ASCO 2024 Solid Tumors

In Stage III Melanoma, Immunotherapy Combo Before Surgery Leads to Improved Survival, Less Therapy

Giving patients with resectable stage III melanoma a combination of ipilimumab (Yervoy) and nivolumab (Opdivo) followed by surgery—and tailoring treatment after surgery to each patient’s response—led to dramatic improvements in event-free survival (EFS), according to results presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

The phase 3 NADINA trial (NCT04949113) represents the fruits of a decade-old idea and follow-up on results seen in smaller studies. Of note, a phase 2 study of pembrolizumab, SWOG 1801 (NCT03698019), showed patients who had 3 neoadjuvant cycles before 15 adjuvant cycles had better EFS than those who received 18 adjuvant cycles.² Ipilimumab and nivolumab are both made by Bristol Myers Squibb, which was among the study’s sponsors.

NADINA not only confirms that immunotherapy before surgery improves survival in these patients but also suggests that for some, it may be possible to eliminate therapy after surgery altogether—a result with huge implications for both patients and the health system. In the study, investigators reported that about 3 of every 5 patients who received neoadjuvant therapy did not need additional adjuvant therapy. Because they had a major pathological response, these patients needed only 6 weeks of treatment.

Christian U. Blank, MD, PhD | Image credit: Netherlands Cancer Institute

As explained during the plenary session by lead study author Christian U. Blank, MD PhD, medical oncologist at the Netherlands Cancer Institute, Amsterdam, the existing standard of care for stage III melanoma calls for removing the tumor and affected lymph nodes via surgery then treating the patient with immunotherapy or targeted therapy to keep the cancer from coming back.

However, as Blank and coauthors wrote in The New England Journal of Medicine, which simultaneously published results, “Despite adjuvant systemic treatment, a substantial proportion of patients have disease recurrence within the first few years after surgery.”³ This is true whether patients receive immune checkpoint inhibitors nivolumab or pembrolizumab—or, for patients with a BRAF mutation, dabrafenib plus trametinib.

During the plenary session, Blank said that exactly 10 years ago, he and collaborator Ton Schumacher developed the idea that checkpoint inhibition “shouldn’t be most effective when given at a lower tumor burden,” and moving therapy ahead of surgery in the treatment queue produced stronger responses. Following the recent studies, the phase 3 NADINA study was designed to test outcomes after administering ipilimumab and nivolumab before lymph nodes were removed.

According to the study protocol, if this neoadjuvant treatment did not destroy at least 90% of the cancer cells—called a major pathological response—patients would receive 1 of the following: adjuvant treatment with nivolumab, or dabrafenib plus trametinib if a BRAF mutation was present.
Between August 2021 and December 2023, NADINA enrolled 423 patients, with 212 receiving neoadjuvant therapy and 211 participants receiving adjuvant therapy. Data cutoff was January 12, 2024, with a median follow-up of 9.9 months. Detailed results show the following¹:

• Significantly fewer events occurred in the neoadjuvant arm vs the adjuvant arm (28 events vs 72 events), for an HR of 0.32 (99% CI, 0.15-0.66; P < .0001).
• Estimated 12-month EFS rates are 83% (99.9% CI, 73.8-94.8) vs 57.2% (99.9 CI, 45.1-72.6), favoring the neoadjuvant arm.
• Among patients with BRAF-mutated melanoma, estimated EFS rates were 83.5% and 52.1%, and in BRAF-mutated wild type, 83.9% and 62.4%, favoring the neoadjuvant arm.
• 58.0% of patients in the neoadjuvant arm had a major pathological response, 8.0% had a partial pathological response, and 26.4% had a pathological nonresponse, whereas 2.4% had progression before surgery.
• Adverse events related to treatment of grade 3 or higher were seen in 29.7% in the neoadjuvant arm vs 14.7% in the adjuvant arm; 1 patient died due to pneumonitis.
• Surgery-related grade 3 or higher AEs were similar: 14.6% in the neoadjuvant arm and 14.4% in the adjuvant arm.

ASCO President Lynn M. Schuchter, MD, FASCO, a melanoma specialist at the University of Pennsylvania, remarked how the idea of using less therapy would run counter to what so many physicians have done for years.

“I have a clinic…when I get back to Philadelphia and I’m sure the clinic has scheduled many new patients,” she said. “So really for the first time, I am going to consider [ipilimumab and nivolumab].… I will say based upon these data and this dosing I am feeling more comfortable. But I am also used to giving a year of therapy.”

Schuchter asked for more discussion on the idea of stopping therapy after only 6 weeks. And commentator Harriet M. Kluger, MD, of Yale Cancer Center, reminded Schuchter and the audience that back when immunotherapy was first approved, some patients had to stop treatment due to toxicity, but their responses continued. Per the study protocol, patients’ pathological responses will drive decisions on adjuvant therapy.

She said she has seen the data, and the idea of giving patients less toxic therapy certainly has appeal. But Schuchter said, “It’s just very different from how we’ve been doing things.”

References
1. Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: the phase 3 NADINA trial. J Clin Oncol. 2024;42 (suppl 17). Abstract LBA2. doi:10.1200/JCO.2024.42.17_suppl.LBA2
2. Patel SP, Othus M, Chen Y. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388(9):813-823. doi:10.1056/NEJMoa2211437
3. Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N Engl J Med. Published online June 2, 2024. doi:10.1056/NEJMoa2402604

TRITON Will Build on Triplet for Patients With Select NSCLC Mutations

The phase 3b TRITON study (NCT06008093) will delve deeper into the effectiveness of a triplet encompassing the immunotherapy of tremelimumab and durvalumab plus standard-of-care (SOC) chemotherapy vs pembrolizumab and SOC chemotherapy for patients with metastatic non–small lung cancer (NSCLC) harboring STK11 and/or KEAP1 and/or KRAS mutations. Tremelimumab (Imjudo) is an anti–CTLA-4 that also can block binding of CD80 and CD 86 to CD28; durvalumab (Imfinzi) is an anti–PD-L1 that also can block binding of PD-L1 to PD-1 and CD80).¹

The trial will build on results seen in the phase 3 POSEIDON trial (NCT03164616), which investigated this same regimen in the first line vs durvalumab with chemotherapy or chemotherapy alone²; findings from the trial led to the FDA approval of tremelimumab and durvalumab plus chemotherapy for NSCLC.³

Results from a subgroup analysis of patients from POSEIDON with the 3 mutations showed they were likely to benefit from the triplet, but the investigators noted the first trial was not powered to thoroughly investigate that outcome.³ The data were presented at the 2024 American Society of Clinical Oncology Annual Meeting, held May 31 to June 5 in Chicago, Illinois.
With a primary outcome of overall survival (OS) indicating treatment efficacy, and secondary outcomes that include safety/tolerability, time to first subsequent therapy or death, and OS at 12 and 24 months, patients in TRITON are being randomly assigned 1:1 to the treatment groups.

Participants, who must be 18 years and older, are required to have a diagnosis of nonsquamous NSCLC refractory to surgery or radiation, at least 1 lesion that has not been irradiated and fits RECIST v1.1 criteria, no systemic therapy for metastasis or immunotherapy in the past 6 months, no EGFR or ALK mutations, an ECOG performance status of 0 or 1, and confirmation of STK11 and/or KEAP1 and/or KRAS mutations or comutations.³
Treatment will initiate with induction of up to 4 cycles in each group. In the treatment group, the cycles will include 75-mg tremelimumab every 3 weeks, 1500-mg durvalumab every 3 weeks, and platinum chemotherapy (either or cisplatin) and pemetrexed every 3 weeks, followed by maintenance of each regimen. In the pembrolizumab/chemotherapy group, induction will consist of 200-mg pembrolizumab every 3 weeks, 1500-mg durvalumab every 4 weeks, and platinum chemotherapy (either carboplatin or cisplatin) and pemetrexed 500mg/m² every 3 weeks.

Maintenance treatment will follow. In the treatment group, this will consist of 75-mg tremelimumab and 1500-mg durvalumab every 4 weeks plus pemetrexed 500mg/m² every 4 weeks. In the pembrolizumab/chemotherapy group, maintenance will consist of 200-mg pembrolizumab every 3 weeks plus pemetrexed 500mg/m² every 3 weeks. Maintenance will be administered until disease progression, unacceptable toxicity, or consent withdrawal. The investigators highlighted that additional doses of tremelimumab can be administered “at the investigator’s discretion” at week 16 after platinum treatment and at month 24.

In nearly 20% and 15% of cases, respectively, individuals with nonsquamous NSCLC who have STK11 and KEAP1 mutations have a greater likelihood of poor outcomes, with previous research identifying correlations between these mutations and both low PD-L1 expression and T-cell activity.^4-7 This effect is amplified in the presence of a KRAS mutation.

Primary findings from POSEIDON show that among the 1013 participants, median progression-free survival (PFS) was 6.2 months with tremelimumab/durvalumab/chemotherapy vs a PFS of 4.8 months with chemotherapy alone, for a 28% reduced risk of death (HR, 0.72; 95% CI, 0.60-0.86; P = .0003). OS was also superior with tremelimumab/durvalumab/chemotherapy, at 14 months vs 11.7 months with chemotherapy, for a 23% reduced risk of death (HR, 0.77; 95% CI, 0.65-0.92; P = .003).

The POSEIDON exploratory analysis, which dovetailed into the TRITON investigation, saw STK11 mutations in 14% of the patients with nonsquamous NSCLC (n = 87), KEAP1 mutations in 6% (n = 51), and KRAS mutations in 30% (n = 182). In this subanalysis, those with KRAS mutations had the longest median OS with tremelimumab/durvalumab/chemotherapy (25.7 months; 95% CI, 9.9-36.7), followed by patients with STK11 mutations (15.0 months; 95% CI, 8.2-23.8) and KEAP1 mutations (13.7 months; 95% CI, 7.2-26.5). The corresponding OS measures for chemotherapy alone were 10.4 months (95% CI, 7.3-12.6), 10.7 months (95% CI, 6.0-14.9), and 13.7 months (95% CI, 7.2-26.5), respectively.

As with the overall POSEIDON investigation, the 5-year OS advantage in the exploratory analysis was clear for the combination compared with chemotherapy alone, respectively as follows:

• KRAS subset: 21.7% vs 8.1%
• KEAP1 subset: 10% vs 0%
• STK11 subset: 12.9% vs 0%

The TRITON investigators are hoping for a patient population of 280; the estimated primary study completion date is August 17, 2027, and the estimated completion date is March 5, 2031.¹ Eleven states have active sites, 10 more sites are planned, and there will be up to 75 sites overall.

References
1. A study to investigate the efficacy of durvalumab plus tremelimumab in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy in metastatic non-small cell lung cancer (NSCLC) patients (TRITON). ClinicalTrials.gov. Updated April 29, 2024. Accessed June 11, 2024. https://clinicaltrials.gov/study/NCT06008093
2. Study of durvalumab + tremelimumab with chemotherapy or durvalumab with chemotherapy or chemotherapy alone for patients with lung cancer (POSEIDON). ClinicalTrials.gov. Updated March 5, 2024. Accessed June 11, 2024.
3. Skoulidis F, Borghaei H, Garon EB, et al. TRITON: Phase 3b study of tremelimumab (T) + durvalumab (D) vs pembrolizumab (P), in combination with chemotherapy (CT), in non-squamous (NSQ) metastatic NSCLC (mNSCLC) with STK11 and/or KEAP1 and/or KRAS mutations. Presented at: ASCO 2024; May 31-June 4, 2024; Chicago, IL. Poster TPS8655.
4. Tanaka I, Koyama J, Itoigawa H, Haya S, Morise M. Metabolic barriers in non-small cell lung cancer with LKB1 and/or KEAP1 mutations for immunotherapeutic strategies. Front Oncol. 2023;13:1249237. doi:10.3389/fonc.2023.1249237
5. Devarakonda S, Morgensztern D, Govindan R. Genomic alterations in lung adenocarcinoma. Lancet Oncol. 2015;16(7):e342-e351. doi:10.1016/S1470-2045(15)00077-7
6. Dabbous F, Wang CY, Simmons D, Huse S. Prevalence of STK11, KEAP1, and KRAS mutations/co-mutations and associated clinical outcomes for patients newly diagnosed with metastatic non-small cell lung cancer. J Clin Oncol. 2023;41(suppl 16):e21186. doi:10.1200/JCO.2023.41.16_suppl.e2118
7. Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19(9):495-509. doi:10.1038/s41568-019-0179-8

Tislelizumab Plus Chemo Improves OS, PFS in Advanced Esophageal Cancer

After 3 years of follow-up, tislelizumab plus chemotherapy continues to show clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) compared with placebo and chemotherapy as a first-line treatment of advanced/metastatic esophageal squamous cell carcinoma.¹

Tislelizumab was recently approved in the United States as a second-line monotherapy for unresectable or metastatic esophageal squamous cell carcinoma after prior systemic chemotherapy.²

Although esophageal cancer makes up approximately 1% of the cancers diagnosed in the United States, it’s much more common in other parts of the world and is the eighth most commonly diagnosed cancer worldwide.³
The 3-year results of the RATIONALE-306 study (NCT03783442), which were presented at the 2024 American Society of Clinical Oncology Annual Meeting, supported the results of the 2-year interim analysis⁴ and the manageable safety profile of tislelizumab plus chemotherapy. After the interim analysis, the study was unblinded.

The study was a randomized, double-blind, phase 3 study including patients who had not received any prior systemic therapy and had an ECOG performance status of 0 to 1. The median age of patients was 64.0 years (59.0-69.0), and the majority (87%) were men.⁴ In addition, 75% of the patients were Asian and 24% were White. Patients were randomly assigned in a 1:1 fashion to receive either tislelizumab 200 mg (n = 326) or placebo (n = 323)

intravenously every 3 weeks plus the investigator’s choice of chemotherapy. The baseline characteristics were similar between the 2 groups.

At 3 years, the median OS was 17.2 months (15.8-20.1) for those receiving tislelizumab vs 10.6 months (9.3-12.0) for those receiving placebo (HR, 0.70; 95% CI, 0.59-0.83). The 36-month OS rate for tislelizumab was 22.1% (17.6-27.0) vs 14.1% (10.4-18.4) for placebo. The OS benefit was seen across all prespecified subgroups. Additionally, the improvement in OS was seen in patients with high and low PD-L1 expression who were receiving tislelizumab. At 3 years, the PFS was 15.0% (10.8-19.9) for tislelizumab vs 2.9% (1.1-6.2) for placebo.

Patients receiving tislelizumab had a longer median exposure to the treatment at 6.4 months vs 4.9 months in the placebo arm. The incidence of any-grade treatment-related adverse events (TRAEs) was comparable between the arms; 67% of patients receiving tislelizumab and 64.5% receiving placebo experienced grade 3 or greater TRAEs, whereas 96.6% of those in the tislelizumab arm and 96.3% in the placebo arm experienced any-grade TRAEs.

However, discontinuation due to AEs was more common in the tislelizumab arm (32.1% vs 22.1%), and patients who were receiving tislelizumab were more likely to have at least 1 TRAE leading to dose modification (76.2% vs 71.3%).

During the interim analysis, the most common grade 3 or greater TRAEs were decreased neutrophil count (31% for tislelizumab vs 33% for placebo), decreased white blood cell count (11% vs 16%), and anemia (15% vs 13%).4 At the time of the 3-year follow-up, there had been 6 (1.9%) deaths in the tislelizumab arm and 4 (1.2%) in the placebo arm.

References
1. Yoon HH, Kato K, Raymond E, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): minimum 3-year survival follow-up. J Clin Oncol. 2024;42(suppl 16):4032. doi:10.1200/JCO.2024.42.16_suppl.4032
2. Rosa K. FDA approves tislelizumab for advanced or metastatic ESCC after chemotherapy. OncLive. March 14, 2024. Accessed June 14, 2024. https://www.onclive.com/view/fda-approves-tislelizumab-for-advanced-or-metastatic-escc-after-chemotherapy
3. Liu CQ, Ma YL, Qin Q, et al. Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer. 2023;14(1):3-11. doi:10.1111/1759-7714.14745
4. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24(5):483-495. doi:10.1016/S1470-2045(23)00108-0

Camrelizumab Plus Rivoceranib Improves Survival vs Standard First-Line Care for HCC

First-line camrelizumab plus rivoceranib continued to demonstrate a clinically meaningful overall survival (OS) benefit compared with sorafenib (Nexavar) for patients with advanced, unresectable hepatocellular carcinoma (HCC) in the final analysis of the phase 3 CARES-310 trial (NCT03764293).¹ The findings were presented at the 2024 American Society of Clinical Oncology Annual Meeting.

In the CARES-310 trial, a total of 543 patients with unresectable HCC who were naïve to systemic treatment were randomly assigned to receive either camrelizumab plus rivoceranib (n = 272) or sorafenib (n = 271), which is the current first-line standard of care. At a median follow-up of 22.1 months in the combination therapy cohort and 14.9 months in the sorafenib cohort, the median OS was 23.8 months (95% CI, 20.6-27.2) in the combination therapy arm compared with 15.2 months (95% CI, 13.2-18.5) in the sorafenib arm (HR, 0.64; 95% CI, 0.52-0.79; 1-sided P < .0001).

The OS rate was 49.0% in the camrelizumab plus rivoceranib cohort vs 36.2% in the sorafenib cohort at 24 months of follow-up, and at 36 months, OS rates were 37.7% and 24.8%, respectively. OS benefits were consistent across most subgroups, including race, geographic region, and HCC etiology. The combination therapy cohort also experienced longer progression-free survival (PFS) at 5.6 months (95% CI, 5.5-7.4) vs 3.7 months (95% CI, 3.1-3.7) in the sorafenib arm (HR, 0.54; 95% CI, 0.44-0.67; P < .0001).

“The phase 3 CARES-310 trial is the first to demonstrate significant PFS and OS benefits with immunotherapy plus an anti-angiogenic tyrosine kinase inhibitor (TKI) over standard TKI as first-line treatment for unresectable HCC,” the authors wrote. Camrelizumab is an anti–PD-1 antibody and rivoceranib is a VEGFR2-targeted TKI.

The median overall response rate in the combination therapy arm was 26.8% vs 5.9% in the sorafenib cohort, and the median durations of response were 17.5 months and 9.2 months, respectively. There were no new safety signals in the final OS analysis compared with earlier studies.

Common treatment-related adverse events (TRAEs) included hypertension, increased aspartate aminotransferase, palmar-plantar erythrodysesthesia syndrome, increased blood bilirubin, decreased platelet count, diarrhea, and increased γ-glutamyl transferase. Decreased neutrophil count, decreased white blood cell count, and fatigue also occurred. TRAEs led to camrelizumab discontinuation in 17.6% of patients, rivoceranib discontinuation in 16.9% of patients, and discontinuation of both agents in 4.4% of the combination arm. In the sorafenib arm, 4.8% of patients discontinued treatment due to TRAEs.

The primary PFS analysis and interim OS analysis both showed significant improvements with camrelizumab plus rivoceranib vs sorafenib, and the new analysis added 16 months of follow-up to the previous data. The updated results further confirmed the combination therapy’s favorable benefit-to-risk profile and supported the use of camrelizumab plus rivoceranib as a novel first-line therapy for unresectable HCC, the authors concluded.

“At the protocol-specified final analysis, camrelizumab plus rivoceranib continued to show clinically meaningful survival improvement compared with sorafenib, with manageable safety,” the authors wrote.

The FDA accepted a new drug application for camrelizumab in combination with rivoceranib in July 2023, which was supported by prior CARES-310 data.² However, the agency issued a complete response letter in May 2024, citing deficiencies related to the manufacturing process.³

References
1. Vogel A, Chan SL, GU S, et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): final overall survival analysis of the phase 3 CARES-310 study. J Clin Oncol. 2024;42(suppl 16):4110. doi:10.1200/JCO.2024.42.16_suppl.4110
2. Elevar Therapeutics announces FDA acceptance for filing of new drug application for rivoceranib in combination with camrelizumab as a first-line treatment for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics. July 17, 2023. Accessed June 4, 2024. https://elevartherapeutics.com/2023/07/17/elevar-therapeutics-announces-fda-acceptance-for-filing-of-new-drug-application-for-rivoceranib-in-combination-with-camrelizumab-as-a-first-line-treatment-for-unresectable-hepatocellular-carcinoma/
3. Jae-hyuk P. HLB fails to win US FDA’s approval for rivoceranib liver cancer drug. Korea Times. Updated May 18, 2024. Accessed June 4, 2024. https://www.koreatimes.co.kr/www/nation/2024/06/129_374825.html

Combining Nivolumab, Cabozantinib Prolongs Treatment-Free Survival in Advanced RCC

Patients with advanced renal cell carcinoma (RCC) who received frontline nivolumab (Opdivo; Bristol-Myers Squibb Company) plus cabozantinib (Cabometyx; Exelixis, Inc) achieved a longer treatment-free survival (TFS) duration vs sunitinib (Sutent; Pfizer Inc), according to findings from an analysis of the phase 3 CheckMate 9ER trial (NCT03141177) presented during the 2024 American Society of Clinical Oncology Annual Meeting.¹

Over the 48-month period following random assignment, patients in the intention-to-treat (ITT) population who received the combination (n = 323) experienced a mean TFS of 7.0 months compared with 4.6 months in the sunitinib arm (n = 328), for a difference of 2.4 months (95% CI,
0.8-3.9). Patients without a grade 2 or higher treatment-related adverse effect (TRAE) experienced a mean TFS of 3.0 months vs 2.3 months, respectively; those who experienced a grade 2 or higher TRAE experienced a mean TFS of 3.9 months vs 2.3 months. The 48-month mean overall survival (OS) was 35.1 months in the doublet arm vs 30.7 months in the sunitinib arm. The mean times on protocol treatment were 22.6 months compared with 14.1 months, respectively.

Additionally, the 48-month OS rates were 49.2% in the nivolumab plus cabozantinib arm vs 40.2% in the sunitinib arm. TFS rates at 48 months were 33.3% compared with 12.9%, respectively.

Charlene Mantia, MD | Image credit: Dana Farber Cancer Institute

“There are multiple immunotherapy-based combination treatments with similar efficacies approved for first-line treatment of advanced RCC. Therefore it’s important to characterize patient survival time after treatment initiation,” Charlene Mantia, MD, a medical oncologist at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School in Boston, Massachusetts, said, during a presentation of the findings. “Over the 4-year period since first-line protocol therapy initiation, [patients treated with] nivolumab plus cabozantinib achieved a 1.5-times longer mean TFS vs sunitinib.”

CheckMate 9ER is an open-label study that enrolled patients with histologically confirmed untreated advanced or metastatic (m) clear cell RCC who had not received prior systemic therapy for RCC. However, treatment with 1 prior adjuvant or neoadjuvant therapy was permitted for patients with completely resectable disease if the agent was not VEGF targeted and if disease recurrence occurred at least 6 months following treatment.^2,3
Patients were randomly assigned 1:1 to receive intravenous nivolumab 240 mg every 2 weeks in combination with oral cabozantinib 40 mg daily or sunitinib 50 mg daily for 4 weeks in 6-week cycles. Treatment in both arms continued until disease progression or unacceptable toxicity, and the maximum duration of nivolumab therapy was 2 years.

The primary end point was progression-free survival by blinded independent central review per RECIST 1.1 criteria. Secondary end points included OS, objective response rate, and safety.

In the ITT population, the baseline characteristics were well balanced between the combination and sunitinib arms; patients’ median age was 62 years (range, 29-90) vs 61 years (range, 28-86), respectively. Most patients in both arms were not from North America or Europe (51.1% vs 50.9%), had a Karnofsky performance status (KPS) of 90 or 100 (79.6% vs 73.5%), had undergone prior nephrectomy (68.7.% vs 71.0%), and had tumors without sarcomatoid features (89.1% vs 87.1%).²

Additional findings from the TFS analysis showed that patients with International mRCC Database Consortium (IMDC) favorable-risk disease in the combination (n = 74) and control (n = 72) arms achieved a 48-month mean TFS of 6.1 months vs 4.3 months, respectively, for a difference of 1.8 months (95% CI, –1.1 to 4.6). The mean OS during this time frame was 38.2 months in the nivolumab plus cabozantinib arm vs 38.6 months in the sunitinib arm. Patients spent a mean time of 25.2 months vs 19.9 months on protocol treatment, respectively.¹

Further, patients with IMDC intermediate- or poor-risk disease in the combination (n = 249) and sunitinib (n = 256) arms achieved a 48-month mean TFS of 7.2 months vs 4.7 months, respectively, for a difference of 2.5 months (95% CI, 0.8-4.3). The 48-month mean OS was 34.2 months vs 28.5 months, respectively, and patients spent a mean time of 21.8 months in the combination arm vs 12.5 months in the sunitinib arm on protocol treatment.

Results from a TFS subgroup analysis showed that investigators observed the benefit with nivolumab plus cabozantinib vs sunitinib across prespecified subgroups. They reported the largest differences in 48-month mean TFS in favor of the combination among patients with a KPS of 80 or less (5.3 months [95% CI, 2.1-8.5]), IMDC poor-risk disease (4.0 months [95% CI, 0.5-7.5]), and a PD-L1 expression of at least 1% (3.5 months [95% CI, 0.8-6.1]).

“Mean TFS differences were similarly longer for nivolumab plus cabozantinib vs sunitinib across most baseline subgroups analyzed,” Mantia said in conclusion. “TFS was more frequently observed after patients stopped therapy due to adverse effects, study drug toxicity, or prespecified other reasons with nivolumab plus cabozantinib vs sunitinib. We believe that future studies should continue to investigate the impact of having a defined treatment duration for patients. This partitioned OS analysis highlights important aspects of patient survival time that can be considered in making decisions when choosing a first-line treatment for patients.”

This article first appeared on OncLive.com.

References
1. Mantia C, Jegede O, Viray H, et al. Partitioned overall
survival: comprehensive analysis of survival states over 4
years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC). J Clin Oncol. 2024;42(suppl 16):4507. doi:10.1200/JCO.2024.42.16_suppl.4507
2. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024;9(5):102994. doi:10.1016/j.esmoop.2024.102994
3. A study of nivolumab combined with cabozantinib compared
to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER). ClinicalTrials.gov. Updated January 17, 2024. Accessed June 4, 2024. https://clinicaltrials.gov/study/NCT03141177

Trastuzumab Deruxtecan Effective for HR+, HER2-Low and HER2–Ultra-Low Breast Cancer Treatment After Endocrine Therapy

At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, researchers presented study results from DESTINY-Breast06 (DB-06) (NCT04494425) that found trastuzumab deruxtecan (T-DXd) reduces cancer growth for patients with hormone receptor (HR)–positive, HER2-low, or HER2–ultra-low metastatic breast cancer that increased in patients after endocrine therapy, published in the Journal of Clinical Oncology.¹
Antibody-drug conjugates (ADCs) such as T-DXd combine monoclonal antibodies with cytotoxic payloads to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens like HER2.2 Patients with breast cancer have experienced effective treatment outcomes with ADCs as they aim to maximize efficacy and decrease the systemic toxicity linked to chemotherapy. These drugs have a wide range of potential, which is why research, development, and approvals of ADCs have occurred within the last decade.

Giuseppe Curigliano, MD, PhD | Image credit: European Institute of Oncology

Giuseppe Curigliano, MD, PhD, director of the early drug development division and cochair for the experimental therapeutics program at the European Institute of Oncology in Milan, Italy, said in his presentation of DB-06 at ASCO 2024: “This is for sure an unmet medical need because activity of treatment after CDK4/6 inhibitor is very poor. Median progression-free survival is 7 months with alpelisib post CDK4/6 inhibitor, 5.5 months with capivasertib, and single-agent chemotherapy is no more than 7 months.”

Results from DB-06 follow the DESTINY-Breast04 (DB-04) study, the showstopper of ASCO 2022, which demonstrated that trastuzumab deruxtecan reduced the risk of disease progression or death by 50% compared with chemotherapy for patients with HER2-low breast cancer, whether HR-positive (HR+) or HR-negative (HR-). The trial also introduced the concept that breast cancer might not be strictly HER2+ or HER2-, but “HER2-low,” meaning that HER2 expression might not be as robust as what had been required for targeting, but it could be treated now with an ADC.³

Following these results, on August 5, 2022, the FDA approved the use of trastuzumab deruxtecan, sold as Enhertu (AstraZeneca/Daiichi Sankyo), for treatment of adult patients with unresectable or metastatic HER2-low breast cancer (immunohistochemistry 1+ or IHC 2+/ISH–) following prior chemotherapy for metastatic disease or recurrence within 6 months of adjuvant chemotherapy.⁴

AstraZeneca and Daiichi Sankyo had previewed top-line results for the DB-06 phase 3 trial and with reports that trastuzumab deruxtecan displayed clinically meaningful progression-free survival (PFS) improvements among patients with HR+, HER2-low metastatic breast cancer after 1 or more forms of endocrine therapy.⁵
The DB-06 trial built upon these results and randomly assigned patients with HER2-low or HER2–ultra-low to receive either 5.4-mg injections of T-DXd or a physician’s choice of chemotherapy.¹

Participants did not have any prior chemotherapy treatment for metastatic breast cancer. Additionally, they had to have had 2 lines or more of endocrine therapy. Individuals who had had 1 line of endocrine therapy could enroll if disease progression occurred less than or equal to 2 years of adjuvant endocrine therapy or less than or equal to 6 months of endocrine therapy with CDK4/6 inhibitors.

The primary end point of the study was PFS by blinded independent central review in HER2-low breast cancer. Some of the secondary end points included intent-to-treat, overall survival, objective response rate, and safety.
As of the data cutoff of March 18, 2024, a total of 866 patients were randomly assigned to receive either T-DXd (n = 436) or a physician’s choice of chemotherapy (n = 430). Patients with HER2-low breast cancer (n = 713) and HER2–ultra-low breast cancer (n = 153) were included. The study population consisted mainly of women aged 28 to 85 years.

The majority of the patient population was previously treated with CDK4/6 inhibitors (90.4%). To treat patients in the chemotherapy group, physicians selected capecitabine (59.8%), nab-paclitaxel (24.4%), or paclitaxel (15.8%).
The highest confirmed objective response rates (ORRs) were found in patients with HER2–ultra-low breast cancer (61.8%) after T-DXd treatment, followed by patients with HER2-low breast cancer treated with T-DXd (56.5%). Both breast cancer groups treated with chemotherapy had lower ORRs (HER2-low, 32.2%; HER2–ultra-low, 26.3%).

The complete response (CR) rates were 0% for both cancers treated with chemotherapy. Patients with HER2-low breast cancer treated with T-DXd had a CR of 2.5%, and patients with HER2–ultra-low had a 5.3% CR.

Partial responses for each cancer group treated with T-DXd were similar for HER2-low (54%) and HER2–ultra-low (56.6%). Patients with HER2-low breast cancer had a slightly higher partial response (32.2%) than those with HER2–ultra-low (26.3%) when treated with chemotherapy.

Progression-free survival improved significantly among patients administered T-DXd compared with the patients treated with chemotherapy. On average, treatment lasted 11 months for the T-DXd group and 5.6 months for the chemotherapy groups because the T-DXd group experienced fewer severe adverse effects, allowing them to receive treatment for longer.⁶

Adverse events classified as grade 3 or higher were reported among the T-DXd group (40.6%) and the chemotherapy-treated group (31.4%). There were only 20.3% serious treatment-emergent adverse events (TEAEs) found among the T-DXd group and 16.1% for the chemotherapy group.¹

Treatment discontinuation associated with TEAEs occurred in 14.3% of the T-DXd treated group and 9.4% of patients treated with chemotherapy. Pneumonitis was the most common TEAE that resulted in discontinuation for T-DXd (5.3%), and peripheral sensory neuropathy was most common for patients treated with chemotherapy (1.4%). Additionally, nausea was the most common TEAE associated with dose reduction for T-DXd (4.4%), and palmar-plantar erythrodysesthesia was found more frequently among patients treated with chemotherapy (16.5%).

Erica L. Mayer, MD, MPH, director of breast cancer clinical research, medical oncologist, and clinical investigator at Dana-Farber Cancer Institute, stated, “These data suggest that trastuzumab deruxtecan may become a preferred first-line treatment option for most patients with HR- metastatic breast cancer after progression on endocrine therapy.”

Patients with HR+, HER2–low, and HER2–ultra-low metastatic breast cancers may benefit from T-DXd treatment after 1 or more lines of endocrine therapy and no prior chemotherapy, but researchers have noted the high levels of more serious toxicities T-DXd has displayed compared with traditional chemotherapy and advise that this treatment may not be the best option for all patients.

References
1. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol 2024;42(17):1-1. doi:10.1200/JCO.2024.42.17
2. Mark C, Lee JS, Cui X, Yuan Y. Antibody-drug conjugates in breast cancer: current status and future directions. Int J Mol Sci. 2023;24(18):13726. doi:10.3390/ijms241813726
3. Caffrey M. Trastuzumab deruxtecan cuts risk of disease progression or death by 50% for patients with HER2-low metastatic breast cancer. The American Journal of Managed Care®. June 5, 2022. Accessed June 11, 2024. https://www.ajmc.com/view/trastuzumab-deruxtecan-cuts-risk-of-disease-progression-or-death-by-50-for-patients-with-her2-low-metastatic-breast-cancer
4. FDA approves fam-trastuzumab deruxtecan-nxhi for HER2-low breast cancer. FDA. August 5, 2022. Accessed July 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer
5. Santoro C. Destiny-Breast06 results offer new hope for patients with HR-positive, HER2-low metastatic breast cancer. The American Journal of Managed Care. May 1, 2024. Accessed June 11, 2024. https://www.ajmc.com/view/destiny-breast06-results-offer-new-hope-for-patients-with-hr-positive-her2-low-metastatic-breast-cancer
Trastuzumab deruxtecan significantly improves progression-free survival in breast cancer patients previously treated with endocrine therapy. News release. American Society of Clinical Oncology. June 2, 2024. Accessed June 11, 2024. https://society.asco.org/about-asco/press-center/news-releases/trastuzumab-deruxtecan-significantly-improves-progression-free

SPOTLIGHT: Bradley McGregor, MD, Describes DAD-IO: Double ADCs With Pembrolizumab

Bradley McGregor, MD, senior physician and clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute; and instructor of medicine, Harvard Medical School, discussed the rationale for the DAD-IO trial in a brief interview during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. Rationale and methods were presented in an abstract.¹

Bradley McGregor, MD | Image credit: Dana-Farber Cancer Institute

DAD-IO is an extension of the phase 1 DAD trial (NCT04724018) that will investigate the efficacy and safety of combination therapy consisting of 2 antibody-drug conjugates, sacituzumab govitecan (SG) (Trodelvy; Gilead) and enfortumab vedotin (EV) (Padcev; Astellas), along with pembrolizumab (Keytruda; Pfizer) for the first-line treatment of patients with metastatic urothelial carcinoma. According to the DAD authors, “This is the first trial in any malignancy to show that antibody-drug conjugates could be safely given in combination”²
In the original protocol for the DAD trial,² investigators evaluated sacituzumab govitecan in combination with enfortumab vedotin in patients with treatment-resistant metastatic urothelial carcinoma. Previous results showed that the combination of the 2 antibody-drug conjugates elicited an overall response rate of 70% in 23 evaluable patients. McGregor noted that the combination was well tolerated.

However, considering the potential for cumulative toxicities with the combination, the recommended phase 2 dose has been established at 7.5 mg/kg of sacituzumab govitecan and 1.25 mg/kg of enfortumab vedotin, to be given on days 1 and 8 of each 21-day cycle.

McGregor: The double antibody-drug conjugate trial was really exciting. We showed that these drugs could be given safely together. We had 23 patients; the median age was over 70 years of age. Only 1 patient progressed on I/O [immuno-oncology]; most patients had received both platinum and immunotherapy.

This is a boring design, [but] what we showed was that the combination of EV and SG can be given safely. And actually, the maximum tolerated dose was full dose: for SG, 10 mg per kg with full dose; for EV, 1.25 mg/kg on days 1 and 8 of a 21-day cycle. But given cumulative toxicity concerns, that was not the dose that’s recommended to go forward. That dose recommendation is made with a caveat in that G-CSF [granulocyte colony-stimulating factor] was given to most patients. And [among] the first 6 patients there were 2 episodes of neutropenia for fever. So that’s when we allowed G-CSF to be given at investigator’s discretion per ASCO guidelines. In 16 of 17 patients, what we saw is when we combined the drugs with G-CSF, it was very, very well tolerated, [with] no synergistic toxicity…. And equally encouraging, we had a 70% objective response rate in the post-platinum I/O setting, which is far more than you would see with either drug alone.

So given that exciting data…we ask, “Is this real?” It’s 23 patients and small numbers, but [it’s] really, really exciting. And so that’s the basis for the expansion of the DAD trial. We’re looking to validate the DAD data in the post-platinum I/O setting, and we’re looking to expand an additional 40 patients. But now, as we allude to with EV plus [pembrolizumab] now a standard of care, can we build upon that? And so that’s the basis for the DAD-IO; we’re looking to add SG to EV and pembro. This is going to be a multicenter, phase 2 trial looking at combination of EV at full dose, 1.25 kg with SG, 7.5 mg per kg, day 1 of a 21-day cycle with pembrolizumab. We’re really excited. The trial has been gone through the process with the [institutional review board] and is ready to activate and start enrolling patients.

This interview first appeared on OncLive.com.

References
1. McGregor BA, Kwak L, Sonpavde GP, et al. Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) for metastatic urothelial carcinoma (mUC) treatment-experienced (DAD) and with pembrolizumab (P) in treatment naïve UC (DAD-IO). J Clin Oncol. 2024;42(suppl 16). Abstract TPS4618. doi:10.1200/JCO.2024.42.16_suppl.TPS4618
2. McGregor BA, Sonpavde GP, Kwak L, et al. The double antibody drug conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. Ann Oncol. 2024;35(1):91-97. doi:10.1016/j.annonc.2023.09.3114