S19 Ep11: Weigh Benefit Against Burden: Defining Lurbinectedin’s Role in a Shifting Small Cell Lung Cancer Landscape

Two Onc Docs, hosted by Samantha A. Armstrong, MD, and Karine Tawagi, MD, is a podcast dedicated to providing current and future oncologists and hematologists with the knowledge they need to ace their boards and deliver quality patient care. Dr Armstrong is a hematologist/oncologist and assistant professor of clinical medicine at Indiana University Health in Indianapolis. Dr Tawagi is a hematologist/oncologist and assistant professor of clinical medicine at the University of Illinois in Chicago.In this episode, OncLive On Air® partnered with Two Onc Docs to deliver a board exam preparation guide for the days leading up to the American Board of Internal Medicine hematology and oncology certification exams, offering test-day strategies and a rapid-fire review of high-yield topics.The discussion began with exam logistics, noting back-to-back testing days on November 17 (hematology) and November 18 (oncology). Drs Armstrong and Tawagi encouraged examinees to use the exam blueprint to prioritize high-yield topics, such as gastrointestinal, breast, genitourinary, and lung cancers in oncology and neoplasms in hematology, and to prepare for the endurance required to read lengthy clinical vignettes.Regarding oncology content, they reviewed topics to know regarding stage II and III non–small cell lung cancer, including staging, perioperative immunotherapy regimens, driver-directed adjuvant therapy, and the clinical implications of the phase 3 PACIFIC trial (NCT02125461). They then covered high-yield breast cancer topics, such as HER2-positive regimens, the 21-gene recurrence score assay cutoffs, triple-negative adjuvant strategies, and use of PARP inhibitors in patients with BRCA mutations.For hematology, they emphasized the malignant hematologic conditions, hemoglobin electrophoresis, von Willebrand disease subtypes, and inherited bone marrow failure syndromes, including dyskeratosis congenita, Fanconi anemia, and Diamond-Blackfan anemia.Drs Armstrong and Tawagi also highlighted other testable areas, including black box warnings, clinical research methodology, ethics, performance status–guided decision-making, and supportive care. They concluded with wellness advice, cautioning against last-minute cramming, and recommended revisiting their prior board review episodes.

In this episode of OncLive On Air, Aditya Juloori, MD, a radiation oncologist and associate professor at the University of Chicago in Illinois, was joined by David Carbone, MD, PhD, a thoracic medical oncologist and director of the Thoracic Oncology Center at The Ohio State University in Columbus. Together, they explored how factors beyond PD-L1 expression, including histology, co-occurring genomic alterations, brain metastases, and patient fitness, can inform first-line regimen selection for patients with driver-negative metastatic non–small cell lung cancer (NSCLC).Dr Carbone began by explaining that immunotherapy has transformed the treatment landscape, with frontline regimens now producing an overall 5-year survival rate of approximately 20% and potentially curing a subset of patients. However, he noted that this benefit is not evenly distributed. Patients with PD-L1–negative disease tend to fare worse than those with PD-L1–positive tumors, and outcomes are particularly poor for patients with PD-L1–negative squamous disease. In the 5-year data from the phase 3 KEYNOTE-407 trial (NCT02775435), survival curves for this subgroup had fully converged with the control arm, and the 5-year survival rate among patients with PD-L1–negative nonsquamous disease in the phase 3 KEYNOTE-189 trial (NCT02578680) was below 10%.Drs Carbone and Juloori emphasized that dual checkpoint inhibition has emerged as an important option for these higher-risk populations. Dr Carbone highlighted that the CheckMate 9LA regimen (NCT03215706) of nivolumab (Opdivo) plus ipilimumab (Yervoy) with 2 cycles of chemotherapy produced a 5-year survival rate exceeding 20% in PD-L1–negative and squamous subsets, making it his preferred approach for patients with PD-L1–negative squamous disease. For PD-L1–negative nonsquamous tumors, he weighs additional factors such as brain metastases and STK11 or KEAP1 alterations. Although dual immunotherapy carries a higher risk of immune-related adverse effects, he noted that outcomes in CheckMate 9LA remained favorable even among patients who discontinued a component of therapy, underscoring the effectiveness of proactive toxicity management. He added that the chemotherapy-free regimen evaluated in the phase 3 CheckMate 227 trial (NCT02477826) demonstrated similar efficacy, and that many patients value receiving only 2 cycles of chemotherapy.The conversation also explored the management of patients with baseline brain metastases. Dr Juloori explained that in both CheckMate 227 and CheckMate 9LA, the benefit of dual immunotherapy was at least as large in patients with brain metastases as in those without. This may reflect the ability of CTLA-4 blockade to convert immunologically cold intracranial tumors, which tend to have fewer activated cytotoxic T cells and tertiary lymphoid structures, into more inflamed ones. He cited a phase 2 trial of ipilimumab, nivolumab, and chemotherapy that reported an intracranial response rate of approximately 50%. For patients with multiple asymptomatic brain metastases, Dr Juloori described starting the 9LA regimen with close monthly brain imaging to assess early intracranial response, an approach that can defer whole-brain radiation therapy and help preserve performance status and eligibility for subsequent therapies. He noted that some of his patients have avoided radiation for more than a year with sustained complete responses.Turning to genomic modifiers, Dr Carbone described STK11 and KEAP1 alterations as markers of immunologically cold, often PD-L1–negative tumors that may require more than standard chemotherapy plus pembrolizumab (Keytruda). The prospective phase 2 TRITON trial (NCT06008093) of durvalumab (Imfinzi) plus tremelimumab-actl (Imjudo) in STK11-, KEAP1-, or KRAS-mutant disease was limited by low accrual, but multiple studies support dual immunotherapy activity in these subsets. He cautioned, however, that mutation status is an imperfect surrogate for STK11 function, noting that his laboratory has identified mutant tumors that retain function and wild-type tumors that have lost it. As a result, he would still favor single-agent immunotherapy for a patient with high PD-L1 expression and an isolated STK11 mutation.Dr Carbone also addressed how to apply trial data to patients who are older, frail, or have reduced performance status. He suggested that limiting chemotherapy exposure may be particularly beneficial in these populations, while noting that patients with interstitial lung disease or active autoimmune conditions requiring aggressive immunosuppression may be poor candidates for dual immunotherapy. He added that age alone should not preclude more intensive treatment in patients with good performance status and organ function. Both experts expressed a preference for nivolumab plus ipilimumab over durvalumab plus tremelimumab, citing stronger supporting data, particularly in squamous disease.Looking ahead, Dr Carbone noted that emerging tools, including serum proteomic assays and SMARCA4 status, may eventually be incorporated into treatment algorithms, though their role in the dual immunotherapy and PD-L1–negative settings remains undefined. Drs Carbone and Juloori concluded that while clinicians often must rely on incomplete data and cross-trial comparisons, decisions should remain grounded in the available evidence as the field works toward more precise tools for moving beyond PD-L1.

In today’s episode, we spoke with Lyudmila Bazhenova, MD, and Sandip Patel, MD. Dr Bazhenova is a thoracic medical oncologist and co-lead of the lung cancer team at University of California San Diego Moores Cancer Center, and Dr Patel is a professor of medical oncology at UC San Diego.In our exclusive interview, Drs Bazhenova and Patel explained why describing a tumor as “MET positive” is no longer specific enough in non–small cell lung cancer (NSCLC). MET protein overexpression, MET exon 14 skipping mutations, and MET amplification are biologically distinct findings detected by different assays, and each carries its own treatment implications. Protein overexpression is identified by immunohistochemistry (IHC) on tumor tissue and defines eligibility for the antibody-drug conjugate (ADC) telisotuzumab vedotin-tllv (Emrelis), which is approved for the treatment of adult patients with locally advanced or metastatic, nonsquamous NSCLC harboring high c-MET protein overexpression who have received a prior systemic therapy; c-MET protein overexpression is defined as at least 3+ staining in 50% or more of tumor cells per IHC testing. Dr Patel noted that roughly 1 in 5 patients may harbor this target. MET exon 14 skipping mutations, found in approximately 2% to 4% of patients, are genomic alterations detectable by next-generation sequencing (NGS) on tissue or liquid biopsy and are treated with the MET inhibitors capmatinib (Tabrecta) or tepotinib (Tepmetko). Dr Bazhenova cautioned that DNA-based NGS can miss MET exon 14 skipping mutations, making RNA-based testing a valuable complement. MET amplification, which can arise de novo or as a resistance mechanism after third-generation EGFR inhibition, lacks a specific FDA-approved therapy, although Dr Patel described combining an EGFR inhibitor such as osimertinib (Tagrisso) with a MET inhibitor in the acquired-resistance setting.Because IHC and NGS measure different things, both experts order the 2 tests together rather than treating one as a substitute for the other. Dr Bazhenova likened NGS to examining a home’s blueprint and IHC to inspecting what was actually built, adding that high protein expression without a corresponding genomic alteration is not a discordant result. Dr Patel described sending liquid biopsy for genomic profiling alongside tissue so that limited tissue can be preserved for PD-L1, HER2, and MET IHC. When tissue is insufficient, he obtains a biopsy before second-line therapy, and he stressed documenting the exact aberration and score in the medical record so the finding can guide treatment years later. Dr Bazhenova also routinely repeats NGS and IHC at progression on EGFR-targeted therapy, since MET alterations are a common escape mechanism and acquired MET overexpression can emerge.The experts also addressed borderline IHC results and assay variability. Dr Patel noted that interpretation tends to be more consistent at high-intensity, high-percentage staining with the SP44 assay, and he encouraged direct conversations with pathologists and multidisciplinary tumor boards for cases near the cutoff. Dr Bazhenova highlighted data from the phase 2 LUMINOSITY trial (NCT03539536) showing activity in MET-intermediate tumors, defined as IHC 3+ staining in 25% to 50% of cells, with an overall response rate of 23% and a median duration of response of about 7 months, although this population falls outside the current label. She pointed to the ongoing phase 3 TeliMET NSCLC-01 trial (NCT04928846) comparing telisotuzumab vedotin with docetaxel in both MET-high and -intermediate disease, and recommended considering a repeat biopsy for patients near the threshold given tumor heterogeneity.On sequencing, Dr Patel described telisotuzumab vedotin as his standard of care for eligible patients after chemoimmunotherapy, citing a more favorable efficacy and toxicity profile than docetaxel, which yields a response rate of roughly 9%. He added that giving docetaxel first may blunt the benefit of a subsequent ADC with a similar mechanism. For patients with EGFR-mutant disease and acquired MET overexpression, Dr Bazhenova said she would favor datopotamab deruxtecan-dlnk (Datroway), noting that telisotuzumab vedotin produced a response rate of only about 16% in this group in LUMINOSITY. Looking ahead, she flagged payload-aware sequencing as a growing challenge, because many ADCs in development share a topoisomerase I inhibitor payload and trials often exclude patients previously exposed to that payload class, leaving little data to guide back-to-back use.

In today’s episode, we spoke with Triparna Sen, PhD, and Jacob Sands, MD. Dr Sen is a professor of internal medicine and the director of the Lung Cancer Preclinical Therapeutics Platform at the Ohio State University Comprehensive Cancer Center—James in Columbus. Dr Sands is associate chief of the Lowe Center for Thoracic Oncology and the oncology medical director of the International Patient Center at Dana-Farber Cancer Institute, as well as an assistant professor at Harvard Medical School in Boston, Massachusetts.In our exclusive interview, Drs Sen and Sands discussed findings from the phase 3 IMforte trial (NCT05091567), which showed that adding lurbinectedin (Zepzelca) to atezolizumab (Tecentriq) maintenance following carboplatin, etoposide, and atezolizumab induction improved outcomes in patients with extensive-stage small cell lung cancer (SCLC). Dr Sen noted that although the regimen’s safety profile was manageable, the combination does increase rate of hematologic toxicities, including anemia, neutropenia, and thrombocytopenia, so the key question is whether the added treatment burden is justified by longer disease control and survival. Dr Sands added that the neutropenia rates in IMforte were lower than in the earlier second-line lurbinectedin experience, likely because primary prophylaxis, such as granulocyte colony-stimulating factor, was permitted.The experts also weighed in on a trial in progress presented at the 2026 World Conference on Lung Cancer evaluating lurbinectedin plus durvalumab (Imfinzi) as maintenance therapy. Dr Sen explained that a positive result could show that the strategy is reproducible with a different PD-L1 inhibitor and induction regimen but cautioned against assuming a class-wide effect or treating the 2 regimens as interchangeable. Dr Sands said he would not expect durvalumab to perform differently from atezolizumab in this context, and that the more pressing question is whether lurbinectedin belongs in maintenance at all, particularly as the IMforte curves have converged with longer follow-up. Both experts pointed to the phase 3 DeLLphi-305 trial (NCT06211036) of tarlatamab (Imdelltra) plus durvalumab vs durvalumab alone as first-line maintenance, which has reported positive OS and PFS results via press release, as the most significant development to watch in this space.Turning to the relapsed setting, Drs Sen and Sands discussed the negative phase 3 LAGOON trial (NCT05153239), in which neither lurbinectedin monotherapy nor lurbinectedin plus irinotecan improved OS vs investigator’s choice of topotecan (Hycamtin) or irinotecan, leading to the withdrawal of lurbinectedin’s second-line indication. Dr Sands highlighted that the control arm median OS was unexpected given the median OS data that supported the original accelerated approval of the agent. Both experts emphasized that the LAGOON results should not be conflated with the maintenance data, and Dr Sands expressed hope that lurbinectedin remains a guideline-listed option in later lines, citing its convenient every-3-week dosing.Finally, the experts looked ahead to emerging therapies. Dr Sands discussed B7-H3–directed antibody-drug conjugates (ADCs), including YL201 and ifinatamab deruxtecan. He also outlined practical toxicity management for ADCs, including cytopenias, nausea, fatigue, alopecia counseling, and the challenge of distinguishing drug-related interstitial lung disease from waxing and waning inflammatory findings common in SCLC. Dr Sen highlighted anticipated data at the 2026 ESMO Congress and stressed that treatment selection in SCLC maintenance will depend on magnitude of benefit, patient selection, toxicity, and center capabilities rather than a one-size-fits-all approach.

In today’s episode, we spoke with Erika P. Hamilton, MD, about the FDA approval of tucatinib (Tukysa) plus trastuzumab (Herceptin) and pertuzumab (Perjeta) for the maintenance treatment of adult patients with unresectable locally advanced or metastatic HER2-positive breast cancer following induction therapy. Dr Hamilton is director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute.This regulatory decision was backed by data from the phase 3 HER2CLIMB-05 trial (NCT05132582), in which treatment with tucatinib plus trastuzumab and pertuzumab generated a median progression-free survival of 24.9 months (95% CI, 21.3-not reached) vs 16.3 months (95% CI, 12.6-18.7) with placebo, translating to a 35.9% reduction in the risk of disease progression or death (HR, 0.64; 95% CI, 0.51-0.80; 2-sided P < .0001).In our exclusive interview, Dr Hamilton highlighted the significance of this approval, key data from HER2CLIMB-05, and potential next steps for the HER2-positive breast cancer treatment paradigm.

In this episode of Oncology Unplugged, host Chandler Park, MD, MSc, FACP, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was joined by Jame Abraham, MD, FACP, the enterprise chairman of the Department of Hematology and Medical Oncology at Cleveland Clinic and a professor of medicine at the Cleveland Clinic Lerner College of Medicine in Ohio.Their discussion centered on recent practice-changing advances in breast cancer, spanning treatment de-escalation, antibody-drug conjugates, and the growing role of artificial intelligence (AI) in oncology. Drs Park and Abraham first addressed findings from the phase 3 ASCENT-04 trial (NCT05382286), in which sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) improved progression-free survival over physician’s choice of chemotherapy in the first-line setting in patients with PD-L1–positive metastatic triple-negative breast cancer. Dr Abraham offered guidance on management strategies for neutropenia and diarrhea associated with this combination.The conversation then turned to treatment de-escalation, highlighting data from the phase 3 OPTIMA trial (ISRCTN42400492), which demonstrated that patients with high-risk, node-positive, hormone receptor–positive early breast cancer and low recurrence scores derived no benefit from adding chemotherapy to endocrine therapy. Dr Abraham underscored the biology-driven rationale for sparing chemotherapy and advocated for ovarian function suppression in high-risk premenopausal patients, citing data from the phase 3 SOFT (NCT00066690) and TEXT (NCT00066703) trials.Drs Park and Abraham also examined the May 2026 FDA approvals of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of patients with early HER2-positive disease, focusing on the results of the phase 3 DESTINY-Breast05 trial (NCT04622319), in which T-DXd reduced the risk of invasive disease or death vs ado-trastuzumab emtansine (Kadcyla). Dr Abraham detailed the importance of interstitial lung (ILD) disease monitoring with T-DXd use and highlighted the reassuring lack of added ILD risk with concurrent radiation that was seen in the trial.Finally, the experts explored AI’s transformative potential in oncology, emphasizing the importance of clinician involvement in its development, tools like OpenEvidence, and takeaways from the Cleveland Clinic’s AI Summit for Healthcare Professionals, which took place in August 2026. Overall, Drs Park and Abraham affirmed that a patient-centered focus for cancer care should always ultimately guide treatment decisions.

In this episode, produced in coordination with Oncology Nursing News®, Beth Faiman, PhD, MSN, APN-BC, AOCN, FAAN, FAPO, and Sikander Ailawadhi, MD, discussed how on-body subcutaneous administration methods could allow for select at-home administration of therapies for patients with multiple myeloma. Dr Faiman is an adult nurse practitioner in the Department of Hematology/Oncology at the Cleveland Clinic and a clinical member of the Cancer Prevention, Control and Population Research Program at Case Comprehensive Cancer Center in Ohio. Dr Ailawadhi is a consultant in the Division of Hematology/Oncology in the Department of Internal Medicine, a consultant in the Department of Cancer Biology, and a professor of medicine at Mayo Clinic in Rochester, Minnesota.In the final episode of a 3-part series, Drs Faiman and Ailawadhi explained how they are integrating on-body administration of isatuximab-irfc (Sarclisa Escena) for subcutaneous injection into clinical practice following its July 2026 FDA approval, and the pair also shared how this method could represent a strategy for at-home treatment within the United States in the future.In the first episode, Drs Faiman and Ailawadhi detailed the transition to subcutaneous administration of anti-CD38 monoclonal antibodies in multiple myeloma management. And in the second episode, they broke down how patient-centric treatment methods are a key focus in myeloma research.

In today’s episode, we spoke with Angeles Alvarez Secord, MD, MHSc. Dr Secord is a professor of obstetrics and gynecology and a member of Duke Cancer Institute in Durham, North Carolina.In our exclusive interview, Dr Secord discussed the emergence of B7-H4 as an attractive antibody-drug conjugate (ADC) target in gynecologic cancers, noting that expression rates of 80% to 90% or higher across endometrial and ovarian cancers distinguish it favorably from other targets such as folate receptor α and HER2, where high expression thresholds are often required for meaningful benefit. She also highlighted a mechanistic distinction: unlike FRα- or HER2-directed ADCs, which target proteins involved in growth signaling, B7-H4 is more deeply embedded in immune regulation, making it a potentially powerful tool for converting immunologically cold tumors into ones that can respond to checkpoint inhibition.She reflected on the phase 1 BEHOLD-1 trial (NCT06431594) data presented at the 2026 SGO Annual Meeting on Women’s Cancer, describing the confirmed overall response rate of over 60% in platinum-resistant ovarian cancer as remarkable in a disease where traditional chemotherapy achieves response rates of 15% or less. Dr Secord expressed strong support for the decision to advance this agent into five pivotal phase 3 trials, noting that data of this magnitude clearly justifies further development.As principal investigator at Duke for the phase 1/2 BEHOLD-2 trial (NCT06796907), Dr Secord walked through the rationale for combining mocertatug rezetecan with dostarlimab-gxly (Jemperli) in endometrial and ovarian cancer. She explained that by suppressing B7-H4’s immunosuppressive effect in the tumor microenvironment, the ADC paradoxically increases immune stimulation and generates neoantigens through cell kill, creating a primed setting for dostarlimab to deliver a synergistic second hit. She also highlighted the BLUESTAR study (NCT05123482) results for puxitatug samrotecan, noting that response rates exceeding 60% in patients previously treated with both platinum and immunotherapy address a critical gap in the current treatment landscape. On toxicity management, Dr Secord described a proactive approach to the topoisomerase 1 payload class, emphasizing aggressive antiemetic prophylaxis, liberal use of growth factor support, early intervention for diarrhea with anti-motility agents and dietary modification, and close laboratory monitoring in the first cycles of treatment. She noted that distinguishing between drug-specific toxicities such as stomatitis, interstitial lung disease, and neuropathy across the ADC class is essential for maintaining dose intensity and quality of life.Finally, Dr Secord addressed the evolving questions of ADC sequencing and B7-H4 biomarker testing. She described herself as a biomarker enthusiast and noted that while current data do not yet show a clear association between B7-H4 expression level and antitumor activity, phase 3 trials represent an important opportunity to conduct robust biomarker collection and assess whether expression magnitude predicts differential benefit. On sequencing, she acknowledged that most phase 3 trials currently exclude patients with prior topoisomerase 1 payload ADC exposure, making clinical trial enrollment essential for generating the cross-ADC sequencing data the field urgently needs. 

From Discovery to Delivery: Charting Progress in Gynecologic Oncology, hosted by Ursula A. Matulonis, MD, brings expert insights into the most recent breakthroughs, evolving standards, and emerging therapies across gynecologic cancers. Dr Matulonis is chief of the Division of Gynecologic Oncology and the Brock-Wilson Family Chair at the Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.In this episode, Dr Matulonis was joined by Joyce F. Liu, MD, MPH, a medical oncologist and associate professor of medicine at Harvard Medical School, associate chief and director of clinical research in the Division of Gynecologic Oncology at Dana-Farber Cancer Institute, and associate clinical research officer for the clinical research program at Dana-Farber, all in Boston, Massachusetts. Together, they explored the rapidly expanding landscape of novel therapies for ovarian cancer, spanning the next generation of antibody-drug conjugates (ADCs), resistance mechanisms, cell cycle targets, and emerging strategies for rare histologic subtypes.Dr Liu opened by surveying the current ADC pipeline in ovarian cancer, noting that while mirvetuximab soravtansine-gynx (Elahere) and fam-trastuzumab deruxtecan-nxki (Enhertu) are already in clinical use, a substantial wave of next-generation agents is now advancing through phase 2 and phase 3 development. She organized these agents by target and payload, highlighting three folate receptor alpha-targeting ADCs with topoisomerase 1 inhibitor payloads: rinatabart sesutecan, sofetabart mipitecan, and torvutatug samrotecan as well as the B7-H4-targeting agent rocertatug rezetecan, CDH6-targeting agents, and Trop-2-directed ADCs including sacituzumab tirumotecan and sacituzumab govitecan-hziy (Trodelvy). Dr Liu noted that early-phase data across several of these agents have shown response rates of 50% or higher, even in heavily pretreated, platinum-resistant populations. Though meaningful, questions remain about response durability as these data continue to mature. A key advantage shared by many of these agents, she emphasized, is the potential for use without high levels of biomarker expression, which could extend eligibility well beyond what current approved ADCs allow.The conversation then turned to ADC resistance mechanisms and the feasibility of sequential ADC use. Dr Liu described three broad categories of resistance: target-mediated mechanisms, payload-dependent mechanisms, and mechanisms independent of both target and payload. Drawing on evidence from the breast cancer setting, she noted that switching payloads while maintaining the same target can preserve activity, a pattern now emerging in early ovarian cancer data with folate receptor alpha-directed ADCs. Sequential use of two topoisomerase 1 payload ADCs, however, remains a concern, with prospective phase 2 breast cancer trial data suggesting limited activity in that setting. Dr Liu cautioned against drawing direct lines between breast and ovarian cancer biology while acknowledging the question must be actively studied. She and Dr Matulonis also discussed the possibility of ADC rechallenge in patients whose disease progressed in a different treatment context as the settings in which ADCs are introduced continue to evolve.Dr Liu also addressed dual-payload ADCs, describing them conceptually as analogous to combination chemotherapy, pairing microtubule inhibitor and topoisomerase 1 inhibitor payloads to potentially overcome resistance and improve depth of response. She highlighted a further frontier of novel ADC payloads, including immune-stimulating antibody conjugates, protein degraders, and ATR inhibitors as representing the earliest translational steps from preclinical models into clinical investigation.Drs Matulonis and Liu then discussed therapeutic strategies for CCNE1-amplified ovarian cancer, a molecularly distinct subset characterized by overexpression of cyclin E1 protein and dependency on the G2/M cell cycle checkpoint. Dr Liu explained that CCNE1 amplification drives constitutive CDK2 activation, forcing cells into premature DNA replication and creating vulnerability to agents that abrogate the compensatory G2/M checkpoint. Two therapeutic approaches have emerged: WEE1 inhibition with azenosertib, which has shown response rates of approximately 30% to 35% in cyclin E1-high platinum-resistant ovarian cancer by immunohistochemistry, compared with 10% to 15% for standard chemotherapy, and CDK2 inhibition and degradation strategies showing similar early signals in CCNE1-amplified tumors. Both approaches are now entering phase 3 evaluation. Dr Liu noted that while CCNE1 amplification is detectable on next-generation sequencing, a validated immunohistochemistry assay for cyclin E1 protein expression is not yet commercially available, though one may emerge as a companion diagnostic if protein-level expression proves to be the more predictive biomarker.The discussion also covered KIF18A, a kinesin motor protein that stabilizes chromosomes at the metaphase plate during mitosis. In cancers with high chromosomal instability KIF18A activity is critical for cell survival; its inhibition leads to mitotic errors and cell death. Several KIF18A inhibitors are now in active clinical development, with early signals of activity emerging. Dr Liu noted that chromosomal instability alone may not be sufficient to identify optimal candidates for these agents and that additional biomarker refinement will likely be necessary.Turning to rare histologic subtypes, Dr Liu highlighted two areas of recent progress. In low-grade serous ovarian cancer, the combination of avutometinib, a RAS/RAF clamp that suppresses signaling through the RAS/RAF/MEK pathway, and the FAK inhibitor defactinib (Avmapki Fakzynja Co-pack) received accelerated FDA approval for patients with KRAS-mutated low-grade serous ovarian cancer, supported by phase 2 data demonstrating meaningful activity in this molecularly defined population. A confirmatory international phase 3 trial is ongoing. In clear cell ovarian cancer, emerging phase 2 data for immunotherapy combinations suggest that immunotherapy may hold particular relevance for this subtype, though randomized phase 3 evidence specific to clear cell disease remains limited.Dr Liu concluded by highlighting two additional areas of interest: BCL-XL inhibition and degradation combinations, which have shown activity in preclinical models and early clinical signals in ovarian cancer; and next-generation immunotherapy approaches, including bispecific antibodies and evolving cellular therapy strategies, which she views as holding genuine potential to generate durable responses in a disease where conventional PD-1/PD-L1 inhibition has had limited reach.

In this episode, produced in coordination with Oncology Nursing News®, Beth Faiman, PhD, MSN, APN-BC, AOCN, FAAN, FAPO, and Sikander Ailawadhi, MD, discussed how on-body subcutaneous administration methods are affecting multiple myeloma management and how these administrations could be a key focus of future health care initiatives. Dr Faiman is an adult nurse practitioner in the Department of Hematology/Oncology at the Cleveland Clinic and a clinical member of the Cancer Prevention, Control and Population Research Program at Case Comprehensive Cancer Center in Ohio. Dr Ailawadhi is a consultant in the Division of Hematology/Oncology in the Department of Internal Medicine, a consultant in the Department of Cancer Biology, and a professor of medicine at Mayo Clinic in Rochester, Minnesota.In the second episode of a 3-part series, Drs Faiman and Ailawadhi explained how on-body administration of isatuximab-irfc (Sarclisa Escena) for subcutaneous injection is setting the stage for future patient-centric treatment methods, and the pair discussed experiences with this method.In the first episode, Drs Faiman and Ailawadhi detailed the transition to subcutaneous administration of anti-CD38 monoclonal antibodies in multiple myeloma management.