Author: RR

Late Breaking Abstract – ASCO 2026: Adjuvant Selpercatinib Delivers Landmark Event-Free Survival Benefit in Early-Stage RET Fusion–Positive NSCLC

RR

SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and adenocarcinoma is now the most frequent histologic subtype of lung cancer. The evolution of precision oncology in NSCLC continues to move beyond the metastatic setting, with targeted therapies increasingly demonstrating meaningful benefits in earlier stages of disease.

The Rationale for Targeting RET in Early Disease

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene result in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, pancreas, breast, and several hematologic malignancies.

Selpercatinib (RETEVMO®) is a highly selective and potent, CNS–penetrant RET inhibitor, designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms. Selpercatinib selectively targets wild-type RET as well as various RET mutants and RET-containing fusion products. Additionally, Selpercatinib inhibits Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), VEGFR3, Fibroblast Growth Factor Receptor 1 (FGFR1), FGFR2, and FGFR3. This results in inhibition of cell growth of tumors that exhibit increased RET activity. This agent has already demonstrated substantial clinical benefit in advanced and metastatic RET fusion–positive NSCLC, leading to its adoption as a standard targeted treatment in that setting.

While targeted therapies directed against EGFR mutations and ALK rearrangements have transformed postoperative management of early-stage NSCLC, patients with RET fusion–positive diseases have not previously had a comparable adjuvant treatment option. Consequently, recurrence following definitive therapy has remained a major concern.

LIBRETTO-432 was designed to determine whether earlier intervention with RET-directed therapy could alter the natural history of the disease and improve long-term outcomes.

Trial Design and Patient Population

LIBRETTO-432 was a global, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 151 patients across 22 countries with Stage IB–IIIA RET fusion–positive NSCLC who had completed definitive locoregional treatment. Participants were randomized in a 1:1 ratio to receive either Sselpercatinib 160 mg twice daily (N=75) or Placebo (N=76) for up to three years. Importantly, the study allowed crossover from placebo to Selpercatinib in the event of disease recurrence, providing patients access to targeted therapy while also enabling assessment of adjuvant treatment benefit. Baseline characteristics were well balanced between treatment arms, ensuring robust comparisons between groups. The Primary endpoint was investigator-assessed Event Free Survival (EFS) in patients with Stage II–IIIA disease. Secondary endpoints included EFS in the overall study population, Blinded Independent Central Review (BICR)-assessed EFS, Overall Survival, and Safety. Median follow-up was 24 months for Selpercatinib and 27 months for Placebo.

Striking Reduction in Recurrence Risk

At the prespecified efficacy analysis, Selpercatinib demonstrated a profound and statistically significant improvement in EFS among patients with Stage II–IIIA disease. The risk of recurrence, progression, or death was reduced by approximately 83% compared with placebo, with a Hazard Ratio of 0.172 (P=0.0003). Median EFS was not reached in the Selpercatinib arm, whereas patients receiving placebo experienced a median EFS of 31.8 months. Only four EFS events occurred among patients receiving Selpercatinib compared with 19 events in the placebo group, underscoring the magnitude of benefit observed.

The separation of the survival curves was reflected in the 24-month EFS rates, which reached 91.5% with Selpercatinib compared with 61.1% with placebo. Independent Central Review confirmed these findings, demonstrating a consistent treatment effect and strengthening confidence in the robustness of the results.

Benefit Extends Across the Overall Study Population

The efficacy advantage observed in the primary analysis population was mirrored in the broader cohort of patients with Stage IB–IIIA disease. In the overall study population, Selpercatinib reduced the risk of an EFS event by approximately 84%, yielding a hazard ratio of 0.165 (P=0.0002). At two years, EFS rates were 93.8% in the Selpercatinib arm compared with 69.6% in the placebo group. The consistency of benefit across both primary and secondary analyses highlights the potential of RET inhibition to become an integral component of postoperative management for RET fusion–positive NSCLC.

Early Survival Signals and Crossover Experience

Although Overall Survival data remain immature, early observations are encouraging.

After a median follow-up of approximately 25 months in the Selpercatinib group, no deaths had been reported. In contrast, three deaths occurred in the placebo arm, all attributed to disease progression.

The crossover design provided valuable insight into treatment sequencing. Sixteen patients initially assigned to placebo crossed over to Selpercatinib after recurrence, with the majority remaining on treatment at the time of analysis. While crossover may ultimately dilute differences in Overall Survival between treatment groups, the substantial EFS benefit observed emphasizes the value of introducing targeted therapy before recurrence occurs.

Manageable Safety Profile Consistent With Prior Experience

The safety findings from LIBRETTO-432 were generally consistent with the established profile of Selpercatinib in advanced RET fusion–positive NSCLC. The most commonly reported grade 3 or higher toxicities included elevations in liver enzymes, specifically ALT and AST, as well as hypertension. Most events were manageable through dose modifications and routine clinical monitoring. Treatment discontinuation due to adverse events occurred in 17.3% of patients receiving Selpercatinib, compared with 1.3% of those receiving placebo. Importantly, no deaths occurred during assigned study treatment, and all reported deaths were confined to the placebo arm as a consequence of disease progression.

These findings suggest that while long-term therapy requires careful toxicity management, the benefit-risk profile remains favorable in light of the substantial reduction in recurrence risk.

Reinforcing the Importance of Comprehensive Biomarker Testing

One of the most important implications of LIBRETTO-432 extends beyond the efficacy of Selpercatinib itself. The study reinforces the necessity of comprehensive genomic profiling at the time of NSCLC diagnosis, regardless of disease stage.

Historically, molecular testing has often been prioritized in advanced disease where treatment decisions depend heavily on biomarker status. However, the emergence of effective adjuvant targeted therapies across multiple genomic subsets, including EGFR, ALK, and now potentially RET, demonstrates that molecular characterization has become equally critical in early-stage disease. Failure to identify actionable alterations at diagnosis may result in missed opportunities to offer therapies capable of substantially reducing recurrence risk and improving long-term outcomes.

Looking Ahead

The success of LIBRETTO-432 reflects a broader transformation in thoracic oncology. Increasingly, therapies initially developed for metastatic disease are being evaluated in earlier-stage settings where the potential impact on cure is greatest. LIBRETTO-432 is the first randomized Phase 3 study to evaluate a RET inhibitor in the adjuvant setting for early-stage RET fusion–positive NSCLC, and its results represent a major advance for this patient population.

With an approximately 83% reduction in the risk of recurrence, progression, or death, Selpercatinib delivered a clinically meaningful and statistically significant improvement in Event-Free Survival while maintaining a manageable safety profile. These findings position adjuvant Selpercatinib as a potential new standard of care for patients with resected RET fusion–positive NSCLC.

Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: Primary results of the phase 3 LIBRETTO-432 trial. Goldman JW, Yang X, Hochmair M, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA3)

Late Breaking Abstract – ASCO 2026: Daraxonrasib Redefines Second-Line Treatment for Metastatic Pancreatic Cancer

RR

SUMMARY: The American Cancer Society estimates that in 2026, about 67,530 people will be diagnosed with pancreatic cancer and 52,940 people will die of the disease. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date. Although pancreatic cancer accounts for only about 3% of all cancer diagnoses in the United States, it is responsible for a disproportionate number of cancer-related deaths due to its aggressive biology and the fact that most patients present with advanced disease. More than half of pancreatic cancers are diagnosed after metastasis has already occurred, and outcomes remain poor despite advances in systemic therapy.

Standard second-line chemotherapy options have historically provided limited benefit, with median Progression-Free Survival (PFS) of approximately 3 to 4 months and median Overall Survival (OS) of just 6 to 7 months. While targeted therapies have transformed treatment paradigms in several solid tumors, their impact in pancreatic cancer has been restricted to relatively uncommon molecular subgroups.

The Phase 3 RASolute-302 trial may represent a turning point. Presented during the Plenary Session of the 2026 ASCO Annual Meeting, the study demonstrated that Daraxonrasib (RMC-6236), a first-in-class oral RAS(ON) multiselective inhibitor, significantly improved survival outcomes compared with standard chemotherapy in patients with previously treated metastatic PDAC.

Targeting a Central Driver of Pancreatic Cancer

The rationale for Daraxonrasib is rooted in the biology of pancreatic cancer itself. Aberrant activation of the RAS signaling pathway is recognized as the dominant molecular driver of PDAC, with oncogenic KRAS mutations identified in more than 90% of tumors. The majority of these alterations occur at codon 12, resulting in constitutive activation of the RAS protein and persistent downstream signaling through pathways that promote tumor growth and survival.

Although several KRAS-directed therapies have emerged in recent years, most are mutation-specific and target only a narrow subset of KRAS alterations. Daraxonrasib was designed to overcome this limitation through a broader mechanism of action.

Rather than binding directly to RAS, Daraxonrasib forms a complex with cyclophilin A that selectively engages the active GTP-bound form of RAS (active “ON” state) and suppresses downstream RAF signaling. This unique approach enables activity across multiple oncogenic RAS variants, including G12, G13, and Q61 mutations, as well as wild-type RAS. The agent also demonstrates activity across all three RAS isoforms: KRAS, NRAS, and HRAS.

This broad-spectrum activity has generated significant interest, particularly in PDAC, where dependence on RAS signaling extends beyond specific mutation subtypes and may also occur through pathway amplification or alterations elsewhere within the RAS-MAPK signaling cascade.

RASolute-302: Evaluating a New Therapeutic Strategy

RASolute-302 was a global, randomized, open-label Phase 3 trial conducted across 59 centers in North America, Europe, and Asia. The study enrolled 500 patients with previously treated metastatic PDAC and ECOG performance status 0–1. Eligible patients had received prior Fluoropyrimidine- or Gemcitabine-based therapy in the metastatic setting and were randomized 1:1 to receive either once-daily oral Daraxonrasib at 300 mg (N=248) or investigator’s choice of standard cytotoxic chemotherapy (N=252).

The trial employed dual Primary endpoints of Overall Survival and Progression-Free Survival in patients harboring RAS G12 mutations, who represented approximately 92% of the study population. Key Secondary endpoints included OS, PFS, objective response rate (ORR), and patient-reported outcomes in both the RAS G12 subgroup and the overall study population. Baseline characteristics were well balanced between treatment arms, allowing for a robust assessment of efficacy and safety.

Survival Outcomes Exceed Historical Expectations

At a median follow-up of 8.5 months, Daraxonrasib met all Primary and key Secondary endpoints, delivering results that substantially exceeded historical benchmarks for second-line treatment in metastatic pancreatic cancer.

Among patients with RAS G12-mutated disease, median Overall Survival reached 13.2 months with Daraxonrasib compared with 6.6 months for chemotherapy (HR=0.40; P<0.0001), translating into a 60% reduction in the risk of death. Progression-free survival similarly improved from 3.5 months with chemotherapy to 7.3 months with Daraxonrasib (HR=0.45; P<0.0001).

Importantly, the survival benefit extended beyond the primary analysis population. In the overall study cohort, including patients with RAS G13 mutations, RAS Q61 mutations, and those without identifiable RAS mutations, median OS remained 13.2 months with Daraxonrasib versus 6.7 months with chemotherapy (HR=0.40; P<0.0001). Median PFS was 7.2 months compared with 3.6 months, respectively (HR=0.49; P<0.0001).

These findings suggest that sustained inhibition of active RAS signaling may provide clinical benefit across a broader spectrum of pancreatic tumors than previously anticipated.

Lead investigator Brian Wolpin, MD, MPH, noted that the study addresses a major unmet need in metastatic PDAC, where no universally accepted second-line standard of care exists and available chemotherapy regimens offer modest efficacy at the cost of significant toxicity.

Response Rates and Quality-of-Life Benefits

Beyond prolonging survival, Daraxonrasib demonstrated meaningful improvements in tumor response.

The confirmed Objective Response Rate (ORR) was nearly three times higher with Daraxonrasib than with chemotherapy. In the RAS G12 population, ORR reached 33.2%, compared with 11.8% for standard treatment. Similar results were observed in the overall study population, where response rates were 31.6% and 11.2%, respectively.

Equally notable were improvements in Patient-Reported Outcomes. Patients receiving Daraxonrasib experienced a significant delay in worsening cancer-related pain and deterioration in overall health status and Quality of Life. Given the substantial symptom burden associated with metastatic pancreatic cancer, these findings underscore the clinical relevance of the survival advantages observed.

The consistency of benefit across multiple efficacy endpoints strengthens the overall therapeutic profile of the agent and suggests that gains in survival are accompanied by meaningful improvements in patient experience.

Favorable Safety Profile Supports Long-Term Use

Safety analyses further distinguished Daraxonrasib from conventional chemotherapy.

Although treatment-related adverse events occurred in nearly all patients, the overall tolerability profile favored the investigational agent. Grade 3 or higher treatment-related adverse events occurred less frequently with Daraxonrasib than with chemotherapy, as did serious treatment-related adverse events, dose reductions, and treatment discontinuations.

The most common toxicities associated with Daraxonrasib were dermatologic and gastrointestinal in nature, including rash, stomatitis, diarrhea, nausea, and vomiting. Most events were low grade and manageable with standard supportive measures and dose modifications.

Importantly, treatment discontinuation due to adverse events occurred in only 1.2% of patients receiving Daraxonrasib, compared with 11.2% among those treated with chemotherapy.

These findings are particularly compelling given the substantially longer median treatment duration achieved with Daraxonrasib, suggesting that prolonged disease control can be attained without a corresponding increase in severe toxicity.

Implications for Clinical Practice

The magnitude of benefit observed in RASolute-302 is noteworthy in the context of metastatic pancreatic cancer, where therapeutic advances have historically been incremental.

Daraxonrasib not only doubled median Overall Survival compared with chemotherapy but also produced consistent benefits across patient subgroups regardless of age, baseline CA19-9 level, prior treatment history, metastatic burden, or RAS mutation status. Such broad activity raises the possibility that targeting the active state of RAS may represent a fundamentally new therapeutic strategy for a disease long considered refractory to precision oncology approaches.

The findings also highlight the potential advantages of multiselective RAS inhibition over mutation-specific approaches. By targeting the activated RAS state rather than a single molecular variant, Daraxonrasib may address the biological heterogeneity that characterizes pancreatic cancer and other RAS-driven malignancies.

Looking Ahead

While RASolute-302 establishes a strong foundation for Daraxonrasib in previously treated metastatic PDAC, additional studies are already exploring its role in earlier disease settings. The ongoing Phase 3 RASolute-303 trial is evaluating Daraxonrasib both as monotherapy and in combination with Gemcitabine plus nab-Paclitaxel in the first-line metastatic setting. Meanwhile, RASolute-304 is investigating the agent as a post-perioperative strategy in patients with resected PDAC. Together, these studies may determine whether broad RAS inhibition can alter the treatment landscape across the continuum of pancreatic cancer care.

Key Takeaway

The Phase 3 RASolute-302 trial represents one of the most significant advances in metastatic pancreatic cancer in recent years. By delivering substantial improvements in Overall Survival, Progression-Free Survival, Response Rates, and Patient-Reported Outcomes, while maintaining a manageable safety profile, Daraxonrasib has emerged as a compelling candidate for a new standard of care in previously treated metastatic PDAC. The results not only validate RAS as a therapeutic target in pancreatic cancer but also signal the arrival of a new generation of broadly active RAS-directed therapies poised to reshape treatment paradigms across oncology.

Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. O’Reilly EM, Wainberg ZA, Hendifar AE, et al. for the RASolute 302 Trial Investigators.  Published May 31, 2026. DOI: 10.1056/NEJMoa2605555

DATROWAY® Demonstrates Survival Advantage in First-Line Metastatic Triple-Negative Breast Cancer

RR

SUMMARY: The FDA on May 22, 2026, approved DATROWAY® (Datopotamab Deruxtecan-dlnk) for adult patients with unresectable or metastatic Triple-Negative Breast Cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Triple-Negative Breast Cancer (TNBC) which accounts for roughly 10-15% of breast cancers remains one of the most biologically aggressive breast cancer subtypes, defined by the absence of estrogen and progesterone receptor expression and lack of HER2 overexpression. The disease is associated with aggressive clinical behavior, high rates of visceral and CNS metastases, early recurrence, and limited Overall Survival once metastatic. Despite therapeutic advances, metastatic TNBC carries a dismal prognosis, with 5-year relative survival rates near 15%. While immune checkpoint inhibitors and targeted therapies have improved prognosis in selected populations, nearly 70% of patients with metastatic TNBC are not candidates for immunotherapy and continue to rely on conventional chemotherapy as first-line treatment. For these individuals, response rates remain modest, disease control is often short-lived, and many patients never reach subsequent lines of therapy. Consequently, there is a critical need for therapies capable of improving outcomes earlier in the disease course.

A Potential New Standard for Patients Ineligible for Immunotherapy

 Datopotamab-deruxtecan (Dato-DXd) is an ADC composed of a TROP2-directed monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker. Trop-2 is a transmembrane calcium signal transducer that stimulates cancer cell growth. TROP-2 is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. It has been associated with poor Overall and Disease-Free Survival in several types of solid tumors. TROP-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to TROP-2, the anti-TROP-2 monoclonal antibody is internalized and delivers the payload directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables the payload to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. The agent has already demonstrated efficacy in Hormone Receptor-positive, HER2-negative metastatic breast cancer and previously showed encouraging activity in heavily pretreated TNBC populations.

Results from the Phase III TROPION-Breast02 trial suggest that Datopotamab Deruxtecan (Dato-DXd) may offer a meaningful new treatment option for this underserved population.

Trial Design and Patient Population

TROPION-Breast02 was a global, randomized, open-label Phase III study evaluating Dato-DXd versus investigator’s choice chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic TNBC, who were not eligible for immunotherapy.

Between May 2022 and June 2024, 644 patients were enrolled and randomized in a 1:1 ratio to receive either Dato-DXd 6 mg/kg IV every three weeks (N=323) or standard chemotherapy (N=321). The study’s dual Primary endpoints were Progression-Free Survival (PFS) assessed by Blinded Independent Central Review and Overall Survival (OS). Importantly, the trial population reflected real-world clinical practice, including patients with early relapse following curative-intent therapy, short disease-free intervals, and brain metastases, groups frequently underrepresented in pivotal studies.

Significant Improvements in Progression-Free and Overall Survival

The study met both of its Primary endpoints, demonstrating statistically significant and clinically meaningful improvements in PFS and OS with Dato-DXd compared with chemotherapy.

Median PFS reached 10.8 months with Dato-DXd versus 5.6 months with chemotherapy, translating to a 43% reduction in the risk of disease progression or death (HR 0.57; P < 0.0001).

Overall Survival findings were equally compelling. Patients receiving Dato-DXd achieved a median OS of 23.7 months compared with 18.7 months for those treated with chemotherapy, representing an approximately five-month survival benefit (HR 0.79; P =0.029).

Beyond survival outcomes, Dato-DXd also demonstrated superior antitumor activity. Confirmed Objective Response Rates were higher and was 64% and 30% in the respective arms. Responses were more durable, with a longer median duration of response.

Investigators noted that efficacy benefits were generally consistent across key patient subgroups, including PD-L1 status, disease-free interval, and geographic region. Although certain regional analyses showed variability in OS hazard ratios, these findings were exploratory and likely influenced by baseline prognostic imbalances and differential use of subsequent ADC therapies.

Expanding the Role of TROP2-Directed ADCs

The positive findings from TROPION-Breast02 further strengthen the emerging role of TROP2-targeted ADCs in metastatic TNBC. The results complement observations from the Phase III ASCENT-03 study evaluating Sacituzumab govitecan in a similar first-line setting. Together, these studies provide growing evidence that TROP2-directed ADCs can outperform standard chemotherapy and potentially redefine treatment paradigms for patients with advanced TNBC.

However, important differences exist between the trials, including eligibility criteria, disease-free interval requirements, chemotherapy comparators, and access to subsequent therapies. Notably, TROPION-Breast02 enrolled patients regardless of disease-free interval, allowing inclusion of patients with particularly aggressive disease who are often excluded from clinical trials.

Manageable Safety Profile Supports Long-Term Treatment

Safety findings were consistent with the established profile of Dato-DXd and did not reveal any new safety signals. Grade 3 or higher treatment-related adverse events occurred in 33% of patients receiving Dato-DXd and 29% of those receiving chemotherapy. Importantly, treatment discontinuation due to adverse events was less frequent with Dato-DXd (4%) than with chemotherapy (7%). No treatment-related deaths were reported in either treatment arm.

The most commonly observed adverse events included stomatitis, nausea, gastrointestinal toxicities, and ocular surface events such as dry eye. Most oral and ocular toxicities were low grade and manageable with supportive care measures. Notably, no patients discontinued Dato-DXd because of stomatitis, while only a small proportion discontinued treatment due to ocular events. When treatment exposure was taken into account, overall adverse event rates, including serious toxicities and treatment discontinuations, were lower with Dato-DXd than with chemotherapy, highlighting the tolerability of prolonged treatment.

Patient-Reported Outcomes Reinforce Clinical Benefit

Beyond traditional efficacy endpoints, Patient-Reported Outcomes (PROs) provided additional evidence supporting the clinical value of Dato-DXd.

Compared with chemotherapy, patients receiving Dato-DXd experienced delayed deterioration in pain, physical functioning, breast and arm symptoms, and overall Quality of Life measures. These findings suggest that the survival improvements achieved with Dato-DXd were accompanied by meaningful preservation of day-to-day functioning and patient well-being.

Looking Ahead

Although the open-label design represents a limitation, the overall results from TROPION-Breast02 are highly encouraging. The study demonstrated robust improvements in both Progression-Free and Overall Survival while maintaining a manageable safety profile in a patient population with historically limited treatment options.

As the treatment landscape for TNBC continues to evolve, these findings position Dato-DXd as a strong candidate for first-line therapy in patients with locally recurrent inoperable or metastatic TNBC who are not eligible for immunotherapy.

For oncology clinicians, the trial marks a significant step forward in addressing one of the most challenging segments of breast cancer care and underscores the growing impact of Antibody-Drug Conjugates in transforming outcomes for patients with aggressive disease.

Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Dent R, Shao Z, Schmid P, on behalf of the TROPION-Breast02 investigators. Annals of Oncology, April 03, 2026. https://doi.org/10.1016/j.annonc.2026.03.008.

CheckMate-9ER primary and exploratory findings: baseline characteristics and treatment outcomes, including depth and durability of response with cabozantinib plus nivolumab

RR

CheckMate-9ER primary and exploratory findings: baseline characteristics and treatment outcomes, including depth and durability of response with cabozantinib plus nivolumab

Written by Dr Manojkumar Bupathi
Sponsored by Exelixis, Inc.

Baseline disease characteristics and tumor biology play a pivotal role in shaping outcomes for patients with advanced renal cell carcinoma (aRCC). As treatment paradigms have evolved toward combination strategies, it has become increasingly important not only to demonstrate efficacy in the overall population, but also to consider the potential for the depth, durability, and consistency of responses across clinically relevant subgroups.1,2

The Phase 3 CheckMate-9ER trial established cabozantinib plus nivolumab as a first-line option for patients with aRCC, demonstrating significant improvements in progression-free survival, overall survival, and objective response rate compared with sunitinib. However, beyond these pivotal results, additional insights from descriptive analyses on long-term outcomes and response characteristics are noteworthy to help inform real-world clinical decision-making.3

In this article, we review the key findings from the CheckMate-9ER trial, including updated 5-year follow-up data, and explore post hoc analyses evaluating baseline characteristics associated with response. In particular, we focus on patients achieving complete responses and examine the depth and durability of response to better contextualize the long-term clinical data observed with cabozantinib plus nivolumab.1,4,5

Overview of CheckMate‐9ER
Cabozantinib is a tyrosine kinase inhibitor, targeting MET, AXL, and VEGFR. Based on the results from the CheckMate-9ER trial, a Phase 3, randomized, open-label, head-to-head trial versus sunitinib, cabozantinib + nivolumab was approved for patients with previously untreated aRCC.3,4

We will begin by reviewing the results from the pivotal trial CheckMate-9ER, which enrolled 651 patients with previously untreated aRCC containing a clear-cell component. Participants were randomized 1:1 to receive cabozantinib 40 mg once daily plus nivolumab 240 mg every 2 weeks, or sunitinib 50 mg once daily administered on a 4 weeks on, 2 weeks off schedule.3,4

  • Endpoints assessed3:
    • Primary endpoint: PFS*
    • Secondary endpoints: OS, ORR*, and safety

*Assessed by BICR.4

CheckMate-9ER studied a broad patient population, including those with a high burden of disease. Select baseline characteristics are shown in Table 1 for the cabozantinib + nivolumab arm.3

Table 13

Renal-Cell-Carcinoma-IMDC-Risk

 

†Data are for tumor sites defined at baseline by the investigators according to RECIST v1.1. The number of target or nontarget lesions at baseline was not reported for 1 patient in the CABOMETYX + OPDIVO group and for 3 patients in the sunitinib group.3

Results in the CheckMate-9ER primary analysis of the intent-to-treat population (median follow-up of 18.1 months; range: 10.6-30.6 months) were as follows3:

  • Median PFS* (mPFS) was 16.6 months with cabozantinib + nivolumab (95% CI: 12.5-24.9) vs 8.3 months  with sunitinib (95% CI: 7.0-9.7) (HR=0.51; 95% CI: 0.41-0.64; P<0.0001)4,6
  • Median OS (mOS) was not reached in either arm (HR=0.60; 98.89% CI: 0.40-0.89; P=0.001)4,6
    • Pre-planned final analysis (median follow-up: 32.9 months; range: 25.4-45.4 months): mOS was 37.7 months for the combination (95% Cl: 35.5-NR) vs 34.3 months with sunitinib (95% Cl: 29.0-NR) (HR=0.70; 95% CI: 0.55-0.90)
  • ORR* was 55.7% (95% CI: 50.1-61.2) with the combination vs 27.1% with sunitinib (95% CI: 22.4-32.3; P<0.0001)4,6
    • Complete response (CR) was 8% (n=26/323) for the combination arm vs 4.6% (n=15/328) with sunitinib
    • Partial response (PR) was 48% (n=154/323) for the combination arm vs
      23% (n=74/328) with sunitinib
  • Serious adverse reactions occurred in 48% of patients receiving cabozantinib + nivolumab (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients4
  • The most common adverse reactions (≥20%) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar‐plantar erythrodysesthesia (PPE) (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), upper respiratory tract infection (20%), and cough (20%)4

The results of the CheckMate-9ER 5-year follow-up analysis (median follow-up of 67.6 months; range 60.2-80.2 months) were as follows. No formal statistical testing was conducted at the time of the updated analysis5:

  • mPFS* was 16.4 months with the combination (95% CI: 12.5-19.3) vs 8.3 months with sunitinib (95% CI: 7.0-9.7) (HR=0.58; 95% CI: 0.49-0.70)
  • mOS was 46.5 months with the combination (95% CI: 40.6-53.8) vs 35.5 months with sunitinib (95% CI: 29.2-42.8) (HR=0.79; 95% CI: 0.65-0.96)
  • ORR* was 55.7% (95% CI: 50.1-61.2) for the combination arm vs 27.4% with sunitinib (95% CI: 22.7-32.6)
    • CR was 13.9% (n=45/323) for the combination arm vs 4.6% (n=15/328)
      with sunitinib
    • PR was 41.8% (n=135/323) for the combination arm vs 22.9% (n=75/328)
      with sunitinib
  • Safety and tolerability were similar to previous follow-ups

*Assessed by BICR.4

To further explore long-term data from the CheckMate-9ER trial, post hoc analyses were conducted to evaluate the baseline characteristics of patients who achieved CR, assess depth of response (DepOR) among those patients with PR, and examine the duration of response in patients with CR or PR.1

Depth and durability of response in patients treated with cabozantinib + nivolumab
The exploratory, post hoc analyses of the 5-year CheckMate-9ER data evaluated depth and durability of response in patients randomized to cabozantinib + nivolumab who were alive 6 months after randomization and who had available data for best overall response (BOR) and sum of diameters of target lesions.1

  • Of the 323 patients randomized to cabozantinib + nivolumab, 293 were alive at the
    6-month landmark
  • Patients were categorized into DepOR subgroups based on BOR per BICR using the maximum tumor reduction observed at any time during the study period

Baseline demographic and disease characteristics of patients receiving cabozantinib + nivolumab by DepOR subgroup are shown in Table 2, which includes patients with characteristics associated with poor prognosis.1

Table 21,7

Characteristics-Demographics

 

  • Among patients who achieved CR (n=45), the median duration of response was not reached at the time of analysis (95% CI: 30.5-NE)1*
  • Among patients who achieved PR (n=135), the median duration of response was 17.3 months (95% CI: 13.8-20.7)7*
  • Median duration of treatment with cabozantinib + nivolumab was 30.4 months for patients achieving CR, over 2 years for those with PR, and 15.3 months for those with stable disease (SD)1*
  • Safety was similar across all subgroups achieving an objective response, and the most frequently reported Grade 3/4 treatment-related adverse events included hypertension (13%), diarrhea (9%), hyponatremia (8%), and PPE (8%)1

These post hoc exploratory analyses are descriptive in nature. No statistical procedure was employed. Results should be considered hypothesis generating.

*Patients who were alive at the 6-month timepoint.1,7

Discussion
In the primary analysis cabozantinib + nivolumab doubled mPFS and demonstrated superior efficacy vs sunitinib across OS and ORR.4 Building on these results, the primary results and exploratory analyses from CheckMate-9ER provide additional context to the established efficacy of cabozantinib + nivolumab in the first-line treatment of aRCC.1,4 Notably, meaningful responses were observed among patients with baseline features traditionally associated with poorer prognosis, underscoring the broad applicability of this combination.1

The median duration of response was not reached among patients achieving complete response. The durability of responses and extended treatment exposure did not appear to be associated with a disproportionate increase in toxicity.1

These findings are derived from post hoc, descriptive exploratory analyses and should be interpreted with caution. Collectively, these data help refine our understanding of which patients may derive the greatest response and further support the role of cabozantinib + nivolumab combination as a first-line therapy option in aRCC.1

Dr Manojkumar Bupathi received a fee for participating in the development of this article, and his comments reflect his opinions and are not intended to constitute medical advice for individual patients.

AXL=AXL receptor tyrosine kinase; BICR=blinded independent central review; CI=confidence interval; HR=hazard ratio; IMDC=International Metastatic RCC Database Consortium; MET=hepatocyte growth factor receptor; NE=not estimable; NR=not reported; ORR=objective response rate; OS=overall survival; PD=progressive disease; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors; VEGFR=vascular endothelial growth factor receptor.

INDICATION
CABOMETYX® (cabozantinib), in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of CABOMETYX patients. Monitor for signs and symptoms, and discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforation.

Thromboembolic Events: CABOMETYX can cause arterial or venous thromboembolic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis.

Cardiac Failure: CABOMETYX can cause severe and fatal cardiac failure. Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue depending on the severity.

Diarrhea: CABOMETYX can cause diarrhea and it occurred in 62% (10% Grade 3) of treated patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1; resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): CABOMETYX can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold CABOMETYX until PPE resolves or decreases to
Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab in RCC can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Monitor liver enzymes before initiation of treatment and periodically. Consider more frequent monitoring as compared to when the drugs are administered as single agents. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or
life-threatening hepatotoxicity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): CABOMETYX can cause ONJ and it occurred in <1% of treated patients. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution; resume at a reduced dose.

Impaired Wound Healing: CABOMETYX can cause impaired wound healing. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): CABOMETYX can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment.

Hypocalcemia: CABOMETYX can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of CABOMETYX patients (2% Grade 3 and 1% Grade 4).
Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume CABOMETYX at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:
CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong or Moderate CYP3A4 Inducers: If coadministration with strong or moderate CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information by clicking here.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

 References

  1. Suárez C, Motzer RJ, Powles T, et al. Characterization of depth and durability of response in patients with previously untreated advanced renal cell carcinoma who received cabozantinib plus nivolumab: long-term follow-up and exploratory analysis of CheckMate 9ER. Poster Presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026.
  2. Zarrabi KK, Lanade O, Geynisman DM. Determining front-line therapeutic strategy for metastatic clear cell renal cell carcinoma. Cancers. 2022;14;4607. doi.org/10.3390/cancers14194607.
  3. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma. N Engl J Med. 2021;384(9):829‐841.
  4. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
  5. Motzer RJ, Escudier B, Burotto M, et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2025; Published online September 23, 2025. doi:10.1016/j.annonc.2025.09.006.
  6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with 2-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. Poster presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium; February 17-19, 2022.
  7. Data on file. Exelixis, Inc.

©2026 Exelixis, Inc.    CA-3913    04/26
OPDIVO® and the related logo are registered trademarks of Bristol‐Myers Squibb Company.

ENHERTU® (fam-Trastuzumab Deruxtecan-nxki; T-DXd)

RR

The FDA on May 15, 2026, approved ENHERTU® for two separate indications in adults with HER2-positive early-stage breast cancer. The first indication is for T-DXd followed by a taxane, Trastuzumab, and Pertuzumab (THP), for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test. The second indication is for T-DXd for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant treatment with Trastuzumab (with or without Pertuzumab) and taxane-based treatment. ENHERTU®  is a product of Daiichi Sankyo, Inc.