Jackie Collins

Treatment with the combination of olaparib (Lynparza) in combination with metronomic cyclophosphamide and metformin demonstrated a significant non-progression rate in patients with recurrent advanced or metastatic endometrial cancer, according to findings from the ENDOLA trial (NCT02755844).

In the dose-escalation phase of ENDOLA, olaparib was started at 150 mg twice daily in cycle 1 and escalated up to 300 mg twice daily. Using the continual reassessment method, the recommended phase 2 trial dose was then confirmed to be 300-mg olaparib twice daily plus 50-mg metronomic cyclophosphamide once daily plus 500-mg metformin thrice daily.

In an evaluation of this dose in the phase 2 portion of the trial, the non-progression rate at 10 weeks was 61.5% (95% CI, 42.8%-80.2%) in the 14 evaluable patients. The overall response rate (ORR) was 20.8%, with a disease-control rate of 66.6%.

“In patients with recurrent endometrial cancer, there is a need for innovative approaches beyond first-line treatment,” Benoit You, MD, academic staff physician in the Medical Oncology department at Lyon University Hospital in France, said in a presentation during the AACR Annual Meeting 2022. “There was a very strong rationale to create a chemotherapy-free triplet regimen with olaparib—a PARP inhibitor—with metronomic cyclophosphamide—known to be an effective alkylating chemotherapy—and metformin—cited for its inhibition of the P13K pathway and reducing the circulation of 

 and the activation of this pathway. We could expect a cytogenic effect from these 3 drugs.”

ENDOLA was a phase 1/2 open-label, dose-escalation trial evaluating olaparib with metronomic cyclophosphamide and metformin in elderly, heavily pretreated patients with recurrent advanced endometrial cancer. A dose-limiting toxicity (DLT) assessment period was implemented every 6 weeks within the 28-day cycles and the optimal dose was determined as that associated with probability of a DLT in less than 20% of patients.

In phase 1, 5.9% of patients experienced a dose-limiting toxicity; specifically, they experienced grade 3 fatigue during cycle 1 with the 150-mg olaparib dose level.

Of the 35 patients enrolled, 31 patients were evaluable—17 patients were in phase 1 and 14 patients were in phase 2.

Notably, the median age was 69 years (range, 46-80), and more than half of the patient population was previously treated with at least 4 lines of therapy (4-5 lines, 25.8%; ≥ 6, 29%).

Most patients had endometroid carcinoma (58.1%), while the remaining had serous carcinoma (11%) or carcinosarcoma (6.5%). Most patients did not receive prior treatment with radiation therapy (93.5%) or immunotherapy (93.5%). Additionally, some patients were previously treated with endocrine therapy, including acetate of megestrol (9.6%), tamoxifen (6.5%), or an aromatase inhibitor (12.9%).

Aside from establishing the recommended phase 2 trial dose of the triplet, the other primary end points in the phase 1 component of the study were safety, dose-limiting toxicities, and treatment-related adverse events (TRAEs).

TRAEs were observed in more than 10% of evaluable patients. Notable TRAEs included: asthenia/fatigue (all grade, 61.3%; grade 3/4, 12.9%), lymphopenia (all grade, 38.7%; grade 3/4, 32.3%), neutropenia (all grade, 32.3%; grade 3/4, 16.1%), and thrombocytopenia (all grade, 29.0%; grade 3/4, 6.5%).

Twelve patients (38%) had a dose reduction, including 9 who had at least 2 reductions. Study treatment discontinuation due to toxicity occurred for 2 patients (6%).

In the phase 2 portion, investigators evaluated the non-progression rate at 10 weeks. The null hypothesis was a P0 of 20% and the alternative hypothesis was a P1 of at least 50%. In the first stage, out of 10 patients, at least 3 needed to have a success to continue onto the second stage. And once in the second stage, out of 17 patients, at least 6 were required to have a success for the trial to be considered positive. Imaging assessment was performed every other cycle.

A secondary end point in the phase 2 component of note was progression-free survival (PFS). The median PFS was 5.1 months (95% CI, 3.7-8.1); specifically, for patients with endometroid carcinomas, the median was 7.5 months (95% CI, 5.1-8.9), and for patients with serous carcinomas, it was 4.3 months (95% CI, 2.7-5.8).

In his presentation, You compared the PFS data to that of the KEYNOTE-755 trial (NCT03517499), in which patients with advanced endometrial cancer who had previously received at least 1 platinum-based chemotherapy regimen received either 20-mg lenvatinib (Lenvima) orally once daily plus 200-mg pembrolizumab (Keytruda) intravenously every 3 weeks (n = 411) or physician’s choice chemotherapy (n = 416). In this phase 3 trial, the median PFS for those who received the doublet was 7.2 months (95% CI, 5.7-7.6) vs 3.8 months (95% CI, 3.6-4.2) with chemotherapy alone (HR, 0.60; 95% CI, 0.50-0.72; 

 < .001). The ORR was 31.9% (95% CI, 27.4%-36.6%) vs 14.7% (95% CI, 11.4%-18.4%).

Specifically, for patients with endometroid carcinomas, the median was 7.6 months, and for patients with serous carcinomas, it was 5.7 months.

“Notably, most of these patients [in KEYNOTE-755] were treated in second-line treatment and were younger,” You added. “So, we consider that [olaparib plus metronomic cyclophosphamide plus metformin] is a chemotherapy-free regimen that warrants further investigation.”

You said the translational research tied to this study includes the effect of PI3K and PAR pathways in PBMCs, CA-125, and 

 kinetics, and circulating tumor DNA, along with DNA repair and PI3K-AMT-mTor biomarkers. This research is ongoing, You concluded.

1. You B, Leary A, Rodrigues M, et al. Safety and efficacy of OLAparib combined to metronomic cyclophosphamide and metformin in recurrent advanced/metastatic ENDOmetrial cancer patients: ENDOLA trial. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022. New Orleans, LA. Abstract CT005.

2. Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial carcinoma. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2180330

3. Colombo N, Lorusso D, Casado Herráez A, et al. Outcomes by histology and prior therapy with lenvatinib plus pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer (Study 309/KEYNOTE-775). Ann Oncol. 2021;32(suppl 5):S729-S730. doi:10.1016/j.annonc.2021.08.1169

Articles

An olaparib triplet demonstrated efficacy in patients with recurrent advanced or metastatic endometrial cancer treated in the ENDOLA clinical trial.

ENDOLA Study Demonstrates Promise of Olaparib Triplet in Endometrial Cancer

At an almost 3-year median follow-up, health-related quality-of-life (QOL) scores were improved or maintained over time among patients with advanced renal cell carcinoma (RCC) who received nivolumab (Opdivo) plus cabozantinib (Cabometyx) compared to patients on sunitinib (Sutent) in updated data from the phase 3 CheckMate 9ER trial (NCT03141177), according to data presented at the 2022 Genitourinary Cancers Symposium.

In the exploratory analysis, patient-reported outcomes (PROs) were assessed using Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (FKSI-19) total score—which included disease-related symptoms (DRS), disease-related symptoms-physical (DRS-P), and functional well-being (FWB)—and the 3-level version of the EQ-5D (EQ-5D-3L)—which included UK utility index and visual analog scale (VAS).

Specifically, the FKSI-19 total score (range, 0-76) in the nivolumab plus cabozantinib arm (n = 323) was 58.74 (standard deviation [SD], 10.57) compared with 58.39 (SD, 9.92) in the sunitinib arm (n = 328). The DRS (range, 0-36) was 30.24 (SD, 5.19) vs 30.06 (SD, 5.03), the DRS-P (range, 0-48) was 38.19 (SD, 6.96) vs 38.14 (SD, 6.47), and the FWB (range, 0-12) was 7.17 (SD, 3.49) vs 7.08 (SD, 3.48) in the nivolumab plus cabozantinib group and sunitinib group, respectively.

Additionally, the EQ-5D-3L VAS (range, 0-100) was 74.23 (SD, 22.23) in patients who received the doublet combination and 75.68 (SD, 20.92) in patients who received sunitinib. The UK utility index (range, 0-1) was 0.78 (SD, 0.25) vs 0.73 (SD, 0.29), respectively.

In the open-label, randomized, multinational CheckMate 9ER trial, patients with previously untreated advanced or metastatic RCC were randomized 1:1 to receive either nivolumab intravenously at 240 mg once every 2 weeks plus cabozantinib by mouth at 40 mg once daily or sunitinib by mouth at 50 mg once daily for 4 weeks of each 6-week cycle.

Investigators presented updated efficacy data from CheckMate 9ER at the 2022 Genitourinary Symposium.

PRO score was an exploratory end point assessed in all randomized patients in the study. PRO instruments—FKSI-19 and EQ-5D-3L—were administered at baseline, before the start of each treatment cycle, and during follow-up visits 1 and 2 on 30 and 100 days from last dose. The EQ-5D-3L was also administered every 3 months during survival follow-up.

FKSI-19 measured disease-related symptoms of kidney cancer, and higher scores indicate better health state and effects of health-related QOL. VAS measured health status in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Higher scores on both assessments were indicative of better health states.

For the FKSI-19, a form was defined as evaluable if at least 50% of the items had been completed. For EQ-5D-3L, a form was defined as evaluable if the VAS item was completed and all 5 items of the descriptive system had been completed.

MMRM adjusted for baseline scores and stratification factors and included all common timepoints (at baseline and every 6 weeks) through week 151 (approximately 37 months).

The authors highlighted that PRO completion rates in both treatment arms were high (> 90%) at baseline but declined over time. At 115 weeks the completion rates remained high in both treatment arms (> 75% except for week 109, where it was 73% in the sunitinib arm). Baseline PRO scores were comparable between the nivolumab plus cabozantinib and sunitinib treatment groups and showed relatively low symptom burden.

Longitudinal changes from baseline in PRO scores was assessed using mixed-model repeated measures (MMRM). Estimated changes from baseline show that nivolumab plus cabozantinib had statistically significant improved health related QOL from baseline through week 151 (

 < .05) in all scoring criteria except FWB.

Particularly, the overall least squares (LS) mean change from baseline for FKSI-19 total score was -0.47 in the nivolumab plus cabozantinib arm compared with -2.84 in the sunitinib arm (

 < .0001). The overall LS mean changes for FKSI-19 DRS score were 0.71 vs -0.46, respectively (

 < .0001). Regarding EQ-5D-3L health status score, the overall LS mean change from baseline was 2.73 in the investigative arm vs -0.95 in the control arm (

 = 001), respectively for EQ-5D-3L UK utility index score.

Time to deterioration analysis was conducted for first (TTFD), confirmed (TTCD), and definitive (TTDD) deterioration events. Nivolumab plus cabozantinib significantly reduced the risk of first and confirmed deterioration in the FKSI-19 total, DRS, DRS-P, and FWB scores compared with sunitinib.

Specifically, TTFD for FKSI-19 total score had a median time to event of 6.24 months in the nivolumab plus cabozantinib group compared with 3.48 months in the sunitinib group (HR, 0.71; 95% CI, 0.57-0.87; 

 = .0011). In terms of DRS, the median time to event was 12.48 months vs 5.78 months, respectively (HR, 0.70; 95% CI, 0.56-0.87; 

 = .0017), and for DRS-P, the median time to event was 7.49 months vs 4.93 months, respectively (HR, 0.73; 95% CI, 0.59-0.91; 

 = .005). Finally, onset of FWB events occurred at a median of 19.38 months vs 6.97 months, respectively (HR, 0.69; 95% CI, 0.54-0.87; 

In regard to TTCD, patients in the combination arm had a median time to first confirmed event of 18.23 months compared with 6.97 months in the sunitinib arm when evaluated by FKSI-19 total score (HR, 0.66; 95% CI, 0.52-0.84; 

 = .0005). In terms of DRS, DRS-P, and FWB in this analysis, the median TTCD was not reached (NR) for the combination vs 15.28 months (HR, 0.65; 95% CI, 0.50-0.86; 

 = .002), 10.05 months (HR, 0.56; 95% CI, 0.43-0.73; 

 < .0001), and 22.77 months (HR, 0.67; 95% CI, 0.50-0.88; 

Also, nivolumab plus cabozantinib significantly reduced the risk of definitive deterioration compared with sunitinib in FKSI-19 total, DRS, and DRS-P scores, but not in FWB score. The median TTDD for FKSI-19 total score was 34.76 months in the investigative arm compared with 30.65 months in the sunitinib arm (HR, 0.68; 95% CI, 0.52-0.90; 

 = .007). In terms of DRS, the median TTDD was NR vs 34.5 months, respectively (HR, 0.53; 95% CI, 0.37-0.75; 

 = .0003). For DRS-P, the median was NR vs 32.23 months, respectively (HR, 0.52; 95% CI, 0.38-0.72; 

 < .0001). The median TTDD was not reached for either arm in the FWB analysis; the total number of events were 74 vs 69 in the combination and sunitinib arms, respectively (HR, 0.79; 95% CI, 0.57-1.11; 

Nivolumab plus cabozantinib also significantly reduced the risk of deterioration in EQ-5D-3L VAS relative to sunitinib, irrespective of the definition used (TTFD, TTCD, or TTDD). Investigators noted that no significant difference was observed between treatment arms for the UK utility index. Specifically, the HRs for UK utility index were 0.86, 0.81, and 0.77, for TTFD, TTCD, and TTDD, respectively.

The median TTFD for EQ-5D-3L VAS was 13.86 months in the nivolumab plus cabozantinib arm compared with 4.67 months in the sunitinib (HR 0.74; 95% CI, 0.59-0.92; 

 = .0019). For TTCD, the median time to event was 34.56 months vs 17.74 months, respectively (HR 0.74; 95% CI, 0.58-0.95; 

 = .0183). Finally, the median TTDD was 37.65 months vs 31.28 months, respectively, for VAS analysis (HR 0.64; 95% CI, 0.48-0.86; 

Investigators highlighted a specific item from the measures of disease symptoms in the FKSI-19 instrument in their analysis: item GP5: “I am bothered by [adverse] effects of treatment.” Responses were dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat,” “quite a bit,” or “very much”).

Overall, fewer patients in the nivolumab plus cabozantinib arm reported to be bothered by AEs compared with patients in the sunitinib arm. Patients who received the doublet were 48% less likely to be notably bothered by AEs than patients treated with sunitinib (odds ratio, 0.52; 95% CI, 0.35-0.77).

Authors of the poster wrote that item GP5 “is highlight associated with clinician-related adverse events and is supported as a single-item summary measure evaluating the impact of treatment-related toxicity.” Further, they noted that the item is recommended in the FDA oncology guidance as a core PRO for cancer clinical trials.

Cella D, Motzer RJ, Blum SI, et al. Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC): CheckMate 9ER updated results. J Clin Oncol. 2022;40(6):323. doi:10.1200/JCO.2022.40.6_suppl.323

A 3-year analysis of updated data from the phase 3 CheckMAte 9ER trial shows the better health-related quality of life outcomes for patients with advanced renal cell carcinoma on nivolumab plus cabozantinib. 

Better Health-Related QOL Outcomes With Nivolumab/Cabozantinib Endure in RCC Compared to Sunitinib

Nivolumab (Opdivo) elicited prolonged clinical benefit in patients with advanced hepatocellular carcinoma (HCC) regardless of prior sorafenib (Nexavar), according to 5-year follow-up data from 2 cohorts of the phase 1/2 openlabel, multicohort CheckMate040 trial (NCT01658878). Patients were stratified into cohorts based on prior sorafenib exposure and enrolled regardless of HCC etiology and PD-L1 expression status, according to Jörg Trojan, MD, head of the Gastrointestinal Oncology Unit at Goethe University Hospital and Cancer Center in Frankfurt, Germany, who presented the data during the 2021 International Liver Cancer Association Conference.

At data cutoff December 2020, patients in the sorafenib-näive cohort (n = 80) had a median followup of 62.9 months (range, 60-94) and a reported objective response rate (ORR) of 20%. Of the responders, 4% had a complete response (CR) and 16% had partial response (PR). Stable disease (SD) was reported in 33%, whereas 40% had progressive disease (PD). The median duration of response (DOR) was 22.6 months (range, 4.2-56.6).

For patients in the sorafenib cohort (n = 154), the median follow-up was 62.8 months (range, 60-86). The ORR was 14%, which included CR and PR rates of 3% and 11%, respectively. SD and PD were reported in 42% and 38%, respectively. The median DOR in this cohort was 39.7 months (range, 3.2-79.8).

“We have seen a clinical benefit from nivolumab regardless of the etiology in both groups,” Trojan said. “We found a similar benefit independent of the level of PD-L1 expression.”

In the sorafenib-näive cohort, the ORR was 21% for uninfected patients (n = 47), 20% for those with hepatitis C virus (HCV; n = 25), and 13% for those with hepatitis B virus (HBV; n = 8). The ORRs were 27% and 20% for patients with PD-L1 expression of at least 1% (n = 27) and less than 1% (n = 20), respectively (TABLE).

In the sorafenib-experienced patient cohort, ORRs for uninfected patients (n = 13), those with HCV (n = 19), and those with HBV (n = 13) were 13%, 19%, and 13%, respectively. The ORRs were 27% and 13% for patients with PD-L1 expression of at least 1% (n = 27) and less than 1% (n = 13), respectively.

Despite a variety of options for patients in the first and second lines, patients with advanced HCC have a poor prognosis and high mortality, Trojan explained. Sorafenib, the first systemic therapy approved by the FDA for this patient population in the first-line setting, has recently been joined by lenvatinib (Lenvima) and the immunooncology– based combination therapy of atezolizumab (Tecentriq) plus bevacizumab (Avastin), which has emerged as the standard-of-care therapy.

Nivolumab was granted an accelerated approval by the FDA in 2017 based on data from CheckMate 040 for the treatment of patients with HCC who have been previously treated with sorafenib. However, in July 2021, Bristol Myers Squibb voluntarily withdrew the indication for nivolumab from the US market following the FDA’s evaluation of confirmatory data for checkpoint inhibitors that have not met their postmarketing requirements.

 The FDA’s Oncologic Drugs Advisory Committee voted 5 to 4 against the continued accelerated approval.

In CheckMate 040 study, 11 patients in the sorafenib-näive cohort received nivolumab monotherapy at escalating dose levels (0.1-10.0 mg/kg) once every 2 weeks and 69 patients received nivolumab 3 mg/kg once every 2 weeks. Patients in the sorafenib-experienced cohort received nivolumab monotherapy at expansion dose levels (3 mg/kg) once every 2 weeks.

The median age for the sorafenib-näive cohort was 65 (range, 20-83) and 63 (range, 19-81) for that of the sorafenib-experienced cohort. In both populations, 90% of patients had Barcelona Clinic Liver Cancer stage 3 HCC, extrahepatic spread (60% and 71%, respectively), Child-Pugh score 5 (73% and 60%, respectively), and tumor cell PD-L1 expression less than 1% (70% and 71%, respectively). Of the patients in the sorafenib-experienced cohort, 91% had previously progressed on or after treatment with sorafenib.

A secondary end point in the follow-up analysis was OS, which was comparable between both treatment groups. In the sorafenib-näive group, the median OS was 26.6 months (range, 95% CI, 16.6-30.6). The sorafenib-experienced group had a median OS of 15.2 months (95% CI, 13.0-18.2). Additionally, in the sorafenib-naïve cohort the 3-year and 5-year OS rates were 28% (95% CI, 18%-38%) and 14% (95% CI, 7%-23%), respectively, and in the sorafenib-experienced cohort they were 20% (95% CI, 14%-27%) and 12% (95% CI, 7%-18%), respectively.

In an analysis of survival by best overall response (CR/PR) the median OS was 39.6 months (95% CI, 30.6-not estimable [NE]) in the sorafenib-näive cohort. The median OS was not reached (95% CI, 28.1-NE) for those with best overall response in the sorafenib-experienced cohort.

Efficacy ranged for patients with differing baseline characteristics. Extrahepatic and α-fetoprotein (AFP) levels of at least 400 μg/L, for example, were associated with shorter OS, and tumor cell PD-L1 expression of at least 1 was associated with longer OS regardless of prior sorafenib, Trojan noted.

Specifically, of patients in the sorafenib-näive cohort who had median OS of less than 1 year (n = 25), 76% had extrahepatic spread, 32% had high AFP levels, and 68% had PD-L1 expression of less than 1%. Similar trends were observed for those with a median OS of less than 1 year in the sorafenib-experienced cohort, with 74% of patients having extrahepatic spread, 42% with high AFP levels, and 71% with PD-L1 expression of less than 1%. Higher levels of CD8 expression at baseline were associated with longer median OS in the sorafenib-näive cohort; the median percentage of CD8-positive cells via immunohistochemistry in 16 patients with a median OS of 3 years or more was 6.5% (range, 1.2%-17.8%).

Investigators also reported survival data stratified by albumin and bilirubin (ALBI) grade and Child-Pugh score. Patients in the sorafenib-näive cohort with ALBI grade 2 (n = 47) had a shorter median OS than those with ALBI grade 1 (n = 33), at 16.6 months (range, 1.0-66.3) and 26.7 months (range, 1.5-65.6), respectively. The median OS for patients in the sorafenib-experienced cohort with ALBI grade 2 (n = 76) was 13.1 months (range, 0.4-86.5). For those in the sorafenib-experienced cohort with ALBI grade 1 disease (n = 78), the median OS was 17.9 months (range, 0.4-64.9).

Baseline Child-Pugh score did not affect OS in patients who were sorafenib näive; OS was 20.1 months for those with Child-Pugh score 5 (n = 58; range, 1.5-66.3) and 20.1 months (range, 1.0-62.7) for those with Child-Pugh score 6 (n = 19). However, for patients who received prior sorafenib, those with worse liver status (Child-Pugh score 6; n = 48) had a shorter median OS at 11.5 months (range, 0.4-64.0) compared with 15.4 months (range, 0.4-86.5) for those who had Child-Pugh score 5 disease (n = 104).

Regarding safety, grade 3/4 treatment-related adverse events (TRAEs) were observed in 33% of patients in the sorafenib-näive cohort and in 21% of patients in the sorafenib-experienced cohort. TRAEs leading to discontinuation occurred in 3% (grade 3/4) and 6% (any grade) of patients who were sorafenib näive and in 2% (grade 3/4) and 3% (any grade) of those who had prior sorafenib. No new safety signals were identified in the follow-up, Trojan said.

Immune-meditated adverse events with nivolumab were mostly grade 1/2, according to Trojan, with any-grade rash (16% and 10%, respectively), hepatitis (6% and 5%, respectively), and hypothyroidism/thyroiditis (6% and 5%, respectively) most reported in the sorafenib-näive and sorafenib-experienced cohorts, respectively. “In summary, these results demonstrate a long-term benefit of nivolumab in a high proportion of patients with advanced HCC,” Trojan concluded.

1. Trojan J, Meyer T, Yau T, et al. Nivolumab in sorafenib-näive and -experienced patients with advanced hepatocellular carcinoma (aHCC): 5-year follow-up from CheckMate 040 cohorts 1 and 2. Presented at: ILCA Annual Conference 2021; September 2-5, 2021; virtual.

2. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 4.2021. Accessed September 6, 2021. https://bit. ly/2VDF3lg

3. Bristol Myers Squibb statement on Opdivo (nivolumab) monotherapy post-sorafenib hepatocellular carcinoma U.S. indication. News release. Bristol Myers Squibb. July 23, 2021. Accessed September 6, 2021. https://bit.ly/3AaaLWw

In CheckMate040, single-agent nivolumab achieved durable responses in patients with advanced hepatocelluar carcinoma.

Nivolumab Continues to Elicit Durable Responses in Advanced HCC

Patients with previously treated HER2-positive metastatic breast cancer experienced a clinically meaningful and statistically significant improvement in progression-free survival (PFS) with fam-trastuzumab deruxtecan-nxki (Enhertu) vs standard of care trastuzumab emtansine (T-DM1; Kadcyla) in the DESTINY-Breast03 trial (NCT03529110), the first randomized head-to-head study of the antibody-drug conjugate, trastuzumab deruxtecan, according to data presented at the 2021 ESMO Congress.

The median PFS for patients treated with trastuzumab deruxtecan was not reached (95% CI, 18.5-not estimable [NE]) vs 6.8 months (95% CI, 5.6-8.2) with T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10

). Among the 261 patients in the trastuzumab deruxtecan the 12-month PFS rate was 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%) among 263 patients treated in the T-DM1 arm.

“These data support trastuzumab deruxtecan becoming the standard of care for the second-line treatment of HER2-positive metastatic breast cancer,” said Javier Cortés, MD, in a presentation of the data. Cortés is head of breast cancer and gynecological cancers at Hospital Universitario Ramón y Cajal in Madrid, Spain, and a clinical investigator for the breast cancer research program at Vall d’Hebron Institute of Oncology in Barcelona, Spain.

In reference to the Kaplan-Meier curves for PFS, Cortés said that there is a “clear and early separation of the curves starting at time of first scan after treatment and proceeding throughout.”

In a discussion of the abstract, Shanu Modi, MD, called attention to the early separation as well saying, “If the waterfall plot from DESTINY-Breast01 was dramatic, I think these PFS curves from DESTINY-Breast03 are startling as is the hazard ratio of 0.28 and the P value of 10-22.” Modi is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, New York.

The median overall survival (OS) was NE in both arms (HR, 0.56; 95% CI, 0.36-0.86; 

 .007172). The 12-month OS rates. were 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%-89.7%).

The OS data did not cross the prespecified boundary of 

 < .000265; however, Cortés noted that this is likely because of immature follow-up of the OS data. Investigators observed relatively few events in each arm at the time of analysis (33 and 53 with trastuzumab deruxtecan and T-DM1, respectively).

DESTINY-Breast03 randomized 524 patients with HER2-positive metastatic breast cancer, previously treated with trastuzumab and taxane, to receive either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or T-DM1 3.6 mg/kg every 3 weeks. Patients with clinically stable, treated brain metastases were eligible for enrollment.

The primary end point was PFS by blind independent central review. A key secondary end point was overall survival and other secondary end points included objective response rate (ORR) by BICR and investigator assessment, duration of response by BICR, PFS by investigator, and safety.

Stratification factors for the analysis included hormone receptor status, prior treatment with pertuzumab (Perjeta), and history of visceral disease. The median follow-up was 16.2 months for the trastuzumab deruxtecan group and 15.3 months for the T-DM1 group.

Baseline characteristics were well balance between the treatment arms: 50.2% vs 51% had a positive hormone receptor, 23.8% vs 19.8% had brain metastases, and 70.5% vs 70.3% had visceral disease, respectively. The median age was 54.3 years (range, 27.9-83.1) vs 54.2 years (range, 20.2-83), respectively.

Nearly half of the patients enrolled to the study had only 1 line of prior therapy in the metastatic setting (49.8% vs 46.8%, respectively). The percentage of patients who received 2 prior therapies was 21.5% in the trastuzumab deruxtecan arm vs 24.7% in the T-DM1 arm. Of note, both groups included a handful of patients who had received 5 or more prior lines of therapy (8.8% vs 6.8%, respectively).

In the trastuzumab deruxtecan arm 62.1% of patients had prior pertuzumab and 16.1% received another anti-HER2 tyrosine kinase inhibitor; these rates were 60.1% and 13.7%, respectively, in the T-DM1 arm.

The data cutoff for interim PFS analysis was May 21, 2021.

 Of note, on July 30, 2021, the independent drug monitoring committee recommended that investigators unblind the study.

“At the time of this analysis more than 50% of patients remain on trastuzumab deruxtecan [n = 132] compared with 18% of patients on T-DM1 [n = 47],” Cortés said.

In a PFS analysis by investigator assessment, the median PFS was 25.1 months (95% CI, 22.1-NE) in the trastuzumab deruxtecan arm vs 7.2 months (95% CI, 6.8-8.3) in the T-DM1 arm (HR, 0.26; 95% CI, 0.20-0.35; 

). The 12-month PFS rates were 76.3% (95% CI, 70.4%-81.2%) vs 34.9% (95% CI, 28.8%-41.2%), respectively.

“Improved efficacy with trastuzumab deruxtecan exists across all prespecified subgroups including hormone receptor status, prior pertuzumab treatment, the presence of visceral disease, number pr prior lines of therapy, and presence of absence of brain metastases,” Cortés said.

In the discussion, Modi called attention to the PFS data for patients with treated and stable brain metastases, the median PFS was nearly 3 times longer with trastuzumab deruxtecan (n = 62) compared with T-DM1 (n = 52). The median PFS was 15.0 months (95% CI, 12.6-22.2) vs 5.7 months (95% CI, 2.9-7.1) with T-DM1 (HR, 0.3796; 95% CI, 0.2267-0.6357). “This is a very clinically important difference to highlight between these 2 agents,” Modi said.

The ORR and best overall response data also favored trastuzumab deruxtecan. Specifically, the confirmed ORR in the trastuzumab deruxtecan arm was 79.7% (95% CI, 74.3%-84.4%) vs 34.2% (95% CI, 28.5%-40.3%) in the T-DM1 arm (

Of the responders in the trastuzumab deruxtecan arm 16.1% had a complete response (CR) and 63.6% had a partial response (PR). Among responders in the T-DM1 arm 8.7% had a CR and 25.5% had a PR. Stable disease was reported for 16.9% and 42.6% of patients, respectively. The disease control rate (CR plus PR plus stable disease) was 96.6% with trastuzumab deruxtecan vs 76.8% with T-DM1.

Modi noted that the ORR with trastuzumab deruxtecan was comparable to that seen with pertuzumab/trastuzumab/docetaxel (80.2%) in the first line in results from the phase 3 CLEOPATRA study (NCT00567190).

 “It’s exciting to see that 16% of patients on trastuzumab deruxtecan had a CR,” Modi said. “We recall in CLEOPATRA that number was 5.5%, so interesting to speculate if we will see a larger proportion of patients with long-term disease remission in the trastuzumab deruxtecan arm.”

In terms of safety, the incidence of grade 3/4 drug-related treatment-emergent adverse effects (TEAEs) was 45.5% with trastuzumab deruxtecan vs 39.8% with T-DM1. This difference extended to incidence of serious drug-related TEAEs (10.9% vs 6.1%, respectively), drug-related TEAEs associated with discontinuation (21.4% vs 12.6%), and drug-related TEAEs associated with dose reductions (21.4% vs 12.6%).

The median treatment duration was 14.3 months (range, 0.7-29.8) for patients who received trastuzumab deruxtecan vs 6.8 months (range, 0.7-25.1) for those who received T-DM1.

Interstitial lung disease (ILD)/pneumonitis was the most common TEAE associated with treatment discontinuation for trastuzumab deruxtecan (8.2%); thrombocytopenia was the most common TEAE that led to discontinuation of T-DM1 (2.7%).

TRAEs associated with dose reduction for trastuzumab deruxtecan were nausea (6.2%) and neutropenia (3.5%) and for T-DM1 were thrombocytopenia (4.2%), alanine aminotransferase (2.7%), and aspartate aminotransferase increase (2.7%).

No drug-related deaths occurred in either arm.

Most drug-related TEAEs were gastrointestinal or hematologic. The most common grade 3 or higher TRAEs with trastuzumab deruxtecan were neutropenia (19.1%), thrombocytopenia (7.0%), nausea (6.6%), leukopenia (6.6%), and anemia (5.8%). For T-DM1, the most common TEAEs grade 3 or higher were thrombocytopenia (24.9%), aspartate aminotransferase increase (5.0%), alanine aminotransferase increase (4.6%), and anemia (4.2%).

“If the efficacy was impressive, I would say the safety [data] from DESTINY-Breast 03 was reassuring,” Modi said, adding that “there were no bad surprises in this trial. T-DM1 certainly sets a high bar for antibody-drug conjugate safety, and I think that is one of its great strengths.”

Modi said that in terms of treatment discontinuation because of TEAEs, lung toxicity with trastuzumab deruxtecan was expected. “Lung toxicity was one of the highly anticipated outcomes from this trial and T-DM1 [had an approximate] 2% incidence of low-grade events,” Modi said. “In comparison trastuzumab deruxtecan had a risk of [10.5%], so 5-fold higher than T-DM1, but lower than that seen inn DESTINY-Breast01 [NCT03248492].”

Most importantly, Modi added, no grade 4 or 5 ILD/pneumonitis events were observed, “a major difference from DESTINY-Breast01 and a major relief.”

In terms of why less lung toxicity was observed in DESTINY-Breast03, it may be because the trial included a patient population that that was less heavily pretreated and therefore exposed to few lines of cancer therapy and stricter patient selection; however, Modi said that this rationale is only a hypothesis at this time.

“Of course, there was also greater awareness [concerning ILD],” Modi said. “There was a large education campaign around the lung toxicity of trastuzumab deruxtecan. If you look at the rates of ILD, the rates were consistent until 2019 when updated management guidelines were implemented and following this incidence rates started to come down.”

Specifically, Modi presented pooled data that demonstrated the incidence of any-grade ILD overtime was 24.3% (n = 18/74) in 2016; 19.6% (n = 33/168) in 2017; 15.3% (n = 87/569) in. 2018; 15.6% (n = 28/179); and 6.9% (n = 11/160) in 2020.

Based on what is known about trastuzumab deruxtecan, both Cortés and Modi stated that the unmatched efficacy and reduced risk of lung toxicity, support the use of trastuzumab deruxtecan in the second-line setting.

Trastuzumab deruxtecan is approved for patients with unresectable, metastatic HER2-positive breast cancer who have received 2 or more prior lines of anti–HER2-based regimens in the metastatic setting.

1. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Presented at: European Society for Medical Oncology Annual Congress 2021. September 16-21, 2021; virtual. Abstract LBA1.

2. Enhertu significantly improved progression-free survival in DESTINY-Breast03 head-to-head trial vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. News release. AstraZeneca and Daiichi Sankyo Company; August 9, 2021. Accessed September 18, 2021. bit.ly/3tRh5zG

3. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Investigators. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. 

. 2012;366(2):109-119. doi:10.1056/NEJMoa1113216

4. Powell CA, Modi S, Iwata H, et al. Analysis of study drug-related interstitial lung disease (ILD) inn patiennts (pts) with HER+ metastatic breast cancer (mBC) treated with trastuzumab deruxtecan (T-DXd). 

 2021;32(suppl 2):S61-S62. doi:10.1016/j.annonc.2021.03.106

5. Enhertu. Prescribing information. Daiichi Sankyo; 2021. Accessed September 18, 2021. bit.ly/3CtlWKm

Patients with previously treated HER2-positive metastatic breast cancer experienced a clinically meaningful and statistically significant improvement in progression-free survival with fam-trastuzumab deruxtecan-nxki vs standard of care trastuzumab emtansine in the DESTINY-Breast03 trial.

Trastuzumab Deruxtecan Shows Efficacy Over T-DM1 in HER2+ Breast Cancer

Roughly 50% of patients with clear cell renal cell carcinoma (RCC) responded to the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) in a Japanese study, and varied responses occurred in those with nonclear cell histology.

The data which were presented during the 2021 American Urological Association Annual Meeting signal a changing role for the timing of cytoreductive nephrectomy for patients with advanced RCC.

A total of 27 patients treated with the combination were included in the analysis; 19 patients had clear cell RCC and 8 patients had nonclear cell RCC. Among all patients 48.1% of patients had a partial response; the partial response rate was 52.6% for those with clear cell histology and 37.5% for those with nonclear cell histology. No patients had a complete response.

Further, 3 patients with clear cell RCC experienced tumor reduction of at least 50% or decreased to 4 cm in diameter or less had no viable tumor cells and their tumors did not have regrowth during the follow-up period.

“From [the results] of this study we propose the timing and indication of cytoreductive nephrectomy,” said Hiroshi Kikuchi, MD, PhD, a member of the Department of Renal and Genitourinary Surgery at the Hokkaido University Graduate School of Medicine in Sapporo, Japan in a poster presentation. “We could judge the primary tumor response at 4 months from the [initiation] of nivolumab plus ipilimumab treatment. If there is no response, consider [cytoreductive nephrectomy] before or after second-line treatment. However, if there is significant response, there is no need to rush to cytoreductive nephrectomy.”

Cytoreductive nephrectomy has been the standard-of-care for patients with advanced RCC. However, data from the CARMENA trial (NCT00930033) demonstrated that immediate cytoreductive nephrectomy should no longer be considered the standard in patients with intermediate- and poor-risk metastatic RCC when medical treatment is required.

Reassessment is needed, and it should rather be considered in a patient-tailored manner.

In the study, investigators evaluated if treatment with nivolumab plus ipilimumab contributed to changes in primary tumor sizes prior to cytoreductive nephrectomy in 51 patients with metastatic RCC or unresectable RCC. Significant response was defined as primary tumor reduction in size by 30% or more.

The median age in the subgroup was 66 years (range, 52-78). The median primary tumor size at baseline was 9.3 cm (range, 3.9-13.7).

At baseline, 13 patients (48.1%) were classified into the IMDC intermediate-risk group, and 14 patients (51.9%) were in the IMDC poor-risk group. Additionally, the median number of IMDC risk factors found in patients was 3 (range, 1-6). Of those patients with non-clear cell RCC, 2 presented with chromophobe RCC, 1 with mucinous tubular and spindle cell carcinoma, and 5 were unclassified.

The identified sites of metastases included: lung (70.4%), lymph nodes (70.4%), bone (25.9%), liver (25.9%), pancreas (18.5%), adrenal (14.8%), pleura/diaphragm (14.8%), brain (7.4%), muscle (7.4%), heart (3.7%), kidney (3.7%), and retroperitoneum (3.7%).

The median follow-up was 9.3 months (range, 0.8-25.3). Of the nonresponders 7 had stable disease and 7 had progressive disease; 5 of the patients with disease progression had nonclear cell RCC and all patients with stable disease had clear cell RCC.

Investigators reported a detailed analysis for 6 patients who underwent cytoreductive nephrectomy of the 10 responders.

Patients 1, 3, 4, and 5 had clear-cell RCC, and patients 2 and 6 had an unclassified disease type.

Patient 3 had a primary tumor size of 8.4 cm prior to receiving immune-checkpoint inhibitors (ICI). After 1 cycle of nivolumab plus ipilimumab and 13 cycles of single-agent nivolumab a –61.90% change in tumor size was recorded. Prior to surgical compete resection the tumor was 3.2 cm. Patient 4 received 4 cycles of the combination and 1 cycle of nivolumab for a tumor reduction of 6.0 cm to 3.1 cm (––48.33%).

Patient 5 had the greatest reduction in tumor size (–64.21%) and received 4 cycles of nivolumab plus ipilimumab and 4 cycles of nivolumab. The primary tumor size was reduced from 9.5 cm to 3.4 cm prior to surgical complete resection.

Patient 6 received 4 cycles of the combination therapy and 7 cycles of nivolumab for a tumor reduction of –43.01%; specifically, a reduction from 9.3 cm to 5.3 cm.

Patient 2 had the lowest reduction in primary tumor size. Specifically, after 2 cycles of nivolumab plus ipilimumab, a –35.62% reduction in tumor size was recorded with a decrease from 7.3 cm to 4.7 cm prior to cytoreductive nephrectomy.

Contrastingly, the 13.7 cm primary tumor of patient 1, who had clear-cell RCC, increased in size by 0.73% after 4 cycles of nivolumab plus ipilimumab and 1 cycle of nivolumab. The patient received axitinib (Inlyta) as a second-line treatment before cytoreductive nephrectomy, which was conducted 8.1 months after initial treatment. Patient 1 had an initial primary tumor size of 13.7 cm, which was recorded as 11.4 cm prior to surgery.

An analysis of the relationship between primary tumor reduction and patient backgrounds was also conducted and included inflammatory markers. Kikuchi said. “IMDC risk score [

= .6714] and [increased C-reactive protein] CRP scores [

= .8521] were not significantly different between responders and nonresponders.”

Additionally, a comparison evaluation showed that the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio tended to decrease in responders compared with nonresponders among the clear-cell RCC patient population 

 = .0691). The platelet-to-lymphocyte ratio significantly decreased in responders in this cohort (

 = .0391). According to Kikuchi, these inflammation markers may be predictive factors of treatment responses in primary tumors.

Although further studies are needed, the results suggest the importance of considering cytoreductive nephrectomy from radiological and pathological viewpoints, Kikuchi noted.

1. Kikuchi H, Osawa T, Matsumoto R, et al. Efficacy of nivolumab plus ipilimumab in primary tumor as first-line therapy in the patients with advanced renal cell carcinoma. 

2021;206(suppl 3):259. doi:10.1097/JU.0000000000001995.16

2. Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology guidelines for cytoreductive nephrectomy in patients with synchronous metastatic clear-cell renal cell carcinoma. 

 2018;74(suppl 6):805-809. doi:10.1016/jeuroro.2018.08.008

3. NCCN. Clinical Guidelines in Oncology. Kidney cancer, version 2.2022. Accessed September 10, 2021. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

4. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. 

. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675

Roughly 50% of patients with clear cell renal cell carcinoma responded to the combination of nivolumab plus ipilimumab in a Japanese study, and varied responses occurred in those with nonclear cell histology.

Efficacy of Nivolumab/Ipilimumab May Change Timing of Cytoreductive Nephrectomy in Advanced RCC

Real-world evidence (RWE) has shown robust adherence rates and prostate-specific antigen (PSA) response to apalutamide (Erleada) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to data presented during 2021 American Urological Association Annual Meeting.

The analysis included data for 193 patients from routine urologic practice; investigators stratified results by Black vs non-Black patients. PSA response was defined as a minimum of 50% decline from baseline PSA; adherence was assessed using the medication possession ratio, defined as the number of days of supply within the entire exposure to therapy.

PSA response in the first 6 months after initiating apalutamide was observed in 83.5%, 86.5%, and 84.1% of patients in the overall (n = 176), Black (n = 29), and non-Black cohorts (n = 126), respectively, who had both pre- and post-index PSA measurements. At the 12 months, PSA response was reported in 86%, 93.1%, and 85.9% of patients in the overall (n = 178), Black (n = 29), and non-Black cohorts (n = 128), respectively.

Adherences rates were 93.6%, 90.1%, and 94.5% for patients in the overall (n = 193), Black (n = 33), and non-Black cohorts (n = 138), respectively.

“Apalutamide, a next-generation androgen receptor inhibitor, in conjunction with androgen deprivation therapy was approved by the [FDA] for [patients with] nmCRPC based on the results of randomized SPARTAN clinical study [NCT01946204],” said Benjamin H. Lowentritt, MD, FACS, director of Minimally Invasive Surgery and Robotics, and director of the Prostate Cancer Care Program at Chesapeake Urology in Towson, Maryland. “However, the effectiveness [of the agent] in real-world practice needs further evaluation.”

In the SPARTAN study, patients treated with apalutamide (n = 806) had a median metastasis-free survival of 40.5 months vs 16.2 months for those who received placebo (n = 401; HR, 0.28; 95% CI, 0.23-0.35; 

< .001), meeting the primary end point of the study and leading the FDA approval.

 PSA response was an exploratory end point of the study.

Investigators reported that 89.7% of patients treated with apalutamide had a PSA response.

“Our real-world study showed that PSA response to apalutamide and continuous androgen deprivation therapy was robust and consistent with that in the SPARTAN study,” Lowentritt said.

To conduct the analysis, investigators used electronic medical records collected as part of routine clinical care from 95 US-based urology practices with dispensaries. PSA response and treatment patterns were evaluated from the index date—the first apalutamide dispensation among patients with non-metastatic CRPC—to the end of data availability (October 4, 2019), switch to another first- or second-generation antiandrogen, or death.

Baseline characteristics were evaluated in 12 months preceding the index date.

In this retrospective longitudinal cohort design, 193 patients with non-metastatic CRPC were treated with apalutamide; 33 (17%) were Black, 138 (72%) were non-Black, and 22 (11%) had an unknown racial background. Among the 3 cohorts, most patients (76%) were aged 71 to 90 years.

Evaluated patients had 2 apalutamide prescription fills and 12 months of prior prostate cancer management at baseline.

The mean baseline PSA levels for the overall (n = 190), Black (n = 33), and non-Black groups (n = 135) were 7 ng/mL, 10.5 nh/mL, and 5.6 ng/mL, respectively. PSA doubling times were reported for 90 (46.6%), 16 (48.5%), and 70 patients (50.7%), respectively, and the mean doubling times were 10.8, 10.2, and 10.1 months. The mean baseline testosterone for the overall (n = 146), Black (n = 22), and non-Black patient cohorts (n = 105) was 16.3 ng/dL, 15.1 ng/dL, and 17.3 ng/dL, respectively.

An additional efficacy end point was persistence rate, assessed as the proportion of patients who did not have a specific gap in treatment within a fixed period following the index date. At 6 months, 79.7%, 81.5%, and 80.6% of patients in the overall (n = 153), Black (n = 27), and non-Black cohorts (n = 108), respectively, did not have a gap in treatment over 45 days. Similarly, an over 90-day gap in treatment was not observed in 88.9%, 92.6%, and 87% of patients in the overall, Black, and non-Black groups, respectively.

A numerically higher proportion of Black patients were persistent at 12 months; specifically, 62.7%, 78.9%, and 58.6% of patients did not have an over 45-day gap in treatment in the overall (n = 102), Black (n = 19), and non-Black groups (n = 70), respectively. Correspondingly, an over 90-day gap in treatment was not observed in 69.6%, 78.9%, and 65.7% of patients in the overall, Black, and non-Black groups, respectively.

Lowentritt noted that although Black patients have higher incidence of prostate cancer, they comprised only 6% of the SPARTAN trial population.

“[This study provided] important information on real-word PSA responses in Black men, a population that is typically not well represented,” he concluded.

1. Lowentritt B, Brown G, Kernen K, et al. Real-world effectiveness and treatment adherence of apalutamide in non-metastatic castration-resistance prostate cancer patients. 

. 2021;206(suppl 1):e58. doi:10.1097/JU.0000000000001969.08

2. Smith MR, Saad F, Chowdhury F, et al; Spartan Investigators. 

. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

Real-world evidence shows robust adherence rates and prostate-specific antigen response to apalutamide in patients with nonmetastatic castration-resistant prostate cancer.