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Spotlight

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Authors

David M. Waterhouse, MD, MPH, and Molly Mendenhall, MBOE, LSSBB, BSN, RN, discuss how the implementation of Lean Six Sigma methodology at Oncology Hematology Care in Cincinnati, Ohio, has transformed clinical operations and elevated the quality of patient care.

Lean Six Sigma in Oncology: Insights From Waterhouse and Mendenhall

ASH 2024 Preview for Community Oncologists: The Show and After Show

The American Society of Hematology (ASH) Annual Meeting and Exposition aims to educate oncology providers across an array of hematologic malignancies, with a focus on novel agents, drugs across the FDA pipeline, and more.

, co-hosts Kristie L. Kahl and Andrew Svonavec offer a glimpse at some of the presentations guaranteed to spark one’s curiosity, spur debate, and enhance the field even further. Some key highlights include:

 Continued advancements in CAR T-cell therapy are expected to revolutionize the treatment of hematologic malignancies.

 Bispecific antibodies, such as Epcoritamab (Epkinly), offer a novel approach to target multiple antigens on cancer cells.

 The assessment of MRD is becoming increasingly important in predicting treatment response and overall survival.

Advances in Acute Lymphoblastic Leukemia (ALL)

Blinatumomab (Blincyto) in pediatric ALL:

 The addition of blinatumomab to chemotherapy has shown promise in improving disease-free survival in high-risk pediatric ALL. This combination therapy may offer a more effective treatment option for young patients.

Acalabrutinib (Calquence) in mantle cell lymphoma (MCL):

 The FDA is set to review the approval of acalabrutinib with bendamustine or rituximab (Rituxan) for previously untreated MCL, based on data from the phase 3 ECHO trial (NCT02972840).

Asciminib (Scemblix) in chronic phase chronic myelogenous leukemia (CML-CP):

 The FDA recently granted accelerated approval to asciminib for newly diagnosed CML-CP. This tyrosine kinase inhibitor has shown favorable safety and tolerability profiles.

 isn't just about data, as the duo also offers food recommendations, tourist attractions and fun activities to partake in, as well as interesting facts about San Diego.

This is just a taste of the wealth of information and inspiration waiting at the 2024 ASH Annual Meeting. Check back for future meeting previews with 

Targeted Oncology co-hosts Kristie L. Kahl and Andrew Svonavec highlight abstracts for community oncologists to look out for at the upcoming ASH Annual Meeting in San Diego, with some additional tidbits to round out the main event.

News

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

According to data from the phase 3 BREAKWATER trial (NCT04607421), the combination of encorafenib (Braftovi), cetuximab (Erbitux), and mFOLFOX6 resulted in a statistically significant and clinically meaningful improvement in overall response rate (ORR) compared to mFOLFOX6 alone in patients with metastatic colorectal cancer (mCRC) harboring 

 V600E mutations. These data were presented at the 2025 Gastrointestinal Cancers Symposium.

Findings demonstrated patients treated with encorafenib plus cetuximab and chemotherapy (n = 110) achieved an ORR of 60.9% (95% CI, 51.6%-69.5%) per blinded independent central review (BICR) compared with 40.0% (95% CI, 31.3%-49.3%) for patients treated with chemotherapy alone (n = 110; odds ratio, 2.443; 95% CI, 1.403-4.253; one-sided 

In the experimental arm, best responses comprised complete response (CR; 2.7%), partial response (58.2%), stable disease (28.2%), progressive disease (PD; 2.7%) non-CR/non-PD (2.7%), and not evaluable (NE; 5.5%). In the control arm, these respective rates were 1.8%, 38.2%, 30.9%, 3.6%, 8.2%, and 17.3%.

“[Data from the BREAKWATER] study support encorafenib plus cetuximab and mFOLFOX6 as a new standard of care in the first line for patients with 

 V600E–mutated mCRC and formed the basis of the accelerated approval by the FDA,” lead study author Scott Kopetz, MD, PhD, FACP, said in a presentation of the data. Kopetz is deputy chair for Translational Research and a professor in the Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine; leader of the Department of Cancer Center Support Grant, GI Program; TRACTION medical director in the Division of Therapeutics Discovery Division; and associate vice president for Translational Integration at The University of Texas MD Anderson Cancer Center in Houston.

the FDA granted accelerated approval to encorafenib in combination with cetuximab and mFOLFOX6

 for the treatment of patients with mCRC harboring a 

 V600E mutation, as detected by an FDA-approved test.

Investigators for the open-label, multicenter study enrolled patients at least 16 years of age (or at least 18 years of age based on the country) with 

 V600E–mutated mCRC per local or central laboratory testing.

 Prior systemic therapy in the metastatic setting was not allowed. Key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria; an ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function.

Patients were excluded if they received prior treatment with a BRAF or EGFR inhibitor; had symptomatic brain metastases; or harbored a 

 mutation. Patients with mismatch repair–deficient/microsatellite instability–high disease were excluded; however, these patients were allowed to enroll if they were ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition.

The study enrolled 637 patients who were randomly assigned in a 1:1:1 fashion to receive encorafenib plus cetuximab alone (n = 158); encorafenib plus cetuximab and mFOLFOX6 (n = 236); or standard-of-care mFOLFOX6 alone (n = 243). Data for the encorafenib/cetuximab arm will be reported at a later date.

Patients were stratified by region (United States/Canada vs Europe vs rest of world) and ECOG performance status (0 vs 1).

Progression-free survival and ORR per BICR assessment for encorafenib plus cetuximab and mFOLFOX6 vs mFOLFOX6 alone served as the trial’s dual primary end points. Notably, for this analysis, ORR was assessed in the first 110 patients enrolled in the respective arms. Overall survival (OS) was a key secondary end point. OS was only tested if the ORR difference was statistically significant.

Among all enrolled patients between the encorafenib plus cetuximab and mFOLFOX6 arm and the mFOLFOX6 arm (n = 479), the median age was 61.0 years (range, 24-84). Most patients were male (50.5%), had an ECOG performance status of 0 (54.3%), right-sided tumors (61.0%), 2 or fewer organs involved (52.4%), liver metastases (62.6%), a carcinoembryonic antigen level of more than 5 µg/L (68.7%), and a C-reactive protein level of no more than 10 mg/L (50.9%).

The median treatment duration was 28.1 weeks (range, 1.3-107.4) in the encorafenib plus cetuximab and mFOLFOX6 arm vs 20.4 weeks (range, 1.1-98.3) in the mFOLFOX6 arm. All patients in both arms were randomly assigned; however, 2.1% and 5.8% of patients were not treated, respectively.

As of the data cutoff date of December 22, 2023, 58.1% of patients in the encorafenib plus cetuximab and mFOLFOX6 arm were still receiving treatment. Reasons for discontinuation included adverse effects (AEs; 4.7%), death (3.4%), PD (20.8%), patient withdrawal (5.5%), global deterioration of health status (3.4%), and other (4.2%). In the mFOLFOX6 arm, 33.7% of patients were still receiving treatment at data cutoff; reasons for discontinuation comprised AEs (9.1%), death (4.1%), PD (31.7%), patient withdrawal (11.5%), deterioration of global health status (1.6%), and other (8.2%).

The median time to response was 7.1 weeks (range, 5.7-53.7) in the encorafenib plus cetuximab and mFOLFOX6 arm vs 7.3 weeks (range, 5.4-48.0) in the chemotherapy arm. The estimated duration of response (DOR) was 13.9 months (range, 8.5-not evaluable [NE]) and 11.1 months (range, 6.7-12.7), respectively. In the experimental arm, the 6- and 12-month DOR rates were 68.7% and 22.4%, respectively. In the control arm, these respective rates were 34.1% and 11.4%.

Kopetz noted that the ORR benefit was consistent across subgroups with the experimental regimen.

The median follow-up for OS was 10.3 months (95% CI, 8.6-11.6) in the experimental arm vs 9.8 months (95% CI, 7.5-11.3) in the control arm. The median OS was NE (95% CI, 19.8-NE) vs 14.6 months (95% CI, 13.4-NE) for the encorafenib plus cetuximab and mFOLFOX6 arm and the mFOLFOX6 arm, respectively (HR, 0.47; 95% CI, 0.318-0.691; 

 = .0000454). At the time of this analysis, the OS difference was not statistically significant.

Regarding safety, any-grade treatment-emergent AEs (TEAEs) occurred in 99.6% of patients in the experimental arm (n = 231) vs 97.8% of patients in the control arm (n = 228). The rates of grade 3/4 TEAEs were 74.0% and 61.0%, respectively. The respective rates of grade 5 TEAEs were 4.3% and 4.4%. Serious TEAEs were reported in 37.7% of patients in the encorafenib plus cetuximab and mFOLFOX6 arm vs 34.6% of patients in the mFOLFOX6 arm.

In the encorafenib plus cetuximab and mFOLFOX6 group, TEAEs led to permanent discontinuation of any treatment, dose reduction of any treatment, and dose interruption of any treatment in 20.8%, 61.0%, and 84.8% of patients, respectively. These respective rates were 14.9%, 47.8%, and 64.0% in the control arm.

Specifically in the experimental arm, TEAEs led to the discontinuation of encorafenib, cetuximab, and mFOLFOX6 in 11.7%, 13.0%, and 15.6% of patients, respectively. The respective rates of dose reduction for each treatment due to TEAEs were 22.1%, 6.1%, and 55.8%. The rates of dose interruptions due to TEAEs were 56.7% for encorafenib, 58.4% for cetuximab, and 75.8% for mFOLFOX6.

Treatment-related AEs (TRAEs) of any grade were observed in 98.7% of patients in the experimental arm and 93.0% of patients in the mFOLFOX6 arm. The rates of grade 3/4 TRAEs were 69.7% and 53.9%, respectively. No grade 5 TRAEs occurred in the encorafenib plus cetuximab and mFOLFOX6 group; 1 patient (0.4%) experienced a grade 5 TRAE in the control arm. The rates of serious TRAEs were 18.2% and 19.3%, respectively.

The most common TEAEs reported in the experimental arm included nausea (grade 1/2, 48.5%; grade ≥3, 2.6%), anemia (25.5%; 10.8%), diarrhea (32.9%; 1.3%), decreased appetite (31.2%; 2.2%), vomiting (29.9%; 3.5%), decreased neutrophil count (13.9%; 18.2%), asthenia (22.5; 4.3%), pyrexia (24.2%; 1.7%), peripheral sensory neuropathy (19.0%; 5.6%), rash (23.8%, 0.9%), fatigue (21.6%; 2.6%), peripheral neuropathy (16.5%; 6.9%), arthralgia (21.2%; 0.9%), neutropenia (7.4%; 14.7%), alopecia (21.2%; 0%), and constipation (19.9%; 0.4%).

In the control arm, the most frequently reported TEAEs comprised nausea (grade 1/2, 45.2%; grade ≥3, 3.1%), anemia (19.3%; 3.5%), diarrhea (43.4%; 3.5%), decreased appetite (23.7%; 1.3%), vomiting (18.9%; 2.2%), decreased neutrophil count (11.4%; 16.7%), asthenia (13.2%; 1.3%), pyrexia (12.7%; 0.4%), peripheral sensory neuropathy (19.3%; 2.2%), rash (2.6%, 0%), fatigue (22.4%; 2.6%), peripheral neuropathy (18.4%; 2.6%), arthralgia (3.5%; 0%), neutropenia (13.2%; 9.2%), alopecia (9.6%; 0%), and constipation (18.9%; 0.4%).

: Dr Kopetz reported stock and ownership interests in Lylon, Lutris, MolecularMatch, and Navire; serving in a consulting or advisory role for AbbVie, Amal Therapeutics, AstraZeneca/Medlmmune, Bayer Health, BicaraTherapeutics, Boehringer Ingelheim, Boston Biomedical, Carina Biotech, Daichi Sankyo, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Genentech, Gilead Sciences, GSK, HalioDx, Holy Stone Healthcare, Inivata, Ipsen, lylon, Jacobio, Jazz Pharmaceuticals, Lilly, Lutris, Merck, Mirati Therapeutics, Natera, Novartis, Numab, Pfizer, Pierre Fabre, RedxPharma, Repare Therapeutics, Servier, and Xilis; and receiving research funding from Amgen, Array BioPharma, Biocartis, Daichi Sankyo, EMD Serono, Genentech/Roche, Guardant Health, Lilly, Medlmmune, Novartis, and Sanofi.

Kopetz S, Yoshino T, Van Cutsem E, et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. 

. 2025;43(supp 4):16. doi:10.1200/JCO.2025.43.4_suppl.16

FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed January 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf

Encorafenib, cetuximab, and mFOLFOX6 improved ORR over mFOLFOX6 alone in BRAF V600E-mutant mCRC in the BREAKWATER trial.

Conference News

Canonical

Encorafenib Combo Boosts ORR in BRAF V600E-Mutant mCRC

Polatuzumab vedotin ± rituximab ± bendamustine

What therapies would you consider for a patient like this? ​

Who is involved in the decision making?​

 More than half of you would think about tafasitamab [Monjuvi] plus lenalidomide [Revlimid] and then a little bit more than a third would consider the polatuzumab [Polivy] combination [with bendamustine and rituximab (Rituxan)], and some would consider a gemcitabine-based regimen.

It sounds like nearly all of you would treat this patient within the context of your practice …while waiting for cell therapy as opposed to referring for a clinical trial or [stem cell] transplant. I’d love to hear from somebody who chose the polatuzumab option. It gives you a lot of plus/minuses there. Would you add rituximab or bendamustine to this [regimen], and how would you use that combination?

During a Targeted Oncology case-based roundtable event, Christopher R. Flowers, MD, MS, discussed the choice of bridging therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma who may receive CAR (chimeric antigen receptor) T-cell therapy. 

This is the second of 2 articles based on this event. 

Molly Mendenhall, MBOE, LSSBB, BSN, RN

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