During colorectal cancer (CRC) awareness month, 

sat down with Jeremy Kortmansky, MD, to discuss frequently asked questions about the complexities of CRC management and the rising incidence of CRC in young adults. The following FAQ, adapted from the conversation, provides clinical insights into potential risk factors for CRC in young adults, gaps in screening and early symptom identification contributing to this phenomenon, and the evolving landscape of molecularly targeted therapies in the space. 

Kortmansky is an associate professor of clinical medicine (Medical Oncology), associate chief medical officer of Network Medical Services; chief of ambulatory services; clinical director of the Division of GI Medical Oncology at Yale Cancer Center, and the Chief Network Officer for the Smilow Cancer Hospital, Yale School of Medicine in New Haven, Connecticut.

Read on to learn more about the shifting demographics and molecular complexities of CRC!

CRC is now the leading cause of cancer death for individuals under age 50; accordingly screening for average-risk individuals should now begin at age 45, and symptoms like rectal bleeding in young adults should not be dismissed as benign conditions.

Early-onset CRC often presents at more advanced stages and may be biologically distinct from late-onset disease, exhibiting different mutational profiles and worse prognoses.

 amplification, and mismatch repair status is vital for modern CRC management and the application of emerging targeted therapies.

Q: What are the current demographic trends regarding CRC incidence and mortality?

A: Although cancer rates in patients over 65 are declining, there is a troubling increase in younger populations.

According to a recent report by the American Cancer Society, CRC is currently:

The third leading cause of cancer in the United States (US) with an estimated 158,850 new cases of CRC in 2026.

The second leading cause of cancer-related death in the US, with an estimated 55,230 deaths from CRC in 2026.

Increasing in incidence by 3% annually in adults aged 20 to 49 years and by 0.4% annually in those aged 50 to 64 years despite decreasing by 2.5% in adults aged 65 and older.

Mortality has decreased in adults 65 years and older by 2.3% annually since 2012; however, it has increased by approximately 1% annually in adults younger than 50 years old since 2004.

“What is upsetting is that it is now the number one cause of cancer mortality in patients under 50 years old,” Kortmansky stated. He highlighted that nearly 50% of new cases now arise in patients under the age of 65 years old, a significant jump from 27% approximately 30 years ago.

Furthermore, most patients diagnosed under age 50 (75%) are presenting with either advanced-stage or metastatic disease, including 27% with distant metastases vs 21% to 23% of older patients, Kortmansky observed.

Q: What factors are driving the increase in early-onset CRC?

 The rise in early-onset CRC may be attributed to a combination of lifestyle, dietary, and environmental factors

High consumption of processed foods, sugar-sweetened beverages, rising obesity rates, and high alcohol consumption.

Changes in the microbiome, potentially linked to antibiotic use in health and food production, are a major area of interest. Specifically, certain bacterial species, including Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, have been implicated in promoting inflammation, DNA damage, and tumor progression.

Emerging concerns include microplastics and other factors that create pro-inflammatory environments.

Although the incidence of genetic syndromes is elevated for patients under 35 vs older than 35, heredity is not the primary factor driving this overall increase in the under-50 population.

Q: Is early-onset CRC considered a biologically distinct entity?

There is growing evidence that CRC in younger patients may be a different disease biologically, characterized by different frequent mutations and more aggressive behavior, Kortmansky shared.

Kortmansky provided an example involving patients with resectable liver metastases: “The prognosis in the younger population was still worse... it was the same stage, the same distribution, but clearly a difference in how the disease behaved.”

Additionally, there is notable dominance of tumors in the distal colon and rectum in younger patients, leading to differences in clinical presentation compared with older patients.

Q: What are the primary challenges in screening and early diagnosis for younger patients?

 In 2021, the US Preventive Services Task Force lowered the recommended starting age for average-risk screening from 50 to 45 years in response to epidemiologic data demonstrating a 15% rise in cases among younger adults over approximately 15 years and modeling data supporting benefit in the 45- to 49-year age group.

Despite these updated recommendations to begin screening at 45 years old, Kortmansky noted that uptake remains low. Many younger patients have busy lives with full-time jobs and families, making it difficult to find time for traditional screening, he explained.

Kortmansky emphasized the need for primary care physicians and gastroenterologists to be more proactive: “We can’t chalk [abdominal pain and bleeding] up to hemorrhoids or irritable bowel. We need to be a bit more proactive and say, ‘let’s make sure this isn’t cancer at an earlier group.’"

He also suggested leaning into non-invasive techniques, such as the Cologuard Plus screening test, to improve screening prevalence. As of October 2024, this next-generation multitarget stool DNA test has been indicated for adults at least 45 years of age who are at average risk for developing CRC.

This regulatory decision was supported by findings from the observational BLUE-C trial (NCT04144738), in which, among a subset of 20,176 evaluable adults undergoing screening colonoscopy, Cologuard Plus showed:

93.9% (95% CI, 87.1%-97.7%) overall CRC sensitivity

90.6% (95% CI, 90.1%-91.0%) specificity for advanced neoplasia

43.4% (95% CI, 41.3%-45.6%) sensitivity for advanced precancerous lesions

92.7% (95% CI, 92.2%-93.1%) specificity for nonneoplastic findings or negative colonoscopy

Q: Why is molecular profiling essential in the current CRC treatment landscape?

Molecular profiling is critical because it identifies targetable mutations and informs treatment selection based on tumor location (left-sided vs right-sided), Kortmansky explained. Surprisingly, many patients still start treatment before these results are available.

Key molecular targets for drug development include:

 G12C is now targetable with approved therapies, and G12D is currently under intense study.

 Approximately 50% of patients show some increase in MET expression.

 Although immunotherapy is effective for patients with microsatellite instability-high disease, researchers continue to struggle with bringing these benefits to the mismatch repair-proficient (pMMR) population.

Q: What emerging trials or therapies are most influential in the field right now?

 Beyond work with KRAS and MET inhibitors, Kortmansky noted the following developments:

Amivantamab (Rybrevant), which targets both MET and EGFR, is showing potential for addressing resistance that occurs with traditional anti-EGFR therapies.

Investigated in studies like the phase 1b/2 OrigAMI-1 trial (NCT05379595), it demonstrated antitumor activity against 

 wild-type CRC and a manageable safety profile when combined with chemotherapy.

The MET-directed ADC telisotuzumab adzuxecan (Temab-A; formerly ABBV-400) has shown promise in heavily pretreated patients, regardless of the level of MET expression.

 In a first-in-human phase 1 study (NCT05029882), Temab-A demonstrated antitumor activity across multiple dose levels in patients with BRAF wild-type, microsatellite-stable or pMMR CRC who experienced disease progression on prior therapies. The agent is currently being evaluated in a phase 2 clinical trial (NCT07023289) in patients with ctDNA-positive CRC after adjuvant therapy.

 The phase 3 STELLAR-303 trial (NCT05425940), investigated the combination of zanzalintinib plus atezolizumab vs regorafenib (Stivarga) in patients with previously treated CRC in the third-line setting; however, it showed only modest overall survival improvements accompanied by significant toxicity.

Kortmansky concluded that although biological differences are recognized, these have not yet fully translated into standard treatment differences, making ongoing clinical trials and toxicity management essential for the future of CRC care.

Siegel RL, Wagle NS, Star J, Kratzer TB, Smith RA, Jemal A. Colorectal cancer statistics, 2026. 

. 2026;76(2):e70067. doi:10.3322/caac.70067

Gomes de Sousa R, Guerreiro CS, Santos I, Cravo M. The knowledge gap in gut microbiome characterization in early-onset colorectal cancer patients: a systematic scoping review. 

. 2025;17(11):1863. doi:10.3390/cancers17111863

US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. 

. 2021;325(20):1965-1977. doi:10.1001/jama.2021.6238

FDA approves Exact Sciences’ Cologuard Plus test, setting a new benchmark in non-invasive colorectal cancer screening. News release. Exact Sciences. October 4, 2024. Accessed March 30, 2026. https://www.exactsciences.com/newsroom/press-releases/fda-approves-exact-sciences-cologuard-plus-test

Imperiale TF, Porter K, Zella J, et al. Next-generation multitarget stool DNA test for colorectal cancer screening. 

. 2024;390(11):984-993. doi:10.1056/NEJMoa2310336

Rybrevant (amivantamab-vmjw) longer-term results show promising and durable responses in difficult-to-treat colorectal cancer. News Release. Johnson & Johnson. January 10, 2026. Accessed March 30, 2026. https://www.investor.jnj.com/investor-news/news-details/2026/RYBREVANT-amivantamab-vmjw-longer-term-results-show-promising-and-durable-responses-in-difficult-to-treat-colorectal-cancer/default.aspx

Sharma MR, Strickler JH, Sommerhalder D, et al. First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: results in colorectal cancer. 

. 2024;42(suppl 16):3515. doi:10.1200/JCO.2024.42.16_suppl.3515

Raghav KPS, Bando H, Ke TW, et al. A phase 2 randomized study comparing telisotuzumab adizutecan monotherapy with standard of care in patients with post-adjuvant circulating tumor DNA-positive colorectal cancer. 

. 2026;44(suppl 2):TPS265. doi:10.1200/JCO.2026.44.2_suppl.TPS265

Hecht JR, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial. 

. 2025;406(10517):2360-2370. doi:10.1016/S0140-6736(25)02025-2

Jeremy Kortmansky, MD, discusses early-onset CRC, the importance of molecular profiling, and emerging therapeutic targets in this clinician-focused FAQ. 

Rising Rates, Screening Gaps, and Emerging Therapeutic Targets in CRC: Your Key Clinical Questions Answered

As treatment options for multiple myeloma continue to expand across the disease continuum, efforts and tools to improve risk stratification and treatment selection will be imperative toward driving personalized medicine approaches for this patient population, according to C. Ola Landgren, MD, PhD.

“I strongly believe that integrating the biology of the disease and the clinical variables and [using] that information to propose a better treatment is the way the field will be going,” Landgren said in an interview with 

 during Multiple Myeloma Awareness Month, observed annually in March. “Precision medicine is here to stay, and that’s going to drive all the good outcomes in the future for patients with myeloma.”

At the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, Landgren and colleagues are developing CORAL-histomorph, which is a novel, next-generation machine-learning model designed to predict genomic abnormalities from routine histopathology bone marrow biopsy images.

 The model is also intended to integrate clinical and treatment data to provide treatment guidance on an individual patient level. Although it remains a research tool rather than a current resource for clinical practice, Landgren and colleagues have explained that CORAL-histomorph can accurately predict genomic subgroups based on histopathology slides, and the scalable architecture allows for continuous databased expansion, which could extend to other tumor types.

In the interview, Landgren explained the need for improved risk-stratification strategies in multiple myeloma, how tools like CORAL-histomorph could aid in determining individual risk and optimal treatment approaches, and the continuing goal of bringing personalized therapy to this patient population.

Landgren is a professor, chief of the Division of Myeloma in the Department of Medicine, director of the Sylvester Myeloma Institute, co-leader of the Translational and Clinical Oncology Program, and the Paul J. DiMare Endowed Chair in Immunotherapy at the Miller School of Medicine at the University of Miami and the Sylvester Comprehensive Cancer Center.

: What are the current approaches for risk stratification in multiple myeloma, and what is the importance of continuing to refine this process?

: Patients with multiple myeloma are risk stratified using different types of prognostic models that have been around for a long time. The first models came in the 1970s, and we have seen updates in the [decades since]. [The University of Miami] has been involved in the development of many of these models.

Current models put patients in categories of being lower risk, intermediate risk, or higher risk for various outcomes, but these are really risks within a group. Patients are not individualized to determine their risk. It’s the group risk we’re talking about. That means a patient can be in the low-risk group, but some [of those low-risk] patients [could still have] adverse outcomes; [conversely,] patients could be in the higher-risk group but not have an adverse outcome. Because you don’t know if [a given patient] is going to have the adverse outcome, it ends up being a probability game where [patients] have lower-risk, intermediate-risk, or high-risk [disease] on a group level.

What we have worked on more recently is to develop individualized prediction models, and I think that’s the direction where the whole field of medicine is going.

AI-Based Risk-Stratification Tools in Multiple Myeloma

A novel AI model, CORAL-histomorph, can predict genomic abnormalities from bone marrow biopsy images, offering a potential new approach to risk stratification in multiple myeloma.

Unlike traditional group-based models, CORAL integrates biological, clinical, and treatment data to generate individualized risk predictions and therapy recommendations.

Although still a research tool, the model highlights how AI-driven precision medicine could improve treatment selection and outcomes in multiple myeloma care.

Researchers at Sylvester Comprehensive Cancer Center at the University of Miami have developed CORAL to help predict individual patient outcomes and guide treatment decisions. How was this model designed?

At the Sylvester Myeloma Institute at the University of Miami, we have worked for a long time developing individualized prediction models for outcomes. More recently, we disclosed and showed outcomes from our CORAL model. We have a CORAL-histomorph model, and we have other types of CORAL models. They take into account all the factors that include disease biology, clinical data from the individual patient, and treatment data. When we know all these variables and we know what the clinical outcome is, we train the model with thousands of cases. Now, when we show the model a patient with certain biological and clinical features, we could ask: Which would be the best treatment to give to this patient? Or we could say: We are planning on giving this treatment; what would be the predicted outcome, and do you have better suggestions? The model is helping us with decision-making.

In the most recent version of the CORAL-histomorph model, we have also integrated what people refer to as multi-modal components of the model. What we have realized is that most people have clinical data; you can capture treatment data for the majority of our patients. However, we may not have all the details of the disease. In order to do full [disease] characterization [via] whole genome sequencing or other types of transcriptomic analysis. Many times, those [data] are not available. A patient may have been diagnosed and worked up somewhere else.

With the CORAL-histomorph model, we take pictures of the bone marrow biopsy from the initial diagnosis, and we have built advanced models that can analyze these pictures and translate that information into the language of all these sequencing technologies.

How are you applying the CORAL tool in myeloma practice?

The CORAL-histomorph model we have developed is a new model. We have just started presenting it at different meetings. We have worked on it for several years, and we have shown that we can take a picture of a bone marrow biopsy that’s been obtained at diagnosis, and if we have the information from fluorescence in situ hybridization [FISH] or sequencing, we have trained the model to [see] what [different presentations] looks like.

Now, with thousands of cases [taught to the model], if we show a picture from the bone marrow of a case where the computer does not know the FISH, the cytogenetics, or sequencing [results], we can ask the computer, and it can then compare the pictures with all those pictures that it has been trained on, when we have that information. We have already found that the prediction [rate] is over 90% correct. In more than 90% of cases, it will, for example, tell us if there is an 11;14 translocation.

We can do a lot of other things [with CORAL]. We can predict the subtype of the disease. Also, by integrating [several] variables, [the computer can] say: Based on what I see, this treatment would be the best, because from all I know, compared with all these other cases that looked like this, if the patient were treated with all these different therapies, this therapy would give the best projected long-term outcome.

We could integrate [this model] for suggestions on [myeloma] management. It’s not yet implemented in clinical care, and I don’t think it will replace doctors, but this will be an important tool going forward. Right now, it’s a research tool, but we are considering this as a tool to enhance and disseminate all the knowledge we have at expert centers to maybe centers where [oncologists] don’t see as many patients [with myeloma].

As the multiple myeloma treatment arsenal continues to grow and provide patients with different options across various lines of therapy, what is the importance of further individualizing risk stratification and treatment decision-making?

The [multiple myeloma] field has come a long way. We have developed many new treatments and strategies for patients, both in the newly diagnosed and relapsed settings. Still, we do not have a curative treatment, for example. We also have patients who don’t do as well with these new, fantastic treatments that the majority of patients can benefit from.

In order to solve those problems and move to the next level, we need to think about the details of the individual cases. Prediction of individual cases takes us back to precision medicine. Instead of giving all the treatment to every patient, where we probably could over-treat some patients, maybe we can give less. For those patients who don’t do as well with the best therapies we have, maybe we need to change those treatments. Maybe we need to add some other drugs. What are those drugs? What are the mechanisms of those drugs that we need? Precision medicine will be the tool.

Rajanna AR, Hurtado Martinez JA, Durante M, et al. Individualized treatment risk stratification using histopathology-based genomics prediction in multiple myeloma: A multicenter study in 1429 participants. Blood. 2025;146(suppl 1):4008.

Myeloma: how AI is redrawing the map of cancer care. News release. Miller School of Medicine. December 19, 2025. Accessed March 30, 2026. https://news.med.miami.edu/a-new-lens-on-multiple-myeloma/

C. Ola Landgren, MD, PhD, discusses the development of the AI risk-stratification model CORAL and its potential role in individualizing myeloma care.

AI Tools Could Drive Improved Risk Stratification, Treatment Decision-Making in Multiple Myeloma

Varying outcomes were observed following treatment with cemiplimab-rwlc (Libtayo) plus chemotherapy in molecularly defined subsets of patients with nonsquamous non–small cell lung cancer (NSCLC), according to findings from an analysis of the phase 3 EMPOWER-Lung 3 trial (NCT03409614) presented during the 

mutations and any PD-L1 status who received cemiplimab plus chemotherapy (n = 32) experienced a median overall survival (OS) of 9.6 months (95% CI, 6.7-36.3) compared with 10.8 months (95% CI, 5-19.1) among patients who received chemotherapy alone (n = 13; HR, 0.67; 95% CI, 0.31-1.45). Those with 

 wild-type disease in the cemiplimab (n = 118) and placebo (n = 28) arms had a median OS of 18.1 months (95% CI, 13.9-24.8) and 7.6 months (95% CI, 5.5-16.1), respectively (HR, 0.49; 95% CI, 0.31-0.78).

Cemiplimab plus chemotherapy produced variable outcomes by genomic profile in patients with nonsquamous NSCLC.

Cemiplimab combined with chemotherapy may provide clinical benefits in molecular subgroups, such as 

 mutations had a negative effect on ORR, however 

 comutations did not appear to affect ORR.

-mutated disease and a PD-L1 expression level of at least 1%, the median OS values in the cemiplimab (n = 15) and placebo (n = 11) cohorts were 36.3 months (95% CI, 6.7-not evaluable [NE]) and 13 months (95% CI, 5-19.1), respectively (HR, 0.39; 95% CI, 0.13-1.13). Those with 

 wild-type disease experienced a median OS of 24 months (95% CI, 18.1-35.5) in the cemiplimab arm (n = 84) compared with 9.2 months (95% CI, 3.8-17.4) in the placebo arm (n = 21; HR, 0.37; 95% CI, 0.21-0.64).

Patients with a PD-L1 expression level of 1% to 49% with 

-mutated disease who received the combination (n = 8) experienced a median OS of 54.2 months (95% CI, 6-NE) compared with 13 months (95% CI, 0.8-19.1) with chemotherapy alone (n = 10; HR, 0.2; 95% CI, 0.04-1). The median OS values for patients with 

 wild-type disease in the cemiplimab (n = 38) and placebo (n = 10) arms were 19.4 months (95% CI, 14-31.9) and 12 months (95% CI, 1.7-18.2), respectively (HR, 0.43; 95% CI, 0.19-0.96).

“Comprehensive genomic analyses revealed differential outcomes with cemiplimab plus chemotherapy in molecularly defined subsets of NSCLC, including benefit in those with historically limited [immune checkpoint inhibitor therapy] response,” Fred R. Hirsch, MD, PhD, and coauthors, wrote in a poster presentation of the data.

Hirsch is a professor of medicine, hematology, and medical oncology, and of pathology, molecular, and cell-based medicine, the Ning Zhao Chair and Professor of Medicine (Hematology and Medical Oncology) and Pathology, and the executive director of the Center for Thoracic Oncology at the Icahn School of Medicine at Mount Sinai in New York, New York. He is also the codirector of the Center of Excellence for Thoracic Oncology and associate director of biomarker discovery at the Mount Sinai Tisch Cancer Center.

Key Takeaways from EMPOWER-Lung3 Genomic Analyses Presented at ELCC

FDA approved cemiplimab in combination with platinum-based chemotherapy

 in adult patients with advanced non–small cell lung cancer with no 

 The regulatory decision was supported by prior data from EMPOWER-Lung 3, which showed that the combination led to a significant OS benefit compared with placebo plus chemotherapy (HR, 0.71; 95% CI, 0.53-0.93; 2-sided 

How was EMPOWER-Lung 3 designed, and what did the genomic analysis examine?

EMPOWER-Lung 3 enrolled treatment-naive patients with stage IIIB/IIIC and IV nonsquamous and squamous advanced NSCLC.

 Other key eligibility criteria included the absence of 

 aberrations, and an ECOG performance status of 0 or 1. Patients with any level of PD-L1 expression were permitted. Stratification occurred based on PD-L1 expression levels (< 1% vs 1%-49% vs ≥ 50%) and histology (nonsquamous vs squamous).

Eligible patients were randomly assigned 2:1 to receive cemiplimab at 350 mg every 3 weeks or a matching placebo. Patients in both arms received investigator’s choice of platinum-doublet chemotherapy every 3 weeks for 4 cycles. In the genomic analysis, baseline tumor samples or plasma was assessed via fixed gene panel next-generation sequencing using the Foundation One Tracker or Liquid CDx assays.

The primary end point was OS. Key secondary end points included progression-free survival and overall response rate (ORR).

At baseline, 78% (n = 362) of patients in the intention-to-treat population had available genomic data. Patients with available data and nonsquamous disease (n = 191) were treated with cemiplimab plus chemotherapy (n = 150) or chemotherapy alone (n = 41). In the PD-L1 all-comer population, disease mutations consisted of 

What additional data from the analysis were shared during the congress?

Additional findings from the genomic analysis revealed that patients with 

 comutations who received the combination (n = 12) experienced an ORR of 33.3%. Patients with 

 wild-type (n = 80) disease achieved respective ORRs of 36.8%, 35%, and 42.5%.

 comutations who received the combination (n = 23) had an ORR of 34.8%. Patients with 

wild-type (n = 46) disease achieved ORRs of 45.8%, 33.3%, and 32.6%, respectively.

 comuations who received cemiplimab plus chemotherapy (n = 13), the ORR was 15.4%. Patients with 

 wild-type (n = 111) disease experienced respective ORRs of 0%, 47.4%, and 43.2%.

–comutated subgroup (n = 12), the ORR was 16.7%. Those with 

wild-type (n = 92) disease had respective ORRs of 42.1%, 0%, and 44.6%.

“These comprehensive genomic analyses [highlighted] the differential effects of driver mutations on clinical outcomes following first-line anti–PD-L1 and chemotherapy combination [treatment] for patients with advanced NSCLC by PD-L1 expression levels,” Hirsch and his coauthors wrote. “Cemiplimab combined with chemotherapy may provide clinical benefits in molecular subgroups, such as 

-mutant NSCLC, which have historically shown [a] limited response to anti–PD-(L)1 therapies.”

Hirsch did not list any financial disclosures in the presentation.

Hirsch FR, Anagnostou V, Gandara DR, et al. Impact of genomic alterations on clinical outcomes with first-line cemiplimab + chemotherapy for advanced NSCLC: an analysis from EMPOWER-Lung 3. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 76P.

FDA approves cemiplimab-rwlc in combination with platinum-based chemotherapy for non-small cell lung cancer. News release. FDA. November 8, 2022. Accessed March 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-combination-platinum-based-chemotherapy-non-small-cell-lung-cancer

EMPOWER-Lung3 Analysis Reveals Differential Outcomes With Cemiplimab/Chemo in Genomic Subsets of NSCLC

Although patients with early-stage kidney cancer often experience a favorable prognosis, there are remaining unmet needs for patients with high-risk disease and those who are at an increased risk of disease recurrence, underscoring the need for further advances in the adjuvant space and effective biomarkers to better personalize therapy, according to Neil Mendhiratta, MD, MS.

“Kidney cancer is one of the most common urologic malignancies that we treat as urologists and as medical oncologists,” Mendhiratta said in an interview with 

®. “[Although] there’s excellent prognosis for [patients with] early-stage disease, there are still patients who require early intervention. It’s important to get the word out there about advances in treatment options and to [ensure] that patients follow up with their providers and understand those options so that they can benefit from early intervention in these situations.”

Mendhiratta is an assistant professor of urology at the GW School of Medicine & Health Sciences in Washington DC.

In honor of Kidney Cancer Awareness Month, which occurs annually in March, Mendhiratta joined us for an interview to discuss data updates in renal cell carcinoma (RCC), including those shared during the 

 (ASCO GU), the emergence of treatment individualization in the space, and notable future research directions in kidney cancer.

Adjuvant treatment with agents such as pembrolizumab and belzutifan has improved outcomes for patients who are at an increased risk of disease recurrence.

Investigators are working to develop biomarkers and testing approaches to better guide treatment personalization.

The role of cytoreductive nephrectomy is being further evaluated in clinical trials such as SWOG 1931/PROBE.

: What have been some of the most notable data updates in kidney cancer in recent years?

: As a urologic oncologist, I’m focused primarily on the localized space. Some of the recent trials that we’re paying attention to and are causing a shift in the paradigm of how we treat kidney cancer are those that focus on treatment in the adjuvant space. [Although] outcomes for [patients with] early-stage, localized disease with surgery are in general excellent, there are a number of patients who have either high-risk features or locally advanced disease who are at a high likelihood of recurrence. Therefore, understanding whether there are strategies that can help reduce that risk of recurrence can be beneficial.

[Data from the phase 3] KEYNOTE-564 trial [NCT03142334] showing that the addition of adjuvant pembrolizumab [Keytruda] can improve outcomes with respect to not just disease-free survival [DFS] but also overall survival [OS] certainly have been practice changing for many providers.

 We saw recently at ASCO GU [with] the [phase 3] LITESPARK-022 trial [NCT05239728] that there’s a benefit with adding belzutifan [Welireg], which targets HIF-2α, to pembrolizumab, in terms of further reducing the risk of recurrence and prolonging DFS.

 We’ll [have to] wait to see whether that translates to an OS benefit, but many of us remain optimistic.

There’s [also] been a lot of work in terms of sequencing therapies in the advanced and metastatic spaces, including the addition of novel agents like belzutifan. Certainly, we’re all interested to see data from [the phase 3] LITESPARK-011trial [NCT04586231] as well.

How has treatment personalization evolved for patients with kidney cancer and where do you see this trend moving in the future?

It’s not a one-size-fits-all [approach] in terms of treatments for patients with localized disease as well as [those with] advanced disease. Some of the ways where we are trying to individualize treatments strategies have to do with identifying patients who are at risk of developing more aggressive RCC vs those who may have more indolent disease. [One] risk factor [is] a family history that can indicate a hereditary syndrome. We know that recognition of those hereditary syndromes can make a difference in terms of outcomes for these patients.

[We also want to] make sure that we know whether these patients are at risk of [developing] aggressive tumors, such as those with HLRCC or SDH deficiencies. [This] can really make a difference in treating early-stage, localized disease. We’re still looking to identify good biomarkers for patients who are going to benefit from adjuvant treatments, certain IO [immuno-oncology] combinations, or IO/TKI combinations. This remains one of the challenges in kidney cancer treatment, but certainly [it’s something] we’re looking forward to understanding better so we can more specifically tailor our treatment strategies to each patient.

Beyond the need for better biomarkers, what are some of the other unmet needs for patients with kidney cancer that investigators are working to fill?

[First], the treatment of [patients with] non–clear cell RCC, certainly in the advanced space, accounts for approximately 20% to 30% of RCC cases and unfortunately has been understudied in terms of treatment strategies for advanced disease. That remains a challenge for many patients and for the field. In the localized space, we struggle sometimes with overtreatment for low-risk and indolent tumors as well as benign entities.

Some of the ways that we’re going to help reduce that risk of over treatment will be with new diagnostic modalities, which will hopefully help us differentiate clear cell RCC from benign entities that can sometimes look similar in terms of radiographic appearance. Recent data [have also] shown us the utility of Tc-sestamibi SPECT/CT, which has excellent sensitivity and specificity for renal oncocytoma, so we can better identify patients who may not benefit from aggressive early interventions.

What are some potential future developments in the space that you are interested in?

I’m excited to see a couple of things be developed in the future. One is biomarker development for identification of patients who benefit from certain treatment strategies, such as immunotherapies and targeted therapies. The other is better understanding the role of cytoreductive nephrectomy, which, as a urologic oncologist, is relevant to my practice. We’ve seen that there may not always be a benefit to upfront cytoreductive nephrectomy, but with the novel therapies that are now available, including IO therapies and TKI combination therapies, questions remain. We’re seeing that the paradigm has shifted from upfront cytoreductive nephrectomy to potentially delayed cytoreductive nephrectomy and [we need to know] whether that benefits patients.

One of the trials that’s exploring [this question] is the [phase 3] SWOG 1931/PROBE trial [NCT04510597] which is looking at delayed cytoreductive nephrectomy after 3 months of FDA-approved systemic therapy vs continued systemic therapy.

 That’s one that I’m keeping an eye on.

What is your takeaway message for oncologists practicing in the community regarding the present treatment landscape of kidney cancer?

Certainly in the localized space, we’re seeing an increased incidence of small renal masses, but still overall excellent long-term outcomes for patients who are treated appropriately. We are seeing that active surveillance has become a viable strategy for many patients with small renal masses without significant reduction in cancer-specific survival or OS.

A major shift over the past decade or so has been the introduction of immunotherapy agents for advanced and metastatic disease, which really changed the outlook for [these] patients. Many patients [can] have long-term, durable responses, which was rarely seen before. The outlook is very promising and we are still determining the best sequencing of therapies for these patients.

Haas NB, Powles T, Tomczak P, et al. Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC). 

. 2025;43(suppl 16):4514. doi:10.1200/JCO.2025.43.16_suppl.4514

Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. 

. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418

Comparing the outcome of immunotherapy-based drug combination therapy with or without surgery to remove the kidney in metastatic kidney cancer, the PROBE trial (PROBE). ClinicalTrials.gov. Updated September 9, 2025. Accessed March 30, 2026. https://clinicaltrials.gov/study/NCT04510597

Neil Mendhiratta, MD, MS, discusses the treatment landscape for patients with kidney cancer during Kidney Cancer Awareness Month.

Adjuvant Treatment Advances Improve Outcomes in Kidney Cancer but Unmet Needs Persist

Lurbinectedin Plus Atezolizumab Maintenance for ES-SCLC: 

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the approval of lurbinectedin (Zepzelca) in combination with atezolizumab (Tecentriq) for the first-line maintenance treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has not progressed following standard induction therapy.

This recommendation was backed by findings from the phase 3 IMforte trial (NCT05091567), in which patients who received lurbinectedin plus atezolizumab achieved a 46% reduction in the risk of disease progression or death and a 27% reduction in the risk of death compared with patients who received atezolizumab alone. The median progression-free survival (PFS) per independent review facility (IRF) was 5.4 months (95% CI, 4.2-5.8) with lurbinectedin plus atezolizumab (n = 242) vs 2.1 months (95% CI, 1.6-2.7) with atezolizumab alone (n = 241; stratified HR, 0.54; 95% CI, 0.43-0.67; 2-sided 

 The respective 12-month IRF-assessed PFS rates were 20.5% and 12.0%.

Furthermore, the median overall survival (OS) was 13.2 months (95% CI, 11.9-16.4) in the lurbinectedin arm compared with 10.6 months (95% CI, 9.5-12.2) in the control arm (stratified HR, 0.73; 95% CI, 0.57-0.95; 2-sided 

 = .0174). At 12 months, the respective OS rates were 56.3% and 44.1%.

“This positive opinion represents a significant step forward in providing patients in Europe with access to an innovative therapy for a disease with a particularly poor prognosis,” Luis Paz-Ares, MD, PhD, head of the Medical Oncology Service at the 12 de Octubre University Hospital in Madrid, Spain, as well as principal investigator of the IMforte trial, stated in a news release.

 “For the first time in this maintenance context, an improvement in OS and PFS has been demonstrated, marking a milestone in the [management] of this disease. For health care professionals, this advancement provides a new treatment option to offer our patients.”

Lurbinectedin plus atezolizumab maintenance therapy improved the median PFS to 5.4 months (95% CI, 4.2-5.8) compared with 2.1 months (95% CI, 1.6-2.7) with atezolizumab alone, representing a 46% reduction in the risk of disease progression or death (stratified HR, 0.54; 95% CI, 0.43-0.67; 2-sided 

The combination also generated a superior median OS of 13.2 months (95% CI, 11.9-16.4) vs 10.6 months (95% CI, 9.5-12.2) in the control group, resulting in a 27% reduction in the risk of death (stratified HR, 0.73; 95% CI, 0.57-0.95; 2-sided 

Based on these milestone survival improvements, the EMA’s CHMP recommended approval of the regimen for the first-line maintenance treatment of patients with ES-SCLC, following a similar FDA approval in October 2025.

What was the design of the IMforte trial?

This trial enrolled patients with ES-SCLC who had received no prior systemic treatment for SCLC, had no central nervous system metastases, and had an ECOG performance status of 0 or 1.

Patients received 4 cycles of induction therapy consisting of atezolizumab, carboplatin, and etoposide every 3 weeks. After induction, patients who had ongoing complete response, partial response, or stable disease and an ECOG performance status of 0 or 1 (n = 483) were randomly assigned to receive maintenance therapy with intravenous (IV) lurbinectedin at 3.2 mg/m² every 3 weeks in combination with atezolizumab at 1200 mg IV every 3 weeks, or atezolizumab monotherapy at the same dosing schedule.

The coprimary end points were PFS by IRF and OS. Secondary end points included investigator-assessed PFS, overall response rate, duration of response, and safety.

What is the safety profile of lurbinectedin plus atezolizumab as first-line maintenance therapy in ES-SCLC?

The most common all-cause adverse effects among patients who received lurbinectedin plus atezolizumab included nausea (36.4%), anemia (31.8%), fatigue (20.2%), decreased appetite (16.9%), decreased platelet count (15.3%), diarrhea (14.0%), vomiting (13.6%), asthenia (12.8%), thrombocytopenia (12.8%), decreased neutrophil count (12.8%), constipation (12.0%), and neutropenia (10.7%).

“The CHMP’s positive opinion represents a very important milestone in facilitating access for European patients to a new therapeutic option,” Luis Mora, managing director of PharmaMar, added in the news release.

 “It also represents important recognition of our Company’s commitment to research and development of innovative new compounds.”

What other regulatory updates for lurbinectedin in SCLC are important to note?

Following a positive opinion from the EMA’s Committee for Orphan Medicinal Products, lurbinectedin was also approved in Europe as an orphan medicinal product for the treatment of patients with SCLC.

the FDA approved lurbinectedin plus atezolizumab

 or atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza) as maintenance therapy for adult patients with ES-SCLC whose disease has not progressed following first-line induction therapy with atezolizumab or atezolizumab and hyaluronidase, carboplatin, and etoposide.

 This regulatory decision was also supported by data from IMforte.

Lurbinectedin plus atezolizumab received CHMP recommendation as first-line maintenance for ES-SCLC that has not progressed following induction therapy.

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