Kristi Rosa

Combined results from the SYNCHRONOUS (ISRCTN30964555) and CCRe-IV (NCT02015923) studies demonstrate that undergoing resection of primary colon tumors and high rectal tumor with synchronous unresectable metastases, did not prolong overall survival (OS).

An intention-to-treat (ITT) analysis showed that at a median follow-up of 36 months, the median survival of all patients was 17.8 months (95% CI, 15.6-19.6), the median survival in those who received systemic chemotherapy alone was 18.6 months (95% CI, 16.2-22.3), and the median survival was 16.7 months (95% CI, 13.2-19.2) in those who underwent primary tumor resection followed by systemic chemotherapy. No statistically significant difference was observed between the arms.

Investigators also performed a Cox regression model pertaining to the primary end point of OS as part of the ITT analysis, which revealed that the random group surgery vs no surgery was not linked with survival (HR, 0.946; 95% CI, 0.740-1.209; 

= .658), but those who did not receive chemotherapy experienced a worse survival (HR, 5.32; 95% CI, 3.55-8.00; 

< .001). Moreover, older age was also associated with worse survival (HR, 1.013; 95% CI, 1.001-1.026; 

“Colorectal cancer is a very prevalent disease, with roughly 20% to 25% of cases presenting as stage IV. Unfortunately, the majority of these patients have unresectable distant disease and will, therefore, only undergo palliative chemotherapy,” Jüergen Weitz, MD, head and professor of surgery in the Department of Visceral, Thoracic, and Vascular Surgery at the University Hospital Carl Gustav Carus of the Technical University Dresden, said in a presentation on the data. “The question that always comes up is: Should the primary tumor, if asymptomatic, be resected in these patients?”

The arguments in favor of resection are that the procedure will prevent primary tumor complications; serve to avoid emergency surgery, which can be dangerous for the patient as they undergo chemotherapy; and that it might improve the prognosis of the patient. Several retrospective papers have suggested this, according to Weitz.

The arguments against primary tumor resection are that the OS of patients is most likely determined by distant disease; that the primary tumor is mostly asymptomatic and will continue to be so during the course of the disease—especially if chemotherapy proves to be effective; and that surgery comes with the risk of complications that can delay palliative chemotherapy for these patients, Weitz added.

“The evidence [that we saw] in 2012 was unclear,” Weitz noted. “A Cochrane analysis concluded at that time that there is still enough doubt with regard to the published papers to justify [for] further randomized trials to be done [to answer that question], so that is exactly what we [decided to do].”

To be included in the analysis, patients were required to have newly diagnosed, histologically confirmed colon or high rectal cancer with synchronous metastases that is not amenable to curative therapy. The primary tumor needed to be resectable and asymptomatic. Moreover, patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, and be able to tolerate surgery and chemotherapy. Those with peritoneal metastases were excluded.

Study participants were randomized in a 1:1 fashion to the investigative arm, where they would undergo primary tumor resection before systemic therapy, or the control arm, where they would just receive up-front systemic treatment without resection of the primary tumor. “Of note in both arms, the chemotherapy was undefined, so it was left to the discretion of the treating team,” Weitz said.

The primary end point of the trial was OS. Key secondary end points in the control arm were time to local tumor symptoms, intervention because of primary tumor complications, interventions with curative intent, administration of chemotherapy, and quality of life (QOL). In the investigative arm, perioperative morbidity and mortality, interventions with curative intent, administration of chemotherapy, and QOL, all served as secondary end points.

For the SYNCHRONOUS trial, the sample size was based on an assumption that surgery would improve the median OS from 20 months to 26 months (HR, 1.3); it was calculated to be 800 patients. In December 2014, low patient recruitment resulted in a protocol amendment after a pooled estimated for median OS for both groups following 166 patients was 18 months. As such, the revised sample size was calculated to show an improvement of the median OS with resection from 15 months to 21 months; this equated to 392 patients.

Moreover, an agreement was made with the principal investigator of the CCRe-IV trial to pool the data from the trials, Weitz added. “This could be done [because] the inclusion criteria and the interventions were virtually identical between the trials,” Weitz explained.

A total of 393 patients underwent randomization at 100 sites between November 2011 and March 2017; this included 295 patients enrolled to 82 sites as part of the SYNCHRONOUS trial, and 98 patients enrolled to 18 sites as part of the CCRe-IV trial. Of the 393 patients included in the analysis, 206 received chemotherapy alone and 187 underwent primary tumor resection followed by chemotherapy; 187 and 164 patients, respectively, received the allocated intervention.

Demographic and disease characteristics between the investigative and control arms were comparable, according to Weitz. In the investigative and control arms, 44.9% and 46.6% of patients, respectively, had right-sided tumors, and the predominant site of metastases was the liver (95.2% vs 95.1%, respectively), followed by the lung (27.8% vs 29.6%) and the nonregional lymph nodes (21.4% vs 15.0%). Most patients in the surgery/chemotherapy and chemotherapy-alone arms had 1 metastatic site (58.8% vs 61.2%, respectively), followed by 2 to 5 sites (40.6% vs 38.3%).

Among those in the investigative arm, 87.7% had their primary tumor resected, and 54.3% had a laparotomy. Moreover, 39.6% of patients underwent a right hemicolectomy, 17.1% underwent a left hemicolectomy, 32.3% underwent a sigmoid colectomy, 5.5% had a segmental resection, and 5.5% underwent another surgical procedure that was not specified. Lastly, 23.2% of patients underwent surgery with an anastomosis fashioned, according to Weitz.

“Of note, one-quarter of patients who were randomized to the surgery-only arm never saw chemotherapy,” Weitz noted. “Of those who received chemotherapy, 90% received [a] doublet or triplet [regimen].”

Moreover, in the investigative and control arms, respectively, some patients received chemotherapy plus bevacizumab (Avastin; 38.0% vs 43.2%), chemotherapy plus an EGFR antibody (26.8% vs 17.4%), or chemotherapy plus bevacizumab and an EGFR antibody (0% vs 0.5%).

Investigators also conducted a subgroup analysis. “There was no subgroup where intervention or control was associated with better survival,” Weitz reported.

Regarding safety, 10.2% of those on the surgery/chemotherapy arm and 18.0% of those on the chemotherapy-alone arm experienced at least 1 serious adverse effect (SAE); gastrointestinal (GI) tract–related SAEs occurred in 4.8% and 10.7% of patients, respectively. “This was a statistically significant difference,” Weitz noted. Most of the GI tract–related SAEs were ileus/bowel obstruction (9.1% in investigative arm vs 41.9% in the control arm).

Analyses pertaining to secondary end points are pending and will be reported at a later date, Weitz concluded.

Rahbari NN, Biondo S, Feißt M, et al. Randomized clinical trial on resection of the primary tumor versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases. J Clin Oncol. 2022;40(suppl 17):LBA3507. doi:10.1200/JCO.2022.40.17_suppl.LBA3507

Articles

Should the primary tumor, if asymptomatic, be resected in patients with colon cancer with synchronous unresectable metastases? Study results hint that the answer is no.

OS Not Extended With Primary Tumor Resection Before Chemo in Colon Cancer With Synchronous Unresectable Metastases

Irrespective of a patient’s tumor type, zenocutuzumab (MCLA-128) produced durable responses in patients with previously treated advanced 

-positive cancers with a well-tolerated toxicity profile, according to data from a phase 1/2 trial (NCT02912949) presented during the 2022 ASCO Annual Meeting.

At a median follow-up of 6.3 months, the HER2 x HER3 bispecific antibody elicited an investigator-assessed objective response rate (ORR) of 34% (95% CI, 24%-46%) by RECIST v1.1 criteria among all patients analyzed (n = 79), with a median time to response of 1.8 months, and a median duration of response (DOR) of 9.1 months (95% CI, 7.4-not reached).

“There are currently no approved therapies targeting 

-positive cancer, and zenocutuzumab offers a potential new standard of care [SOC],” Alison M. Schram, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a presentation on the data.

 are rare oncogenic drivers in a wide range of solid tumors, and are enriched in pancreatic and lung cancers, according to Schram. In lung cancer, 

 fusions are linked with poor prognosis, lower response rates to standard chemotherapy and immunotherapy, and shorter overall survival. Zenocutuzumab has been shown to have efficacy in 

 fusion–positive preclinical models spanning tumor histologies.

Zenocutuzumab docks on HER2 and blocks the binding of NRG1 to HER3, preventing heterodimerization of HER2 with HER3 in downstream signaling, Schram said. In January 2021, the agent was granted a fast-track designation from the FDA for use in patients with metastatic solid tumors harboring 

gene fusions that had progressed on SOC treatment.

 Previously, in June 2020, the FDA granted zenocutuzumab an orphan drug designation for the treatment of patients with pancreatic cancer.

The global, open-label, multicenter, phase 1/2 trial enrolled patients with locally advanced, unresectable or metastatic solid tumors that were 

 positive. To be eligible for enrollment, patients must have been at least 18 years of age, have been previously treated with or unable to receive standard therapy, and have an ECOG performance status ranging from 0 to 2.

Study participants received intravenous zenocutuzumab at 750 mg, given every 2 weeks, until disease progression. Moreover, tumor assessments were conducted every 8 weeks.

The primary end point of the trial was ORR by RECIST v1.1 criteria and per investigator assessment. DOR, ORR per central review, safety, pharmacokinetics, and assessment for antidrug antibodies served as secondary end points.

At a data cutoff date of April 12, 2022, a total of 110 patients were enrolled, and 83 patients met the predefined criteria for the primary analysis population. “The primary analysis population included those who had at least 1 dose of zenocutuzumab, had the opportunity for greater than or equal to 6 months of follow-up, and met criteria for the primary efficacy population,” Schram explained.

Among the 27 patients who were excluded from the analysis, the most common reason was having less than 6 months of follow-up (n = 21), followed by having a baseline scan that happened more than 5 weeks before the first dose of study treatment (n = 2), having other genetic drivers beyond 

 (n = 2), having received prior anti-HER3 inhibitors (n = 2), or having an ECOG performance status of 3 (n = 1).

Among the 83 patients, the median age was 59 years (range, 22-84), and 59% were female. Most patients had an ECOG performance status of 0 (42%) or 1 (57%) and were White (57%) or Asian (33%). Moreover, 99% had metastatic disease and 95% had measurable disease.

The most common tumor types were non–small cell lung cancer (NSCLC; 57%) and pancreatic ductal adenocarcinoma (PDAC; 23%). Additional histologies treated included breast cancer (8%), cholangiocarcinoma (4%), colorectal cancer (4%), endometrial soft tissue sarcoma, pancreatic neuroendocrine carcinoma, renal cell carcinoma, and cancer of unknown primary (5%). Study participants received a median of 2 prior lines of systemic therapy (range, 0-8), with 11% of patients having previously received afatinib (Gilotrif).

 fusions included 26 distinct fusion partners, most commonly CD74 [31%], SLC3A2 [16%], and ATP1B1 [13%],” Schram noted.

Additional data showed that among the 19 patients with PDAC, “a disease with few treatment options and a poor prognosis,” zenocutuzumab produced a confirmed ORR of 42% (95% CI, 20%-67%) per investigator assessment, Schram reported. In the 46 patients with NSCLC, the ORR achieved with the bispecific antibody was 35% (95% CI, 21%-50%), “which is higher than that reported for standard chemoimmunotherapy in this population,” Schram added. Notably, 70% of patients experienced tumor shrinkage with treatment.

The median duration of exposure to treatment was 6.3 months (range, 1-21). Twenty-four percent of patients were still receiving treatment with zenocutuzumab at data cutoff. The most common reason for discontinuation was progressive disease (73%). Two other patients discontinued because of an unrelated adverse effect (AE) of dyspnea because of underlying progression (n = 1) and pregnancy (n = 1).

“Responses were durable…76% [of patients] responded for more than 6 months and 27% [responded] for at least 1 year,” Schram said.

Schram also shared a few cases that underscored the efficacy of zenocutuzumab that has been observed to date. A 51-year-old male who had 

 fusion–positive pancreatic adenocarcinoma underwent neoadjuvant FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) and surgery, followed by the development of metastatic disease to the liver and lymph nodes. After starting zenocutuzumab, the patient experienced an “immediate and durable” partial response (PR) before coming off the study 9 months later because of disease progression.

 fusion–positive NSCLC that was metastatic to the lung and lymph nodes, who was deemed ineligible to receive chemoimmunotherapy, was initiated on zenocutuzumab and experienced a rapid response. This patient continues to respond to treatment nearly 16 months later and remains on study.

 fusion–positive, estrogen receptor–positive breast cancer with metastasis to the liver and bone had progressed following several lines of systemic treatment was given zenocutuzumab. She experienced a rapid PR per RECIST v1.1 criteria and a complete response per PERSIST criteria. “She remains on treatment and is doing well with no evidence of progressive disease,” Schram added.

Pharmacokinetics demonstrated a half-life of approximately 4 days, with greater than 95% predicted receptor occupancy for HER3 and HER2 throughout the dosing interval in most patients following the first dose of zenocutuzumab. Notably, no treatment-emergent antidrug antibodies were identified.

“Zenocutuzumab is extremely well tolerated, with a very low incidence of grade 3 and higher treatment-related AEs, including low rates of severe gastrointestinal and dermatologic toxicity and no clinically significant cardiotoxicity,” Schram said.

Among all patients who received zenocutuzumab at the recommended phase 2 dose across indications on the phase 1/2 trial—not just those with 

 fusions, 92% of patients experienced at least 1 all-grade AE, 36% experienced grade 3 or 4 toxicity, and 3% experienced a grade 5 effect.

All-grade treatment-related AEs (TRAEs) occurred in 61% of patients, 5% experienced grade 3 or 4 TRAEs, and 0.5% experienced a grade 5 TRAE. The most common all-grade TRAEs experienced with zenocutuzumab were diarrhea (21%), asthenia/fatigue (12%), infusion-related reactions (15%), and nausea (10%).

Less than 1 percent of patients discontinued treatment because of toxicity.

Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105

Merus granted FDA fast track designation of zenocutuzumab for the treatment of patients with neuregulin 1 fusion cancers. News release. Merus NV. January 7, 2021. Accessed June 5, 2022. http://bit.ly/3bobmtY

Merus announces FDA orphan drug designation of zenocutuzumab for the treatment of pancreatic cancer. Merus NV. July 27, 2020. Accessed June 5, 2022. https://bit.ly/3QeKlLN

Zenocutuzumab produced durable responses in patients with previously treated advanced NRG1-positive cancers and had an extremely well-tolerated toxicity profile, according to data from the 2022 ASCO Annual Meeting. 

Regardless of Tumor Histology Zenocutuzumab Shows Robust and Durable Efficacy in Advanced NRG1+ Cancer

CLN-081, a selective EGFR inhibitor induced objective responses in heavily pretreated patients with non–small cell lung cancer (NSCLC) with 

 exon 20 insertions and demonstrated an acceptable toxicity profile, according to results from the phase 1/2a CLN-081-001 trial (NCT04036682) presented during the 2022 ASCO Annual Meeting.

Among the 39 patients who received the agent at 100 mg twice daily, the confirmed partial response (PR) rate was 41%, the median duration of response (DOR) was over 21 months (95% CI, 8-not calculated [NC]), and the median progression-free survival (PFS) was 12 months (95% CI, 5-NC).

In the overall population (n = 73), the agent elicited a confirmed PR rate of 38.4%, with a median DOR of 10 months (95% CI, 6-NC), and a median PFS of 10 months (95% CI, 6-12). In the subset of patients who received CLN-081 at a twice-daily dose of 65 mg or less, the confirmed PR rate was 35%, with a median DOR of greater than 19 months (95% CI, 5-NC) and a median PFS of 8 months (95% CI, 5-13). In the 11 patients who received CLN-081 at a twice-daily dose of 150 mg, the confirmed PR rate was 36.4%, the median DOR was 7 months (95% CI, 4-NC), and the median PFS was 8 months (95% CI, 1-10).

“The safety profile of CLN-081 is amenable for long-term treatment [when given] at doses less than 150 mg twice daily,” Helena Alexandra Yu, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, added in a presentation on the data. “Most adverse effects [AEs] were grade 1 or 2. There was no grade 3 rash or diarrhea at doses less than 150 mg twice daily.”

The novel, irreversible, oral EGFR inhibitor possesses a unique pyrrolopyrimidine scaffold. Preclinical data have showcased that the agent has strong, broad-spectrum activity against 

exon 20 insertions. The agent also has selectivity against wild-type 

CLN-081-001 was a phase 1/2a dose-escalation and -expansion trial. The dose-escalation portion of the research utilized an accelerated titration and rolling-six design, Yu said. Moreover, the phase 1 and 2 dose-expansion cohorts enrolled additional patients at dose levels that met predefined thresholds for efficacy and tolerability.

To be eligible for participation, patients were required to have recurrent or metastatic NSCLC harboring 

 exon 20 insertion mutations that had be confirmed via local laboratory. Patients must have previously received treatment in the recurrent or metastatic setting, including a platinum-based chemotherapy regimen.

In the dose-escalation cohorts, patients were allowed to have previously received an agent that targeted 

 exon 20 insertion mutations. Notably, those who had untreated central nervous system (CNS) metastases that had been stable for at least 4 weeks before the first day of the first cycle of treatment were permitted.

Study participants received CLN-081 twice daily, at a dose level starting at 30 mg. Investigators evaluated tumor response at 6 weeks and then every 9 weeks thereafter.

At a data cutoff date of May 9, 2022, 73 patients had been enrolled across doses that ranged from 30 mg twice daily to 150 mg twice daily. However, enrollment to the group evaluating the agent at 150 mg twice daily was closed after 11 patients due to toxicity.

Of these 73 patients, 33% continue to receive CLN-081, and 67% have discontinued treatment. The most common reason for discontinuation was disease progression (61%), followed by toxicity (25%), another unspecified reason (8%), and withdrawn consent (6%).

Yu noted that those enrolled to the trial were heavily pretreated, with 44% of patients having received 2 prior lines of systemic anticancer therapy and 22% having received 3 or more prior lines of treatment. Notably, the median prior lines of therapy received was 2, with a range of 1 to 9 prior regimens received.

Thirty-six percent of patients previously received an EGFR TKI in the form of afatinib (Gilotrif) or gefitinib (Iressa; 18%), or osimertinib (Tagrisso; 18%); 4% of patients previously received poziotinib and/or mobocertinib (Exkivity). Moreover, approximately half of patients (55%) had prior immunotherapy. Notably, 38% of patients had a history of CNS involvement at baseline.

Additional data showed that the median time on study was 11 months, and the median time to response with CLN-081 was 1.5 months.

Yu shared additional data on 3 patients who had CNS target lesions at baseline before study entry. One patient was 69 years of age and had initially presented with early-stage disease; this patient had undergone surgical resection and had received adjuvant chemotherapy. One year later, he experienced CNS recurrence. “A large right frontal lobe lesion was resected and radiated,” Yu said. “A separate asymptomatic cerebellar lesion was growing prior to study entry. By cycle 6, there was a decrease from 19 mm to 10 mm and decreased enhancement.”

The second patient, who has received at least 1 year of treatment and continues to receive the agent, achieved stable disease with CLN-081, both intracranially and systemically. The third patient experienced disease progression at cycle 3.

Most toxicities were grade 1 or 2 in severity, and dose reductions and discontinuations were uncommon at doses below 150 mg. Notably, no grade 3 or higher rash or diarrhea was noted in those who received doses of less than 150 mg. Four patients experienced treatment-emergent pneumonitis; this occurred in 1 patient who received the agent at 65 mg twice daily, 2 patients who received it at 100 mg twice daily, and 1 patient who received it at 150 mg twice daily. Notably, however, these cases were noted to be asymptomatic (n = 1) or cofounded by comorbid medical illness (n = 3).

“Enrollment into the phase 2b portion of the study is planned for the second half of this year and there are prespecified cohorts that plan to enroll patients with active untreated CNS metastases and those who have progressed on prior EGFR exon 20 therapies,” Yu concluded.

Yu HA, Tan DSW, Smit EF, et al. Phase (ph) 1/2a study of CLN-081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (ins20). 

. 2022;40(suppl 16):9007. doi:10.1200/JCO.2022.40.16_suppl.9007

Data from the phase 1/2a CLN-081-001 trial showed the clinical benefit of CLN-081 in patients with EGFR exon 20 insertion-positive non–small cell lung cancer.

CLN-081 Demonstrates Antitumor Activity in Heavily Pretreated EGFR Exon 20 Ins+ NSCLC

Treatment with relugolix (Orgovyx), had an acceptable toxicity profile with favorable tolerability in patients with advanced prostate cancer, according to Results from a detailed safety analysis of the pivotal phase 3 HERO trial (NCT03085095) presented during the AUA 2022 Annual Meeting.

A lower percentage of patients who received relugolix experienced major adverse cardiovascular events (MACE) compared with those who were given leuprolide (Lupron), at 2.9% and 6.2%, respectively. Specifically, Kaplan-Meier estimates of incidence rate revealed a risk reduction of 54% with relugolix (HR, 0.46; 95% CI, 0.24-0.88).

Notably, in a subset of men who had a reported medical history of cardiovascular events, MACE rates on study drug treatment in the investigative and control arms were 3.6% and 17.8%, respectively; this translated to 5.8-fold higher odds of experiencing MACE with leuprolide vs relugolix.

“Relugolix, an oral nonpeptide GnRH receptor antagonist, was generally well tolerated in the phase 3 HERO study,” lead study author Bryan Mehlhaff, MD, of the Oregon Urology Institute, and colleagues, wrote in a poster on the data. “Adverse effects [AEs] occur with varying time of onset and duration depending on the type of event.”

HERO enrolled patients with histologically or cytologically confirmed adenocarcinoma of the prostate that needed at least 1 year of continuous androgen deprivation therapy.2 To be eligible for enrollment, patients needed to be at least 18 years of age, and have 1 of the following 3 clinical presentations: evidence of biochemical or clinical relapse after local primary intervention with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease that is not likely to be cured by local primary intervention with curative intent.

If patients experienced MACE within 6 months of study start, they were excluded.

Study participants were randomized 2:1 to receive oral relugolix at a once-daily dose of 120 mg following a single loading dose of 360 mg, or leuprolide injections given every 12 weeks for 48 weeks. Stratification factors included geographic region, the presence or absence of metastatic disease, and age.

The primary end point of the trial was sustained castration rate, and key secondary end points included noninferiority of relugolix to leuprolide with regard to sustained castration rate with a noninferiority margin of -10 percentage points.

Other end points included cumulative probability of testosterone suppression to less than 50 ng per deciliter on day 4 and 15, the percentage of patients with a prostate-specific antigen (PSA) response at day 15 with confirmation at day 29, the profound castration rate on day 15, and the FSH level at the end of week 24.

In December 2020, the FDA approved relugolix for use in patients with advanced prostate cancerbased on earlier findings from HERO.

 Data showed that 96.7% (95% CI, 94.9-97.9) of those who received relugolix (n = 622) maintained castration through 48 weeks vs 88.8% (95% CI, 84.6%-91.8%) of those who were given leuprolide (n = 308); the difference of 7.9 percentage points (95% CI, 4.1-11.8) was indicative of noninferiority and superiority of relugolix.

Notably, all secondary end points showed superiority with relugolix over leuprolide (

< .001). The cumulative probability of castration on day 4 with relugolix was 56.0% vs 0% with leuprolide; on day 15, these rates were 98.7% and 12.0%, respectively. Moreover, the cumulative probability of testosterone suppression to profound castrate levels on day 15 was 78.4% with relugolix and 1.0% with leuprolide. More patients in the investigative arm had a confirmed PSA response at day 15 vs those in the control arm, at 79.4% and 19.8%, respectively (

Updated data from the HERO trial shared at the 2021 AUA Annual Meeting showed that relugolix did not significantly delay onset of castration resistance vs leuoprolide.

 At 48 weeks, the castration resistance–free survival (CRFS) rate was 74.3% (95% CI, 68.6%-79.2%) with relugolix vs 75.3% (95% CI, 66.7%-81.9%) with leuprolide in the metastatic disease cohort (n = 434; HR, 1.03; 95% CI, 0.68-1.57; 

= .84). Similar CRFS rates were reported in the modified intention-to-treat population (n = 1074).

At this year’s meeting, investigators shared a review of the safety findings from the trial, including an analysis of toxicity onset and duration. The safety population was comprised of 622 patients who received relugolix and 308 patients who were given leuprolide.

Data indicated that 92.9% of those in the investigative arm and 93.5% of those in the control arm experienced AEs. The AEs that occurred in more than 10% of patients in the relugolix and leuprolide arms, respectively, included hot flash (54.3% vs 51.6%), fatigue (21.5% vs 18.5%), constipation (12.2% vs 9.7%), diarrhea (12.2% vs 6.8%), and arthralgia (12.1% vs 9.1%).

Grade 3 or higher toxicities were experienced by 18.0% of those in the relugolix arm vs 20.5% of those in the leuprolide arm. Grade 3 or higher AEs reported in 1% or more of patients in the investigative and control arms, respectively, comprised hypertension (1.6% vs 0.6%), diabetes (1.0% vs 0.6%), and syncope (1.0% vs 1.0%). All other grade 3 or higher toxicities were reported with comparable incidence in both arms.

For the toxicities that were experienced by more than 10% of patients, the median time to onset ranging from 19.0 days to 142.0 days in the investigative arm and 41.0 days to 188.5 days in the control arm. The duration of these effects varied.

Notably, diarrhea was noted to have a short median duration compared with other toxicities; this AE had a median duration of 9 days (range, 1-370) in the relugolix arm vs 3 days (range, 1-224) in the leuprolide arm. Fatigue and hot flash were found to be more persistent. The median duration of fatigue in those who received relugolix was 289 days (range, 2-429) vs 274 days (range, 3-426) in those who were given leuprolide. Moreover, hot flash lasted for a median of 342 days (range, 15-477) with relugolix vs 331 days (range, 1-428) with leuprolide.

Regarding MACE, the median time to onset with relugolix was 177 days (range, 38-343) vs 132 days (range, 8-352) with leuprolide.

“MACE appeared to occur earlier and with a higher percentage in leuprolide vs relugolix groups, possibly supporting a different risk/mechanism between GnRH agonists and antagonists,” the study authors concluded.

1. Mehlhaff B, Shore ND, George DJ, et al. Oral relugolix for androgen deprivation therapy in advanced prostate cancer: detailed safety analysis from the randomized phase 3 HERO study. Presented at: 2022 American Urology Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP27-16. 

2. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. 

. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325

3. FDA approves first oral hormone therapy for treating advanced prostate cancer. News release. FDA. December 18, 2020. Accessed May 14, 2022. http://bit.ly/2Ws5nvz 

4. Saad F, George DJ, Cookson MS, et al. Relugolix vs leuprolide effects on castration resistance-free survival from the phase 3 HERO study in men with advanced prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-07.

The safety profile of relugolix in patients with advanced prostate cancer has been demonstrated in the phase 3 HERO clinical trial. 

Relugolix Shows Tolerable Safety in Advanced Prostate Cancer

In the phase 2 CheckMate-848 study (NCT03668119). The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) elicited encouraging and durable responses with acceptable safety in patients with advanced or metastatic tumor mutational burden (TMB)–high solid tumors that were refractory to standard therapies, meeting the study’s primary end point.

Data, which were presented during the AACR Annual Meeting 2022, indicated that the doublet (n = 148) produced an objective response rate (ORR) of 35.3% (95% CI, 24.1%-47.8%) in the cohort of patients determined to have tissue TMB–high (tTMB-H) disease (n = 68), which was higher than the ORR of 22.5% (95% CI, 13.9%-33.2%) achieved by the cohort of patients with blood TMB–high (bTMB-H) disease (n = 80).

Among those who received nivolumab alone (n = 81), the immunotherapy elicited an ORR of 27.8% (95% CI, 14.2%-45.2%) in the tTMB-H cohort (n = 36) and 15.6% (95% CI, 6.5%-29.5%) in the bTMB-H cohort (n = 45).

“Nivolumab plus ipilimumab demonstrated clinical efficacy with a manageable safety profile in patients with advanced or metastatic tTMB-H and/or bTMB-H solid tumors that were refractory to standard therapies, with increased efficacy observed in patients with tTMB-H tumors,” lead study author Michael Schenker, MD, PhD, of Sf Nectarie Oncology Center and University of Medicine and Pharmacy, Craiova, Romania, said in a presentation on the data.

Because TMB is known to correlate with neoantigen load, tumors that are TMB-H are expected to be more immunogenic and responsive to treatment with immunotherapy, according to Schenker. Data have also indicated that TMB is a key predictive biomarker for immunotherapy spanning a range of solid tumor types. It is known that TMB can be determined from both the tissue and the blood.

In the prospective CheckMate-848 trial, investigators set out to examine whether nivolumab with or without ipilimumab would improve responses in patients with advanced or metastatic solid tumors that have high tTMB and/or high bTMB. Notably, the trial was not powered to compare the doublet with the monotherapy.

During the meeting, Schenker shared data from an interim analysis of the tTMB-H cohort and findings from final analyses of the bTMB-H cohort.

Patients with immunotherapy-naïve solid tumors that were refractory to standard therapies or who did not have standard treatment options available to them were enrolled. Patients needed to have tTMB and/or bTMB of at least 10 mutations/megabase (mut/Mb). Those with melanoma, non–small cell lung cancer, and renal cell carcinoma were excluded.

Participants were prospectively randomized in a 2:1 fashion to receive either nivolumab at 240 mg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks for up to 24 months or nivolumab at 480 mg every 4 weeks for up to 24 months. Key stratification factors included line of therapy, tTMB of at least 16 mut/Mb, and bTMB of at least 16 mut/Mb.

The primary end points were ORR in patients with tTMB-H tumors and ORR in those with bTMB-H tumors. Key secondary end points comprised duration of response (DOR), investigator-assessed ORR, time to response, clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety.

To determine TMB in tissue specimens that were collected from participants, investigators leveraged the FoundationOne CDx-based Clinical Trial Assay. To identify TMB in the blood specimens that were collected, they used the Foundation Medicine bTMB Clinical Trial Assay.

Participants were prospectively classified as being tTMB-H or bTMB-H utilizing a cutoff of 10 mut/Mb or higher, according to Schenker. Patients were also stratified using a cutoff of at least 16 mut/Mb to ensure an even distribution of patients with relatively low TMB and relatively high TMB, as well as to allow for further analyses based on TMB stratification.

A total of 1954 patients were prescreened. Of these patients, 1141 had available tTMB data, 1573 had available bTMB data, and 1017 had both bTMB and tTMB data available. A total of 319 patients were screened and 212 patients underwent randomization on the trial. Of the 212 patients, 201 were refractory to standard therapies; 135 of these patients were determined to be tTMB-H and 147 patients were determined to be bTMB-H.

A total of 170 patients comprised the primary analysis population; 104 of these patients had tTMB-H tumors and 125 had bTMB-H tumors. Thirty-eight percent (n = 65) of the 170 patients were found to have both tTMB-H and bTMB-H tumors, Schenker said.

The trial population included over 40 different tumor types, which included biliary cancer (n = 7), carcinoma of unknown primary (n = 7), neuroendocrine cancer (n = 5), anal cancer (n = 5), sarcoma (n = 5), small bowel cancer (n = 4), squamous cell carcinoma (n = 3), glioblastoma (n = 3), adrenal cancer (n = 3), basal cell carcinoma (n = 3), vulvar cancer (n = 3), thymus cancer (n = 2), and penile cancer (n = 2), among others.

“The patient characteristics of age, sex, and geographic region were comparable and well distributed across tTMB-H and bTMB-H cohorts and across the treatment arms,” Schenker noted. “Additionally, the number of previous standard treatments was comparable across groups; this was the second stratification factor after TMB status.”

The median DOR was not yet evaluable in any of the cohorts examined on the trial. A DOR of 9 months or longer was observed in 91% (95% CI, 68%-98%) of those with tTMB-H disease who received the doublet (n = 68) and 88% (95% CI, 61%-97%) of those in the bTMB-H cohort who received the combination (n = 80).

Moreover, 78% (95% CI, 37%-94%) of patients who had tTMB-H tumors and received nivolumab monotherapy (n = 36) and 86% (95% CI, 33%-98%) of those with bTMB-H tumors who received nivolumab alone (n = 45) experienced a DOR of at least 9 months.

“Regarding the subgroup analysis of ORR in the tTMB-H cohort, the most important observation is that responses were independent of bTMB-H status,” Schenker explained. “The responses were observed in those with microsatellite instability–high (MSI-H), microsatellite stable, PD-L1–positive, and PD-L1–negative subgroups. In the bTMB-H cohort, responses were improved with tTMB-H status. MSI-H prevalence was too small to reach any kind of conclusions.”

Similar depths of response were observed in those with tTMB-H tumors, regardless of bTMB status, Schenker added. In those with bTMB-H tumors who received the doublet, depth of response seemed to be driven by tTMB-H status, and similar findings were noted in those who received nivolumab alone.

Additionally, although the study was not designed to directly compare PFS in the tTMB-H and bTMB-H cohorts, a trend toward a prolonged median PFS was observed in those with tTMB-H tumors vs those with bTMB-H tumors who received nivolumab plus ipilimumab.

Within the doublet arm, the median PFS was 4.1 months (95% CI, 2.8-11.3) in the tTMB-H cohort vs a median of 2.8 months (95% CI, 2.3-3.0) in the bTMB-H cohort. In the nivolumab-monotherapy arm, the median PFS was 2.9 months (95% CI, 2.6-5.7) in the tTMB-H cohort and 2.8 months (95% CI, 2.6-3.2) in the bTMB-H cohort.

A similar trend was observed with regard to OS, according to Schenker. In the nivolumab/ipilimumab cohort, the median OS was 14.5 months (95% CI, 7.7–not evaluable [NE]) in the tTMB-H cohort and 8.5 months (95% CI, 5.8-10.5) in the bTMB-H cohort. In the nivolumab-alone cohort, the median OS was 11.7 months (95% CI, 5.3-NE) in the tTMB-H cohort and 11.3 months (95% CI, 5.3-19.0) in the bTMB-H cohort.

Regarding safety, nivolumab plus ipilimumab was found to have a manageable toxicity profile; these profiles were consistent with what has previously been observed with the doublet and with nivolumab monotherapy. The most frequently experienced treatment-related adverse effects of any grade with the doublet included pruritus, diarrhea, and fatigue.

One patient who was included in both the tTMB-H and bTMB-H cohorts experienced a fatal toxicity associated with a study drug, which was hyperglycemia.

Schenker M, Burotto M, Richardet M, et al. CheckMate 848: a randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT022.

Results from the  phase 2 CheckMate-848 study show that nivolumab in combination and ipilimumab may be effective for the treatment of advanced or metastatic tumor mutational burden–high solid tumors that were refractory to standard therapies.

Nivo/Ipi Induces Promising Response in Advanced tTMB- and bTMB-High Solid Tumors

olaparib (Lynparza) to durvalumab (Imfinzi) did not demonstrate a significant extension in progression-free survival (PFS) compared with durvalumab alone in patients with previously untreated, platinum-ineligible metastatic urothelial carcinoma, missing the primary end point of the phase 2 BAYOU trial (NCT03459846).

The data, which were presented during the 

, showed that the median investigator-assessed PFS with the doublet (n = 78) in the intent-to-treat (ITT) population was 4.2 months (95% CI, 3.6-5.6) vs 3.5 months (95% CI, 1.9-5.1) with durvalumab alone (n = 76; HR, 0.94; 95% CI, 0.64-1.39; log-rank 

However, data from a prespecified secondary analysis suggested that olaparib plus durvalumab had a potential PFS benefit in a subgroup of patients with homologous recombination repair (HRR) mutations. In this population, the median PFS achieved with the doublet (n = 17) was 5.6 months (95% CI, 1.9-8.1) vs 1.8 months (95% CI, 1.7-2.2) with single-agent durvalumab (n = 14; HR, 0.18; 95% CI, 0.06-0.47; log-rank 

“The PFS results suggest a potential role for PARP inhibitors in the treatment of metastatic urothelial carcinoma with HRR mutations, and further investigation is warranted,” Jonathan E. Rosenberg, MD, chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology, and Enno W. Ercklentz Chair at Memorial Sloan Kettering Cancer Center, said in an oral presentation on the data.

Patients with metastatic urothelial carcinoma are known to have a poor prognosis, particularly those who cannot tolerate platinum-based chemotherapy, Rosenberg said. For these patients, atezolizumab (Tecentriq) and pembrolizumab (Keytruda) are given, irrespective of PD-L1 status; however, a high unmet need for additional therapeutic options remains.

Defects in DNA damage repair occur in approximately 24% of patients with urothelial carcinoma, and the dysregulation of DNA repair genes has been associated with poorer outcomes. Notably, these defects are known to make cancer cells sensitive to PARP inhibitors. As such, investigators hypothesized that HRR mutations and PARP inhibition could strengthen the antitumor response achieved with immune checkpoint inhibitors.

To this end, BAYOU sought to enroll approximately 150 patients with unresectable, stage IV urothelial carcinoma, a transitional cell carcinoma of the bladder, renal pelvis, ureter, or urethra. Patients needed to be at least 18 years of age and have an ECOG performance status ranging from 0 to 2.

Study participants were randomized 1:1 to receive either intravenous (IV) durvalumab at a dose of 1500 mg every 4 weeks plus oral olaparib at a twice-daily dose of 300 mg or durvalumab alone. Key stratification factors included HRR status (mutant vs wild-type) and Bajorin risk index (0 vs 1 vs 2).

The primary end point of the trial was PFS by RECIST v1.1 criteria and per investigator assessment. Key secondary end points comprised PFS by RECIST v1.1 criteria in the subgroup of patients with HRR mutations, overall survival (OS), duration of response (DOR), objective response rate (ORR), and PFS at 6 months by RECIST v1.1 criteria in both the ITT population and the HRR-mutated subset. Other end points of interest included safety and tolerability.

The data cutoff date was October 15, 2020. The median follow-up in the investigative arm was 9.8 months (range, 0.0-29.0) vs 10.7 months (range, 1.0-29.0) in the control arm.

Those who received the doublet were slightly older than those who received durvalumab monotherapy, at a median of 79 years (range, 47-89) vs 72 years (range, 45-88). Slightly more than half of patients in both arms were male. In the investigative arm, 51% of patients were White, 49% were Asian, and none were Black or African American; in the control arm, these rates were 46%, 51%, and 3%, respectively.

Regarding ECOG performance status, 15% of patients who received olaparib plus durvalumab had a status of 0, 38% had a status of 1, and 44% had a status of 2. Of those who were given durvalumab monotherapy, 18% had an ECOG performance status of 0, 45% had a status of 1, and 37% had a status of 2. Most patients in both arms had pure transitional cell carcinoma.

Moreover, 67% of patients who received the doublet had visceral metastases, and 33% had lymph-node only disease; these rates were 63% and 37%, respectively, in those who received the monotherapy. In the investigative and control arms, 11.5% and 10.5% of patients, respectively, received previous therapy.

In the investigative arm, 21% of patients did not have any Bajorin risk factors, 49% had 1 risk factor, and 31% had 2. In the control arm, 24% did not have Bajorin risk factors, 47% had 1, and 29%, and 2. Seventy-eight percent of patients in the doublet arm had HRR wild-type disease, and 22% had HRR-mutated disease; in the control arm, these rates were 82% and 18%, respectively.

The 20 most frequent gene mutations demonstrated a pattern that proved to be consistent with what has previously been observed in bladder cancer, according to Rosenberg. Across all patients, the most common HRR gene mutations were loss of p53 function (59.5%) and TERT promoter mutations (55.6%).

Utilizing the validated FoundationOne assay, investigators tested tumor samples for loss of function alterations in the following 15 prespecified HRR genes: 

. HRR mutations were found in 7 of the 15 genes analyzed. The most frequent included 

, which was identified in 8.5% of all tumors and in 41.9% of patients in the HRR-mutated subset, as well as 

, which was found in 4.6% of all tumors and in 22.6% of those in the HRR-mutated subgroup.

Exploratory subgroup analyses also showed that PFS favored olaparib/durvalumab over durvalumab alone in those with a Bajorin risk index of 0 (HR, 0.42; 95% CI, 0.18-0.92). However, PFS appeared to favor single-agent durvalumab over the doublet in those with HRR wild-type disease (HR, 1.29; 95% CI, 0.85-1.96), in those with a Bajorin risk index of 1 (HR, 1.90; 95% CI, 1.07-3.49), and in those with a Bajorin risk index of 2 (HR, 1.19; 95% CI, 0.63-2.28).

Data from the prespecified secondary analysis of OS showed that olaparib plus durvalumab did not result in improved OS vs durvalumab monotherapy in the ITT population. Specifically, the median OS with the doublet 10.2 months (95% CI, 7.0-13.9) vs 10.7 months (95% CI, 7.2-17.3) with durvalumab alone (HR, 1.07; 95% CI, 0.72-1.61; log-rank 

The same was true in the subgroup of patients with HRR wild-type disease. The median OS with olaparib plus durvalumab (n = 61) was 10.9 months vs 13.7 months with single-agent durvalumab (n = 62; HR, 1.35; 95% CI, 0.85-2.16). However, the doublet (n = 17) was found improve median OS in the subset of patients with HRR-mutated disease vs the monotherapy (n = 14), at 8.6 months vs 5.8 months, respectively (HR, 0.56; 95% CI, 0.25-1.23).

The addition of olaparib to durvalumab resulted in an ORR of 28.2% in the ITT population vs 18.4% with durvalumab alone. In the investigative arm, 3.8% of patients achieved a complete response, 24.4% had a partial response (PR), 34.6% achieved stable disease (SD) for at least 7 weeks, 32.1% experienced disease progression, and 5.1% were not evaluable. The median DOR in the investigative arm was 8.9 months (range, 4.7-12.1) vs 14.8 months (range, 7.5-17.2) in the control arm.

In the HRR-mutated subset, the combination produced an ORR of 35.3% vs 0% with durvalumab alone. Among those who responded to the doublet, 35.3% achieved a PR and 29.4% had SD for 7 weeks or longer. Moreover, 29.4% had progressive disease and 5.9% were not evaluable. The median DOR with olaparib/durvalumab was 6.7 months (range, 3.7-12.0) in this subset.

No new safety signals were observed with the combination of olaparib and durvalumab, according to Rosenberg. Any-grade treatment-related adverse effects were experienced by 72.4% of patients who received the doublet (n = 76) vs 60.5% of those given the monotherapy (n = 76).

The most common toxicities observed in the investigative arm included anemia (any grade, 23.7%; grade 3 or 4, 6.6%), nausea (any grade, 19.7%; grade 3 or 4, 1.3%), fatigue (any grade, 15.8%; grade 3 or 4, 1.3%), decreased appetite (any grade, 10.5%), diarrhea (any grade, 10.5%), and hypothyroidism (any grade, 9.2%). In the control arm, the most common toxicities included anemia (any grade, 13.2%; grade 3 or 4, 1.3%), pruritus (any grade, 10.5%), fatigue (any grade, 6.6%), rash (any grade, 5.3%), nausea (any grade, 3.9%), hypothyroidism (any grade, 3.9%).

One death was reported in the durvalumab monotherapy arm, and this was because of anemia.

Rosenberg JE, Park SH, Dao TV, et al. BAYOU: a phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC). J Clin Oncol. 2022;40(suppl 6):437. doi:10.1200/JCO.2022.40.6_suppl.437.

The phase 2 BAYOU study failed to meet its primary end point of improvement in progression-free survival with olaparib plus durvalumab in patients with platinum-ineligible metastatic urothelial carcinoma. 