiatives [will present on them],” Jagsi said. “We’ll have Eleftherios P. Mamounas, MD, MPH, and Julia R. White, MD, speaking about the landmark phase 3 NSABP B-51/RTOG 1304 trial [NCT01872975] that looked at whether we can get away without regional nodal irradiation in patients who had neoadjuvant chemotherapy and a pathologic complete response. We’re going to have a chance to hear from the experts who led that trial, their perspectives, and how the findings should be applied in practice.”

The trial data revealed that omitting adjuvant regional nodal irradiation treatment did not increase the risk of disease recurrence or death 5 years after surgery in select patients. Patients with biopsy-proven axillary node involvement whose axillary nodes convert to ypN0 after neoadjuvant chemotherapy did not experience improvements in 5-year invasive breast cancer recurrence–free interval or OS following treatment with chest wall plus regional nodal irradiation after mastectomy or whole breast plus regional nodal irradiation after lumpectomy.

Regarding the trial’s primary end point of invasive breast cancer recurrence–free interval, there were 59 events in those who did not receive regional nodal irradiation (n = 784) and 50 events in those who did receive regional nodal irradiation (n = 772; HR, 0.88; 95% CI, 0.60-1.29; 

Additionally, Jagsi noted she is “going to present a series of studies conducted whose findings have demonstrated that not only are there unacceptable disparities in mortality and financial toxicity, but also in pain experiences and acute toxicities [for patients when] receiving radiation treatment. Not only are there disparities in those acute toxicities but there are disparities in providers’ recognition of those toxicities, which in part might explain why we’re seeing uncontrolled toxicities that are more frequent in our patients of color.”

Chapman CH, Jagsi R, Griffith KA, et al. Mediators of racial disparities in heart dose among whole breast radiotherapy patients. 

. 2022;114(12):1646-1655. doi:10.1093/jnci/djac120

McClelland S 3rd, Harris EE, Spratt DE, et al. Navigator-assisted hypofractionation (NAVAH) to address radiation therapy access disparities facing African-Americans with breast cancer. 

. 2022;27(3):583-588. doi:10.5603/RPOR.a2022.0064

Kunkler IH, Williams LJ, Jack WJL, Cameron DA, Dixon JM. Breast-conserving surgery with or without irradiation in early breast cancer. 

. 2023;388(7):585-594. doi:10.1056/NEJMoa2207586

Jagsi R, Griffith KA, Harris EE, et al. Omission of radiotherapy after breast-conserving surgery for women with breast cancer with low clinical and genomic risk: 5-year outcomes of IDEA. 

. 2024;42(4):390-398. doi:10.1200/JCO.23.02270

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Radiotherapy to regional nodes in early breast cancer: an individual patient data meta-analysis of 14 324 women in 16 trials. 

. 2023;402(10416):1991-2003. doi:10.1016/S0140-6736(23)01082-6

41st Annual Miami Breast Cancer Conference Agenda. Physicians’ Education Resource®. Accessed January 25, 2024. bit.ly/3vOyhel

ASTRO issues patient-centered clinical guideline on partial breast irradiation for early-stage invasive breast cancer and DCIS. News release. ASTRO. November 15, 2023. Accessed January 25, 2024. bit.ly/48DdQ2t

Mamounas E, Bandos H, White J, et al. Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS02-07.

Articles

The article discusses the ongoing research into the potential omission of radiation therapy for certain groups of patients, such as older women with early-stage hormone receptor–positive, node-negative disease after breast-conserving surgery. It also highlights the disparities in cardiac radiation doses among different racial groups and the potential benefits of de-escalation or omission of radiation for patients with favorable characteristics.

Investigating when radiation therapy can be appropriately omitted and striving to uncover disparities are areas of focus in the field of radiation oncology.

Jagsi Holds a Magnifying Glass to Radiation Oncology: Uncovering Key Disparities  and When to Omit Radiation  in Breast Cancer

Immunotherapy for patients with advanced MCC

In the treatment of patients with unresectable or metastatic Merkel cell carcinoma (MCC), immune checkpoint inhibitors (ICIs) against PD-1 and PD-L1 have completely supplanted chemotherapy due to their superior activity and tolerability. This has spurred investigations testing the reaches of ICI therapy in the adjuvant and metastatic settings. Treatment with an anti–PD-(L)1 antibody induces a response in approximately 40% to 60% of patients with metastatic MCC, according to data from 3 key studies, especially when given as first-line therapy. Approximately one-third to half of the responses are complete responses, which are very durable, with the majority of responses still ongoing at 1 year of follow-up (

 As in other cancer populations, the drugs are tolerable, and approximately less than 15% of patients discontinued therapy due to adverse effects.

Avelumab (Bavencio), an anti–PD-L1 antibody, was approved by the FDA for MCC in 2017 as the drug’s first indication. In the phase 2 JAVELIN Merkel 200 trial (NCT02155647), patients with chemotherapy-refractory MCC who received avelumab experienced rapid and robust responses within a brief period of days to weeks. Approximately 25% of individuals had already met the criteria for an objective response by the first on-study tumor assessment, which was performed at week 7. The overall survival (OS) rate among patients with a response at week 7 (n = 20) at 18 months was 90% (95% CI, 65.6%-97.4%) vs 26.2% (95% CI, 15.7%-37.8%) among patients who did not have a response at week 7 (n = 62). After adjustment for age, presence/absence of visceral metastases, and number of previous therapies, patients who achieved a response at any point on the study had a 95% reduced risk of death compared with patients who did not respond (HR, 0.052; 95% CI, 0.018- 0.152).

 These data on the interplay between response and long-term survival underscore how difficult it is to counsel newly diagnosed patients with stage IV MCC about prognosis prior to the initiation of treatment, as their response to PD-(L)1-directed therapy is the key factor in predicting long-term survival.

The FDA approval of avelumab for the treatment of patients with MCC was followed by approvals for pembrolizumab (Keytruda) in 2018 and retifanlimab- dlwr (Zynyz) in 2023. Pembrolizumab and retifanlimab are monoclonal antibodies against PD-1. MCC is the first indication for retifanlimab, and the approval was based on findings from the phase 2 POD1UM-201 study (NCT03599713) of 65 patients with MCC who had not had prior systemic therapy for advanced disease. The overall response rate (ORR) was 52% (95% CI, 40%-65%). In the safety population (n = 105), no new safety signals were identified. Retifanlimab is given at a flat dose of 500 mg intravenously (IV) every 4 weeks.

Despite extensive analysis of biomarkers, such as PD-L1, tumor mutational burden, and viral status, no biomarker has been shown to be a reliable and significant predictor of response. Because responses are frequent, even among those without favorable features, pretreatment testing is not performed in standard practice prior to the initiation of therapy. Recently, the ratio of a subset of intratumoral myeloid cells (CD163+, CD14+, S100A8+) to intratumoral CD8 cells using a multiplex immunohistochemistry panel has been proposed as a biomarker of unfavorable response, but more data are necessary to determine its clinical validity.

Exploring ICI Utility in the Adjuvant Setting

Currently there are no published data or guidelines to support the use of adjuvant immunotherapy in patients with MCC who have been definitively treated with surgery and/or radiation therapy. In melanoma, studies have demonstrated the efficacy and safety of ICIs in the adjuvant setting, leading to the FDA approvals of pembrolizumab and nivolumab (Opdivo) for fully resected stage IIB to III melanoma. Given that response rates to PD-(L)1 inhibitors are generally higher in studies of patients with metastatic MCC compared with patients with metastatic melanoma, and that the rates of recurrence are substantially higher in MCC, it is a worthwhile venture to test ICIs in the adjuvant setting for patients with definitively treated MCC.

The phase 2 ADMEC-O study (NCT02196961) assessed the effect of adjuvant PD-1 inhibition on disease-free survival (DFS) in patients with stage I to IV MCC who had been adequately treated by surgical resection or curative irradiation. A total of 179 patients at 20 centers in Germany and the Netherlands were randomly assigned 2:1 to receive adjuvant nivolumab 480 mg IV every 4 weeks for 1 year (n = 118) or observation (n = 61). At a median follow-up of 24.3 months (IQR, 19.2-33.4), the DFS rate at 1 year in the nivolumab group was 85% vs 77% in the observation group for an absolute risk reduction of 9% (95% CI, 2%-20%). The HR was 0.58 (95% CI, 0.30-1.12); however, the authors considered this to be an exploratory study. More than one-third of the study population had stage I or II disease, and the number of events observed was fewer than anticipated at the 12-month landmark. Another feature of the ADMEC-O study that limits the interpretation of its findings is that adjuvant radiation therapy was more common in the observation group vs the nivolumab-treated group (74% vs 50%), which may have narrowed the difference in DFS between the groups. Median OS data are immature and have not been reported to date.

Two US multisite randomized controlled studies for adjuvant therapy completed accrual within the past year. The phase 3 STAMP study (NCT03712605) is an ECOG trial in which patients were randomly assigned to adjuvant pembrolizumab 200 mg IV every 3 weeks for 1 year vs standard observation. The study enrolled its goal of 280 patients, and data have not been reported yet. The other trial, the phase 3 ADAM study (NCT03271372), randomly assigned 100 patients with stage III MCC to treatment with avelumab vs placebo in double-blind fashion. On this study, avelumab is given for a total of 2 years, including maintenance dosing every 4 months during the second year, which is a unique feature of this trial. The results from these 2 studies and the final analysis of the ADMEC-O trial are highly anticipated, as the results are potentially practice changing.

In the metastatic setting, when anti–PD-(L)1 therapy fails to control the patient’s disease, there are very few options besides chemotherapy or a clinical trial. Given the responsiveness to monotherapy in metastatic MCC, it was hypothesized that dual checkpoint blockade including CTLA-4 inhibition, much like in melanoma, would be beneficial to patients with MCC refractory to anti–PD-1 therapy. In a multicenter retrospective study of the prospective multicenter skin cancer registry ADOREG, 14 patients with unresectable MCC who had disease refractory to avelumab were treated with ipilimumab (Yervoy) plus nivolumab as subsequent therapy (second or later line). Seven patients responded to ipilimumab plus nivolumab for an ORR of 50%. At 12 months and 24 months, the progression-free survival rates were 42.9% and 26.8%, respectively. The OS rate at 36 months was 64.3%.

Ipilimumab plus nivolumab was further explored in a phase 2 trial (NCT03071406) using stereotactic body radiation therapy (SBRT) as an adjunct to dual ICI. All patients, including previously treated patients and ICI-naive patients, were treated with low-dose ipilimumab (1 mg/kg IV every 6 weeks) and nivolumab (240 mg IV every 2 weeks). Fifty patients with MCC were randomly assigned to receive ipilimumab plus nivolumab (n = 25) vs ipilimumab plus nivolumab in combination with SBRT (n = 25) to 1 metastatic site. The primary intervention, the SBRT, did not show any improvement in response rate. In fact, the response rate was slightly lower. In a secondary subset analysis of patients who had received prior treatment with ICI (n = 26), the response rate was 31% (95% CI, 15%-52%). On the other hand, all patients who had not received an ICI (25/25) achieved an objective response.

This surprisingly favorable finding led to further interest in dual checkpoint blockade as a first-line treatment. Data from the phase 1/2 CheckMate 358 study (NCT02488759) were presented at the 2023 American Society of Clinical Oncology Annual Meeting. In this study, ICI-naive patients with recurrent or metastatic MCC were assigned to an arm by their treating physician in an open-label fashion, either nivolumab monotherapy or ipilimumab plus nivolumab. In the nivolumab arm (n = 25), 15 patients responded, and in the ipilimumab plus nivolumab arm (n = 43), 25 patients responded, which constituted an ORR of 60.0% (95% CI, 38.7%-78.9%) vs 58.1% (95% CI, 42.1%-73.0%), respectively. The results between the arms should not be compared directly because patients were not randomly assigned. It can be assumed that the treating physicians might have assigned patients with a heavier tumor burden or more visceral disease to the dual checkpoint arm more often than those with a limited tumor burden.

Given the large difference in response rates between the ICI-naive subset in the SBRT study by Kim, et al and the CheckMate 358 study population, there are conflicting data about exactly how effective dual immunotherapy checkpoint combination therapy is for first-line patients with untreated MCC. Despite these differences, a plurality of ICI-naive patients in both prospective clinical trials responded to ipilimumab plus nivolumab. However, the activity against the disease must be balanced with the toxicity of the regimen, especially in the firstline setting wherein monotherapy performs well with less toxicity. In the SBRT study, 16% of patients of patients discontinued therapy due to treatment-related toxicity.

 Similarly, in the CheckMate 358 study, 25.6% of patients discontinued therapy.

 Due to toxicity concerns, ipilimumab plus nivolumab has not been widely adopted as a first-line regimen for metastatic MCC and remains an off-label treatment. However, ipilimumab plus nivolumab remains an appealing alternative to chemotherapy as a salvage regimen for patients who have progressive disease despite treatment with a PD-(L)1 inhibitor, and it is listed in the NCCN guidelines as consideration for salvage therapy.

The high rate and durability of responses to checkpoint blockade therapy in MCC led to approvals for 3 drugs based on single-arm studies in metastatic disease. High-quality clinical trial data in the adjuvant setting are being collected now and will be extremely important for the advancement of the field. In the salvage setting, additional clinical investigations are needed to define the optimal population for treatment with ipilimumab plus nivolumab, and explorations of novel immune and molecular targets are urgently needed.

 is codirector of the Merkel Cell Carcinoma Center of Excellence and a physician at Dana-Farber Cancer Institute as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

 is a physician at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School.

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Kim S, Wuthrick E, Blakaj D, et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. 

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In the treatment of unresectable or metastatic Merkel cell carcinoma, immune checkpoint inhibitors have activity and tolerability. 

Extending the Frontiers of Checkpoint Inhibition in Merkel Cell Carcinoma

Although newer agents such as androgen receptor (AR) inhibitors have prolonged survival for patients with metastatic castration-resistant prostate cancer (mCRPC) and gained FDA approval, there remains an unmet need for additional effective therapies in the space, as cross-resistance between treatments can occur and mCRPC remains incurable.

 Investigators are hoping that positive early data from the phase 1/2 APEX-01 trial (NCT04662580) will lead to the eventual addition of the novel antibody-drug conjugate (ADC) ARX517 to the arsenal of agents available for the treatment of patients with mCRPC.

“It’s a very exciting time in mCRPC, [as] there are many novel compounds in [preclinical] study and clinical development,” John Shen, MD, a medical oncologist at University of California, Los Angeles Health, said in an interview with 

. “[ARX517] has shown encouraging early activity, but we’d love to treat more patients to learn more about its true efficacy. To do that, we’re happy to evaluate more patients for the study.”

ARX517 is a prostate-specific membrane antigen (PSMA)-targeted ADC that has been designed to address the stability issues observed with other PSMA-targeted ADCs, which can lead to severe toxicities due to premature release and off-target delivery of the cytotoxic payload. To increase stability, the developers of ARX517 included a non–cell permeable payload, a noncleavable PEG linker, and unique oxime conjugation chemistry via a genetically encoded and biosynthetically incorporated synthetic amino acid.

In July 2023, the FDA granted fast track designation to ARX517 for the treatment of patients with mCRPC following progression on an AR pathway inhibitor.

APEX-01 is an open-label, multicenter, first-in-human trial of ARX517 as monotherapy and in combination with enzalutamide (Xtandi) in patients with mCRPC. The study aims to enroll approximately 222 adult patients with mCRPC who are resistant or refractory to prior standard therapies.

To be eligible for enrollment, patients must have castration-resistant disease with serum testosterone levels of 50 ng/dL or lower at screening. Patients who have not undergone an orchiectomy must currently be receiving treatment with either a luteinizing hormone-releasing hormone agonist or antagonist and must consent to maintain this therapy throughout the study treatment. Additionally, patients must have adequate blood counts and have undergone at least 2 FDA-approved treatments for mCRPC, including at least 1 second-generation AR inhibitor.

Patients will receive intravenous ARX517 every 3 or 4 weeks as monotherapy or combination therapy with enzalutamide in the phase 1 portion of the trial. Phase 1a (the dose-escalation portion) and phase 1b (the dose-expansion portion) will identify the maximum tolerated dose (MTD) and/or the recommended phase 2 doses (RP2Ds). During the phase 2 portion, patients will be randomly assigned to receive ARX517 at the RP2D(s) or the comparator arm consisting of an immune checkpoint inhibitor to be determined after a review of the phase 1 data.

The primary end point is the incidence of adverse effects (AEs). Secondary end points include the area under the serum concentration-time curve for ARX517 and enzalutamide, maximum serum concentration for both agents, trough concentration for both agents, the incidence of antidrug antibodies against ARX517, overall survival, changes in serum prostate-specific antigen (PSA) levels, and progression-free survival. Exploratory end points include biomarker evaluation and PSMA expression.

During the European Society for Medical Oncology (ESMO) Congress 2023, which took place from October 20 to 24 in Madrid, Spain, investigators presented 2 abstracts that demonstrated strong preclinical findings with ARX517.

Findings from Tagawa et al showed that ARX517 displayed a long terminal half-life of approximately 6 to 10 days at doses of at least 1.4 mg/kg, leading to maximal agent exposure. Additionally, ARX517 demonstrated strong stability in circulation. Investigators noted the agent displayed virtually overlapping total antibody and ADC pharmacokinetic concentration-time curves across examined doses, and this was the first anti-PSMA ADC to display strong stability in circulation. They explained that the technology utilized by the agent has the potential to be used in the development of the next generation of ADCs to improve efficacy and minimize toxicity.

“The most important takeaway is the stable conjugation of this compound,” Shen said. “Several earlier attempts to target PSMA with prior ADCs were limited and didn’t progress into further clinical development due to early toxicity.”

Additional data was presented at ESMO regarding the preclinical antitumor activity of ARX517 in enzalutamide-resistant and enzalutamide-sensitive tumor models, as well as in a nonhuman primate model.

 In the enzalutamide-sensitive model, treatment with ARX517 at doses of 1 mg/kg and 3 mg/kg led to a reduction in tumor volume of 28% and 66%, respectively, compared with 42% for enzalutamide at 10 mg/kg. In the enzalutamide-resistant model, the tumor volume reduction rates for ARX517 at 1 mg/kg and 3 mg/kg were 37% and 79%, respectively, vs 14% with enzalutamide at 10 mg/kg.

Early Findings From APEX-01 Reveal Preliminary Efficacy, Tolerability

Building on the preclinical data presented during ESMO, Shen also shared preliminary findings from APEX-01 in a poster presentation. At the September 5, 2023, data cutoff, a total of 65 patients were enrolled across different cohorts. Patients received ARX517 at doses of 0.32 mg/kg (cohort 1; n = 1), 0.64 mg/kg (cohort 2; n = 3), 1.07 mg/kg (cohort 3; n = 3), 1.4 mg/kg (cohort 4; n = 21), 1.7 mg/kg (cohort 5; n = 5), 2.0 mg/kg (cohort 6; n = 20), 2.4 mg/kg (cohort 7; n = 6), and 2.88 mg/kg (cohort 8; n = 6).

At baseline, the median age across cohorts was 68.0 years (range, 50-100), the median PSA level was 47.0 μg/L (range, 1-3845), and the median number of prior AR inhibitor treatments was 2 (range, 1-5). Most patients received a prior taxane (66%), did not receive a prior immunotherapy (54%), did not receive a prior PSMA-targeted radionuclide therapy (TRT; 83%), and had an ECOG performance status of 1 (59%). Regarding second-generation AR inhibitors, patients were previously treated with abiraterone acetate (Zytiga; 75%), enzalutamide (69%), and both abiraterone acetate and enzalutamide (48%).

Findings from the study showed that deep PSA reductions were present with increasing doses of ARX517; among patients treated in cohorts 6 through 8 (n = 23), at what investigations deemed to be putative doses, PSA reductions of at least 30% (PSA30), 50% (PSA50), and 90% (PSA90) occurred at rates of 61%, 52%, and 26%, respectively. Comparatively, patients treated in cohorts 1 through 3 (n = 7) experienced PSA30, PSA50, and PSA90 rates of 29%, 0%, and 0%, respectively.

Additionally, 81% of evaluable patients given putative doses (n = 21) experienced reductions of at least 50% in circulating tumor DNA at a rate of 81%. Among patients with evaluable target lesions at baseline (n = 9), target lesion reduction occurred at a rate of 56% in 5 patients, including 2 confirmed responses per RECIST 1.1 criteria. Notably, PSA reductions of 50% or greater were achieved in patients who underwent prior PSMA-TRT and received a dose of at least 2 mg/kg (n = 6) at a rate of 50%.

“Deep PSA reductions have been seen with increasing ARX517 doses,” Shen said. “This included patients who had received prior PSMA-[TRT], and we’re still seeing significant PSA reductions in several of those patients.”

In terms of safety, patients in all cohorts experienced any-grade treatment-related AEs (TRAEs) at a rate of 74% and grade 3 TRAEs at a rate of 9%. Two patients experienced AEs leading to treatment discontinuation. No patients experienced serious AEs or grade 4/5 AEs. Notably, no dose-limiting toxicities were reported.

Treatment-related decreased lymphocyte count (5%), decreased platelet count (3%), and left ventricular dysfunction (2%) were reported sparingly. Common grade 1 or 2 TRAEs across dose levels included dry mouth (28%), dry eye (22%), fatigue (20%), and diarrhea (15%).

Study authors concluded that ARX517 monotherapy demonstrated a favorable safety profile with early efficacy, absent of PSMA imaging selection, among patients with mCRPC who experienced disease progression on multiple FDA-approved treatments. They highlighted that an expansion of cohort 8 and an escalation into the next higher dose (cohort 9) are planned.

“We’re continuing to dose escalate and learn more about this compound,” Shen said. “However, the stable conjugation of this ADC is the most encouraging feature. In terms of efficacy, we love seeing PSA50s and PSA90s, but ultimately, we’d like to see how long patients can sustain those for in a heavily pretreated patient population.”

Shen noted that an additional 40 patients have been enrolled in APEX-01 in recent months and that additional data will be read out at a future medical meeting. “[ARX517] could become, in some ways, a replacement for taxane chemotherapy,” Shen said in conclusion. “Of course, we don’t know that, and we need to study that question. However, I could see this as a first-line mCRPC treatment option eventually. This is a very early look at the data, and it’s encouraging to see that it has demonstrated safety and tolerability. But we have not yet reached the MTD [or] the RP2D. We’re continuing to expand into higher cohorts and dose escalation.”

Hatano K, Nonomura N. Systemic therapies for metastatic castration-resistant prostate cancer: an updated review. 

. 2023;41(4):769-784. doi:10.5534/wjmh.220200

Tagawa ST, Shen J, Skidmore L, et al. ARX517: a next generation anti-PSMA antibody drug conjugate (ADC) demonstrates notable stability and pharmacokinetic (PK) profile in the ARX517 phase I clinical trial (APEX-01). 

. 2023;34(suppl 2):S990. doi:10.1016/j.annonc.2023.09.2776

FDA awards fast track designation to ARX517 for metastatic castration-resistant prostate cancer. News release. FDA. July 19, 2023. Accessed November 20, 2023. bit.ly/3MWljka

ARX517 as monotherapy and in combination regimens in subjects with metastatic castration-resistant prostate cancer (ARX517). ClinicalTrials.gov. Updated November 22, 2023. Accessed November 20, 2023. https://clinicaltrials.gov/study/NCT04662580

Shen J, Pachynski R, Nordquist L, et al. APEX-01: first-in-human phase I/II study of ARX517 an anti- prostate-specific membrane antigen (PSMA) antibody-drug conjugate (ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). 

. 2023;34(suppl 2):S974-S975. doi:10.1016/j.annonc.2023.09.2752

Zhang S, Mills D, Kim JY, et al. Evaluation of ARX517: a next-generation anti-PSMA antibody drug conjugate for prostate cancer treatment, in preclinical enzalutamide-resistant and enzalutamide-sensitive pharmacology models and in toxicology models. 

. 2023;34(suppl 2):S199. doi:10.1016/j.annonc.2023.09.1543

John Shen, MD, discusses the phase 1/2 APEX-01 trial of ARX517 in metastatic castration-resistant prostate cancer.

APEX-01 Looks to Add First PSMA-Directed ADC to Treatment Paradigm in mCRPC

As investigators continue to refine and carve out a role for targeted therapies in the treatment paradigm across tumor types, preferentially expressed antigen in melanoma (PRAME) has emerged as an intriguing treatment target in multiple solid tumors. 

PRAME encodes the HLA-A24 antigen and is a member of the cancer testis antigen family of genes that can act as an oncogene or a tumor suppressor gene in multiple cancer types; high expression of PRAME is observed in 88% of primary and 95% of metastatic melanoma tissues. PRAME expression is regulated by SOX17, MZF1, miR-211, and miR-421, and overexpression affects several cellular processes via downstream regulation of targets such as p21, p53, RAR, TRAIL, S100A4, and HSP27.

PRAME is not present in healthy tissue aside from the testes and limited expression in the ovaries, adrenals, and endometrium. Preclinical findings have shown that the antigen is key in the immunotherapy response and thus it has been identified as an attractive target for the development of these agents.

“PRAME is attractive as a pan-tumor target due to its overexpression in multiple solid tumors,” Omid Hamid, MD, director of immuno-oncology and the codirector of the Melanoma Program at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, in Los Angeles, California, said in an interview with OncologyLive. “High PRAME levels are associated with poor prognosis. It’s interesting that we’ve found this and have been able to target PRAME now in a way that we can evaluate PRAME-targeted therapies that are showing some promise in multiple solid tumors. Melanoma has the lead indication, [but] PRAME is overexpressed in a whole host of solid tumors, [such as] ocular melanoma, non–small cell lung cancer [NSCLC], serous ovarian cancer, endometrial cancer, and synovial sarcoma. You can develop a therapeutic that can be the backbone or combinatorial [partner] that works for multiple solid tumors.” 

PRAME-Directed Agents Display Preliminary Efficacy in Multiple Solid Tumor Types 

One approach that has displayed promise in effectively targeting PRAME-expressing solid tumors is the use of T-cell receptor-redirecting agents. During the European Society for Medical Oncology Congress 2022, investigators presented findings from the first-in-human phase 1/2 study (NCT04262466) of the novel bispecific protein IMC-F106C, which targets HLA-A2–presented peptide from PRAME, in patients with advanced solid tumors who were positive for HLA-A*02:01.

 The primary end point was determining the maximum tolerated dose (MTD). 

“IMC-F106C [contains] an immune-mobilizing monoclonal T-cell receptor on a platform similar to tebentafusp-tebn [Kimmtrak],” Hamid explained. “One side targets CD3, which brings the T cells in, and the other side targets PRAME like tebentafusp targets Gp-100. It brings T cells into PRAMEpositive tumors.” 

Findings from the study demonstrated that efficacy- evaluable patients (n = 31) experienced an overall response rate (ORR) of 22.6%, all of which were partial responses (PRs); 2 PRs were ongoing for at least 7 months. Patients with serous ovarian cancer (n = 2/4), cutaneous melanoma (n = 2/6), and tebentafusp-naive uveal melanoma (n = 3/6) experienced PRs. Notably, patients in the efficacy population were heavily pretreated: all patients with ovarian cancer were platinum resistant, all of those with cutaneous melanoma had received prior anti–PD-1 and anti-CTLA4 therapy, all of those with NSCLC had received a prior anti–PD-1 agent, and those with triple-negative breast cancer or endometrial cancer had received 2 to 5 lines of previous treatment.

Moreover, treatment with IMC-F106C led to a reduction in circulating tumor DNA (ctDNA) in 90% of evaluable patients across tumor types (n = 20). Thirteen patients experienced a 50% reduction in ctDNA and 25% achieved ctDNA clearance, despite 2 of these patients having a best response of disease progression.

In terms of safety, any-grade adverse effects (AEs) in the safety population (n = 55) occurred at a rate of 95%, including pyrexia (56%), cytokine release syndrome (CRS; 49%), and fatigue (35%). Investigators noted that the CRS events were all manageable, with 77% occurring within the first 3 doses of IMC-F106C, 71% being grade 1, and the remaining 29% being grade 2. Grade 3 or higher AEs were reported in 35% of patients. The MTD was not reached and there were no treatmentrelated discontinuations and no grade 5 AEs.

“The major toxicity to be aware of is CRS,” Hamid noted. “[However], what is good here is that there isn’t a lot of overlap in toxicities with these PRAME-directed agents and our anti–PD-1 therapies, which are standard in multiple indications. This allows us to have combinatorial trials.” 

Study authors concluded that IMC-F106C activates T cells with a tolerable safety profile, producing durable responses per RECIST 1.1 criteria across multiple tumor types. At the time of the data presentation, expansion cohorts were open in cutaneous melanoma, NSCLC, and endometrial and ovarian cancer. Dose escalation was still in progress and combination regimens with chemotherapy and checkpoint inhibitors were being planned.

Following the promising early-phase results, IMC-F106C is set to be evaluated in patients with previously untreated advanced melanoma in the phase 3 PRISM-MEL-301 trial (NCT06112314). The study will compare the safety and efficacy of nivolumab (Opdivo) plus low-dose or high-dose IMC-F106C with nivolumab monotherapy and nivolumab plus relatlimab-rmbw. The study will be initiated in quarter 1 of 2024, according to an investor presentation by Immunocore, the manufacturer of IMC-F106C.

“These novel approaches past checkpoint inhibition are really cementing the role of immunotherapeutics in multiple solid tumors,” Hamid said. “Our initial checkpoint inhibitor experience has shown that we can benefit with combinations, we can manage toxicity, and we can have durable responses, and we’re seeing the same here. These [novel] therapies are helpful because they do something that checkpoint inhibition has lacked for an extended period––being able to turn cold tumors hot by initiating T-cell infiltration into tumors.” 

Another T-cell receptor-based agent that targets PRAME and is under evaluation in advanced solid tumors is the personalized cell therapy IMA203. IMA203 is being developed by Immatics and is composed of the patient’s T cells, which are engineered to express a T-cell receptor directed against PRAME. The agent is being examined as monotherapy or in combination with nivolumab in the phase 1 ACTengine trial (NCT03686124) enrolling patients with recurrent or refractory solid tumors.

In May 2023, the manufacturer of IMA203 reported updated findings from cohort A, the IMA203 monotherapy cohort, of the phase 1b dose-expansion portion of the study. The agent displayed a confirmed ORR of 67% (n = 6/9) across all tumor types, cutaneous melanoma, ovarian cancer, uveal melanoma, head and neck cancer, and synovial sarcoma. Two confirmed PRs were ongoing at over 9 months following treatment and 3 PRs were ongoing at the April 4, 2023, data cutoff.

At the data cutoff, 5 of the 7 responses remained ongoing, including 2 confirmed PRs in cutaneous and uveal melanoma ongoing at 9 months, 1 confirmed PR in cutaneous melanoma at 6 months, 1 confirmed PR in ovarian cancer at 3 months, and 1 PR in synovial sarcoma at 6 weeks. At a median follow-up of 8.5 months, the median duration of response was not reached (range, 1.3+ to 8.8+). The initial ORR at week 6 was 64% (n = 7/11), all of which were PRs.

The patient population was heavily pretreated, with a mean of approximately 4 prior lines of treatment, and had exhausted all available standard- of-care therapies. Patients with cutaneous melanoma were refractory to treatment with checkpoint inhibitors, and all patients with ovarian cancer were platinum resistant.

 Safety findings showed that IMA203 monotherapy displayed a manageable tolerability profile with no dose-limiting toxicities observed in cohort A since the initial phase 1a dose escalation. Ninety-one percent (n = 10/11) of patients experienced grade 1 or 2 CRS and no instances of immune effector cell–associated neurotoxicity syndrome were reported.

“The future is bright for PRAME-targeted agents,” Hamid said. “We are building this bank of information that’s helping us to understand how to give these drugs, how to manage toxicity, which subgroups are benefiting, and which ones need to go into combination therapies. Early on, we’re seeing responses in heavily pretreated tumors. This makes us push harder for these types of therapies, not only in melanoma or cutaneous melanoma but in multiple solid tumors.” 

Preferentially expressed antigen in melanoma has emerged as a target for treatment development in multiple solid tumors.

PRAME Shows Promise as a Treatment Avenue in Melanoma, Other Solid Tumors

Multiple myeloma has an estimated global incidence of 7.1 per 100,000 individuals, making it the second most common hematologic malignancy worldwide. Although significant treatment advances have occurred, especially in recent years, multidrug resistance at an early stage and relapse are common. This is due in part to the combination regimens that are often administered, underscoring the need for the continued development of more effective therapeutics.

®, a panel of expert oncologists in multiple myeloma highlighted updated findings from clinical trials primarily presented during the 65th American Society of Hematology Annual Meeting & Exposition (2023 ASH Annual Meeting), which took place in December 2023 in San Diego, California. They discussed recent updates from studies evaluating agents for the treatment of patients with newly diagnosed multiple myeloma and examined the role of chimeric antigen receptor (CAR) T-cell therapies and bispecifics in relapsed/refractory disease. 

Recent Updates in the Treatment of Newly Diagnosed Multiple Myeloma

The panelists opened their conversation by discussing treatment options for patients with newly diagnosed disease who are eligible for stem cell transplant. Induction therapy with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by autologous stem cell transplant (ASCT), VRd consolidation, and lenalidomide maintenance therapy is considered a standard of care for this patient population.

During the 2023 ASH Annual Meeting, investigators presented findings from the phase 3 Perseus trial (NCT03710603), which randomly assigned patients with newly diagnosed multiple myeloma aged 18 to 70 years who were eligible for high-dose therapy and ASCT 1:1 to receive VRd followed by ASCT induction and ASCT consolidation with lenalidomide maintenance therapy with (n = 355) or without subcutaneous daratumumab (Darzalex; n = 354). Patients who were treated with daratumumab also received maintenance therapy with the agent. The primary end point was progression-free survival (PFS). Key secondary end points included overall complete response or better (≥ CR) rate, overall minimal residual disease (MRD) negativity rate, and overall survival (OS).

At a median follow-up of 47.5 months, the median PFS in was not reached (NR) in the daratumumab or the control arm; the estimated 48-month PFS rates were 84.3% vs 67.7%, respectively (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). Notably, PFS was improved with the addition of daratumumab across clinically relevant subgroups, such as patients with International Staging System stage III disease and those with high cytogenetic risk. The greater than or equal to CR rate in the investigational and control arms was 87.9% vs 70.1%, respectively (

 < .0001), and the MRD negativity rate was 75.2% vs 47.5%, respectively (

Study authors from the Perseus trial wrote in the conclusion of their presentation at the 2023 ASH Annual Meeting that their data, together with findings from the phase 2 GRIFFIN trial (NCT02874742), which evaluated the same combination in the same patient population but delivered daratumumab intravenously, support daratumumab plus VRd followed by maintenance with daratumumab and lenalidomide as a new standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. They also noted that the safety profile of the regimen was consistent with the known profile of subcutaneous daratumumab as well as that of VRd.

During the 2023 ASH Annual Meeting, investigators also presented findings from the phase 3 IsKia trial (NCT04483739), which compared carfilzomib (Kyprolis), lenalidomide, and dexamethasone with or without the addition of the anti-CD38 monoclonal antibody isatuximab-irfc (Sarclisa) before ASCT induction and post ASCT consolidation therapy. The study randomly assigned patients with newly diagnosed multiple myeloma younger than 70 years 1:1 to the isatuximab (n = 151) or control arm (n = 151). The primary end point was the MRD negativity rate after consolidation; secondary end points included the MRD negativity rate after induction and PFS.

At the data cutoff on May 22, 2023, the MRD negativity rate in the investigational and control arms after consolidation at the 10

 cutoff by next-generation sequencing (NGS) was 77% vs 67%, respectively (OR, 1.67; 

 = .049); the respective rates at an NGS cutoff of 10

 < .001). The MRD negativity rates after induction were 45% vs 26%, respectively (OR, 2.34; 

 cutoff and 27% vs 14%, respectively (OR, 2.36; 

“There are a lot of different options for our patients with both standard- and high-risk disease,” Krina K. Patel, MD, MSc, said. “We have enough data to say quadruplets beat out triplets. So for patients [with] standard-risk or high-risk [disease] who are fit and transplant eligible, most of us will say we try to do the quadruplets.” 

Role of CAR T-Cell Therapy in Relapsed/Refractory Multiple Myeloma

There are currently 2 FDA-approved CAR T-cell agents for the treatment of patients with relapsed/ refractory multiple myeloma: idecabtagene vicleucel (Abecma; ide-cel) and ciltacabtagene autoleucel (Carvykti; cilta-cel). In March 2021, ide-cel became the first FDA-approved cell-based gene therapy for multiple myeloma when it received an indication for the treatment of adult patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy. In February 2022, the FDA approved cilta-cel for the treatment of adult patients with multiple myeloma after 4 or more prior lines of therapy.

During the 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023), which took place in June in Chicago, Illinois, investigators presented the final results from the phase 1b/2 CARTITUDE-1 study (NCT03548207), which supported the February 2022 FDA approval of cilta-cel. CARTITUDE-1 enrolled patients with relapsed/refractory multiple myeloma who received at least 3 prior lines of therapy or had disease double refractory to a proteasome inhibitor and an immunomodulatory drug. The primary end points were objective response rate (ORR) and safety; secondary end points included PFS, OS, and MRD negativity.

At a median follow-up of 33.4 months (range, 1.5-45.2), patients who received cilta-cel (n = 97) achieved a median duration of response (DOR) of 33.9 months (95% CI, 25.2-not estimable [NE]) and a median PFS of 34.9 months (95% CI, 25.2-NE); the median OS was NR. Among patients evaluable for MRD (n = 49), 26 achieved MRD negativity for at least 1 year. Previous findings conducted with a median follow-up of 27.7 months showed that the ORR was 98%, with a stringent CR (sCR) rate of 83%.

 Study authors noted that patients treated with cilta-cel achieved a longer median PFS than any previously reported therapy in heavily pretreated patients with relapsed/refractory multiple myeloma.

Beyond the FDA-approved indications for CAR T-cell agents, there has been interest in moving these therapeutics into earlier lines of therapy. During 2023 ASH Annual Meeting, investigators presented findings from the phase 2 CARTITUDE-2 (NCT04133636) and the phase 3 CARTITUDE-4 (NCT04181827) trials, both of which evaluated cilta-cel in patients with relapsed/refractory multiple myeloma. CARTITUDE-2 enrolled patients after 1 to 3 prior lines of therapy (cohort A; n = 20) and those with early relapse following frontline treatment (cohort B; n =19). CARTITUDE-4 enrolled patients with lenalidomide-refractory disease after 1 to 3 prior lines of treatment.

At the April 2023 data cutoff, all 17 MRD- evaluable patients in cohort A of CARTITUDE-2 achieved the MRD negativity threshold of 10

 as well as 14 of 15 MRD-evaluable patients in cohort B. The ORRs in the full populations of cohort A and B were 95% (95% CI, 75.1%-99.9%) and 100% (95% CI, 82.4%-100%), respectively (

 The median PFS was NR in either cohort, and the 24-month PFS rates were 75% (95% CI, 50.0%-88.7%) and 73.3% (95% CI, 47.2%-87.9%), respectively. The 24-month OS rates were 75% (95% CI, 50%-88.7%) and 84.2% (95% CI, 58.7%-94.6%), respectively.

“We heard a little bit at ASH this [past] year about functional patients [with] high-risk [disease] who didn’t achieve a VGPR [very good partial response] or better after their transplant, and we’re looking at where we can use cilta-cel in that regard,” Caitlin Costello, MD, said. “Some of those patients even had lenalidomide maintenance after cilta-cel. We are starting to explore that a bit for our patients [with] higher-risk [disease]. I’d like to see a thoughtful approach to using it in [patients with] early-risk [disease] and not just across the board, since we can’t even get it for the people we know it works for right now.” Findings from CARTITUDE-4, which had a shorter median follow-up of 16 months compared with approximately 29 months in CARTITUDE-2, revealed that cilta-cel significantly improved PFS compared with standard-of-care pomalidomide (Pomalyst), bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone (HR, 0.26; 

 < .0001). Additionally, the ORR was 99.4%, including a CR/sCR rate of 86.4%, among 176 patients who received cilta-cel as study treatment. Eighty-eight percent of MRD-evaluable patients (n = 144) achieved MRD negativity at any time, and 77% achieved both MRD negativity and at least a CR.

CARTITUDE-4 study authors concluded that “in the context of longer-term data from cohort A of the CARTITUDE-2 study in a similar patient population, these results support the potential for prolonged disease control and the benefit of ciltacel for patients with multiple myeloma as early as after first relapse.”

“The challenge [with CARTITUDE-4] is that most of the patients [did] not [have] daratumumab-refractory [disease],” Amrita Krishnan, MD, commented. “They have not yet plateaued on that curve, and we are seeing that you can still get a great curve in fifth relapse for those patients. I would be very reluctant to use [ciltacel] at first relapse; second or third relapse is where I see it fitting in right now.” 

Expanding on the design of the phase 2 KarMMa trial (NCT03361748), which supported the 2021 FDA approval of ide-cel in multiple myeloma and evaluated the agent in patients with relapsed/refractory disease following treatment with at least 3 regimens, the phase 3 KarMMa-3 trial (NCT03651128) compared the CAR T-cell agent with standard regimens in patients with triple class–exposed relapsed/ refractory multiple myeloma. Patients needed to have received at least 2 to 4 prior regimens and have disease refractory to the latest one. The primary end point was PFS; secondary end points included ORR and OS.

Updated findings from KarMMa-3 showed that at the data cutoff of April 28, 2023, with 30.9 months (range, 12.7-47.8) of median follow-up, patients in the ide-cel arm (n = 254) and the standard regimens arm (n = 132) achieved a median PFS of 13.8 months (95% CI, 11.8-16.1) vs 4.4 months (95% CI, 3.4-5.8), respectively (HR, 0.49; 95% CI, 0.38-0.63; 

Experts discuss treatment in newly diagnosed multiple myeloma and the role of CAR T-cell therapies and bispecifics in relapsed/refractory disease.

Vol. 25 No. 4 | Oncology Live®

Jagsi Holds a Magnifying Glass to Radiation Oncology: Uncovering Key Disparities and When to Omit Radiation in Breast Cancer

Extending the Frontiers of Checkpoint Inhibition in Merkel Cell Carcinoma

APEX-01 Looks to Add First PSMA-Directed ADC to Treatment Paradigm in mCRPC

PRAME Shows Promise as a Treatment Avenue in Melanoma, Other Solid Tumors

Data From 2023 ASH Annual Meeting Provide Positive Updates in Multiple Myeloma

Phase 3 Randomized Trials: Expanding Clinically Meaningful Analysis Beyond the Stated Goals