Hayley Virgil

Results from the DUNE trial (GETNE 1601; NCT03095274) of durvalumab (Imfinzi) added to tremelimumab in patients with advanced neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origins showed limited activity, according to a presentation held during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.

The addition of durvalumab (Imfinzi) to tremelimumab showed modest activity in patients with advanced neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origins, according to results from the DUNE trial (GETNE 1601; NCT03095274) presented during the 2020 ESMO Virtual Congress.1

The multicohort study included patients whose disease stemmed from typical/atypical lung carcinoid (cohort 1), grade 1/2 gastrointestinal (cohort 2), grade 1/2 pancreatic (cohort 3), and grade 3 gastroenteropancreatic origins (cohort 4).

Results showed that at a median follow-up of 10.8 months, the clinical benefit rate (CBR), defined as complete response (CR) plus partial response (PR) and stable disease (SD), was determined to be 7.4% in cohort 1 (n = 27), 32.3% in cohort 2 (n = 31), and 25.0% in cohort 3 (n = 32). Moreover, the 9-month overall survival (OS) in cohort 4, which was one of the primary end points of the trial, was 36.1% (n = 33; 95% CI, 22.9-57) with the combination.

“The CBR at 9 months was not met at the prespecified 50% [threshold for futility],” Jaume Capdevila, MD, PhD an oncologist within the GI and Endocrine Tumor Unit with Vall d'Hebron University Hospital and the Developmental Therapeutics Unit with Vall d'Hebron Institute of Oncology, said in a presentation during the 

. However, he added, “Cohort 4 really met the prespecified threshold for OS of 9 months, [with] 36% of patients being alive at 9 months.”

The rationale to utilize immune checkpoint blockade in neuroendocrine neoplasms (NENs) has been limited, as these neoplasms typically have low tumor mutational burden, PD-L1 expression, and lymphocyte infiltration. To date, PD-1 inhibitors such as pembrolizumab (Keytruda) and spartalizumab have demonstrated a limited overall response rate (ORR) of less than 5%, although they have yielded more intriguing data in thoracic well-differentiated NETs, noted Capdevila. For example, spartalizumab has been shown to result in an ORR of 20% in this patient population.2,3 Recently, the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy), showed encouraging activity in this patient population.4

“In trying to revert this intrinsic resistance in this tumor [type], the combination of anti–PD-L1 and anti–CTLA-4 may play a role in [treating] these patients,” Capdevila explained. “It’s important to know that, recently, nivolumab and ipilimumab reported some promising activity in high grade NENs with an ORR of 44%. However, no response was shown in low or intermediate grade–disease.

To participate in the DUNE trial, patients needed to have advanced NENs of gastroenteropancreatic or lung origin following progression on standard therapies. Patients in cohort 1 had received previous treatment with somatostatin analogues and/or targeted therapies or chemotherapy; cohort 2 received prior somatostatin analogues and targeted therapies such as everolimus (Afinitor) or radionucleotides; cohort 3 received previous chemotherapy, somatostatin analogues, and targeted therapies (2-4 systemic treatment lines); and cohort 4 had received first-line treatment with platinum-based chemotherapy.

Participants received 4 cycles of durvalumab at 1500 mg in combination with 75 mg of tremelimumab followed by an additional 9 cycles of durvalumab monotherapy, given at a dose of 1500 mg.

“After 1 year of therapy, for patients who achieved SD, PR, or CR, treatment was stopped and follow-up was started,” Capdevila noted. “In the case of disease progression during this follow-up period, patients were allowed to start the same treatment.”

Primary efficacy end points of the trial included CBR for cohorts 1-3 per RECIST v1.1 criteria and the 9-month OS rate in cohort 4. Key secondary end points of the trial included safety, PFS, OS, ORR, duration of response (DOR), and biomarker analyses.

“With a unilateral alpha level of 5% and 80% power, we expected to increase the CBR from 30% to 50% in cohorts 1, 2, and 3,” explained Capdevila said. “For that, we decided to estimate 28 patients per cohort. In cohort 4, we estimated to increase the OS rate of 9 months from 13% to 23%. For that reason, we estimated to include 30 patients in this cohort.”

The median ages of patients on the trial were 61 (n =27; 100%), 62 (n = 31; 100%), 66 (n = 32; 100%), and 55 (n = 33; 100%) in cohorts 1-4, respectively. The majority of patients were male in most cohorts (cohort 1, 66.7%; cohort 2, 58.1%; cohort 4, 66.7%), with the exception of cohort 3, which included more female patients (56.3%).

Additional results from the trial showed that in terms of best change from baseline in target lesions per cohort, cohorts 1 and 2 had an ORR of 0%. Cohorts 3 and 4 achieved higher ORRs of 6.9% and 7.2%, respectively, with 1 CR in cohort 4.

When it came to treatment response according to PD-L1 expression, cohort 1 experienced an ORR of 7.4% per irRECIST criteria. In those with PD-L1 positivity, the ORR was 16.6%; in those without PD-L1 expression the ORR was 0%. In cohort 2, the ORR was 0% in those with or without PD-L1 expression. In cohort 3, the ORR was 6.3%; those with PD-L1 positivity experienced an ORR of 25%. In cohort 4, the ORR was 9.1% with an ORR of 0% in those with PD-L1 positivity and 7.7% in those who were negative for PD-L1.

“As a general message, the number of patients with PD-L1–positive tumors was very low. In cohort 1, only 6 patients with PD-L1–positive tumors were included; there were only 4 patients in cohort 3 with pancreatic origins. These number should be taken with caution,” Capdevila emphasized. “Even with that, we can see a trend toward a better ORR in most patients with PD-L1–positive tumors, mainly in [cohort 1].”

Investigators additionally examined progression-free survival (PFS) in each cohort and found a median PFS of 5.3 months in cohort 1 (95% CI, 4.52-6.06), 8 months in cohort 2 (95% CI, 4.92-11.15), 8.1 months in cohort 3 (95% CI, 3.80-12.46), and 2.5 in cohort 4 (95% CI, 2.15-2.75).

The most commonly reported adverse effects (AEs) for patients who were treated with durvalumab plus tremelimumab included fatigue (all grades, 43.1%; n = 53), diarrhea (31.7%; n = 39), pruritus (23.6%; n = 29), nausea (13.8%; n = 17), skin and subcutaneous tissue disorders (8.9%; n = 11), and hypothyroidism (9.8%; n = 12). The only grade 4 (0.8%; n = 1) and grade 5 (0.8%; n = 1) toxicities reported were diarrhea.

Although objective responses were infrequent using both RECIST v1.1 criteria and irRECIST criteria, durvalumab plus tremelimumab met the predefined threshold of 9-month OS and should be further explored in this patient population, noted Capdevila.

“No new safety concerns were observed in this population of advanced NENs,” Capdevila concluded. “As a final thought, the CBR based on prior studies may not reflect the clinical behavior of this advanced, heavily pretreated population.”

1. Capdevila J, Teulé A, López C, et al. "A multi-cohort phase II study of durvalumab plus tremelimumab for the treatment of patients (pts) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic or lung origin: The DUNE trial (GETNE 1601). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020. Virtual. Accessed September 20, 2020. Abstract 1157O.

2. Strosberg J, Mizuno N, Doi Toshihiko, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 Study. 

. 2020;26(9):2124-2130. doi:10.1158/1078-0432.CCR-19-3014

3. Yao JC, Strosberg J, Fazio N, et al. Activity & safety of spartalizumab (PDR001) in patients (pts) with advanced neuroendocrine tumors (NET) of pancreatic (Pan), gastrointestinal (GI), or thoracic (T) origin, & gastroenteropancreatic neuroendocrine carcinoma (GEP NEC) who have progressed on prior treatment (Tx). 

. 2018;29(supp 8):viii467-viii478. doi:10.1093/annonc/mdy293

4. Patel SP, Othus M, Chae YK, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors. 

. 2020;26(10):2290-2296. doi:10.1158/1078-0432.CCR-19-3356

Articles

Results from the DUNE trial of durvalumab added to tremelimumab in patients with advanced neuroendocrine tumors of gastroenteropancreatic and lung origins showed limited activity, according to a presentation held during the 2020 European Society of Medical Oncology Virtual Congress.

Limited Activity Shown With Durvalumab/Tremelimumab in Advanced NETs Subtypes

In the phase 3 ATTRACTION-4 study, nivolumab (Opdivo) added to chemotherapy led to a statistically significant improvement in progression-free survival (PFS) and induced higher overall response rates in patients with previously untreated advanced or recurrent gastric and gastroesophageal junction cancer (GEJ), according to results presented during the 2020 ESMO Virtual Congress.

“The prespecified objective of the phase 3 part of the ATTRACTION-4 study was achieved, showing good, clinically meaningful efficacy,” said Narikazu Boku, MD, PhD, deputy director of the National Cancer Center Hospital in Tokyo, Japan. “Nivolumab plus chemotherapy demonstrated a manageable safety profile, [as well].”

Results from the interim analysis presented during 

revealed that patients who were given nivolumab plus chemotherapy (n = 362) experienced a median PFS of 10.45 months (95% CI, 8.44-14.75) versus 8.34 months (95% CI, 6.97-9.40) in those who were given chemotherapy plus a placebo (n = 362; HR, 0.68; 98.51% CI, 0.51-0.90; 

 = .0007). The 1-year PFS rate was determined to be 45.4% in the nivolumab/chemotherapy arm versus 30.6% in the chemotherapy-alone arm.

However, no statistically significant improvement in overall survival (OS) was observed with nivolumab plus chemotherapy. Specifically, the median OS was 17.45 months (95% CI, 15.67-20.83) in the investigational arm versus 17.15 months (95% CI, 15.18-19.65) in the control arm (HR, 0.90; 95% CI, 0.75-1.08; 

“Although the OS was slightly higher in the nivolumab arm than the placebo arm,” Boku explained. “However, the [investigational] arm did not [experience a] significant survival benefit.”

Previously, nivolumab demonstrated a notable survival benefit in this heavily pretreated patient population; that activity supported the rationale to launch the randomized, multicenter, phase 2/3 ATTRACTION-4 study, according to Boku.

 Results from the phase 2 portion of the trial also showed encouraging activity with the combination.

To be eligible for enrollment on the double-blind, controlled study, which was conducted in 130 centers across Japan, Taiwan, and Korea, patients needed to have been diagnosed with unresectable, advanced or recurrent HER2-negative gastric or GEJ cancer. Patients also needed to be chemotherapy naïve with an ECOG performance status of 0 or 1. However, neoadjuvant or adjuvant chemotherapy was permitted if it was completed within 180 days prior to disease recurrence.

For the trial, patients were randomized 1:1 to receive either 360 mg of intravenous nivolumab and S-1 plus oxaliplatin (SOX) or capecitabine and oxaliplatin therapy or placebo plus SOX or CapeOX therapy. Stratification factors included country, performance status, PD-L1 expression, and disease status.

Treatment continued until disease progression, intolerable toxicity, or consent was withdrawn. The co-primary end points of the trial were PFS per central assessment by IRRC and OS. Key secondary end points included investigator-assessed PFS, ORR, duration of response (DOR), time to response (TTR), best overall response, and safety.

At the data cutoff for the interim PFS analysis, which was October 31, 2018, the median follow-up period was 11.6 months. The median follow-up at the January 31, 2020 data cutoff for the final analysis of OS was 26.6 months. A total of 724 patients underwent randomization from March 2017 to May 2018.

Notably, the primary objective could only be achieved if at least 1 of the null hypotheses of the primary end points is rejected. Additionally, the level of significance, which was 2-sided, was set at 4% and 1% for PFS and OS, respectively, for the final analysis. Should the PFS null hypothesis be rejected, the OS analysis would be performed at a reallocated level of significance, explained Boku. The interim PFS analysis was planned at approximately 323 events, while the final OS analysis was planned at approximately 464 events.

The median age of participants in the nivolumab/chemotherapy arm was 63.5 years versus 65.0 years in the placebo/chemotherapy arm. The majority of patients enrolled on the study were male (69.9% and 74.6%, respectively) with a female minority (30.1% and 25.4%, respectively). Between the 2 arms, 54.7% of those on the nivolumab arm and 54.4% of those in the placebo arm were from Japan, 40.9% and 39.5%, respectively, were from Korea, and 4.4% and 6.1%, respectively, were from Taiwan.

The median duration of treatment in patients who received nivolumab plus SOX (n = 229) was 6.3 months (95% CI, 0-32) and 5.2 months in those who were given nivolumab plus CapeOX (n = 130; 95% CI, 0-33). The median duration of treatment was 5 months (95% CI, 0-31) in the placebo plus SOX arm (n = 230) and 5.7 months (95% CI, 0-33) in the placebo plus CapeOX arm (n = 128). Moreover, 89.7% (n = 322) of patients in the experimental arm discontinued treatment with nivolumab or placebo, while 94.7% (n = 339) of patients in the control arm discontinued treatment.

In the nivolumab cohort, 59.1% of patients discontinued treatment due to disease progression (n = 212), 5.3% due to worsening of clinical symptoms associated with disease progression (n = 19), 6.1% because of unacceptable toxicities (n = 22), 8.6% because of investigator decision (n = 31), and 11.4% due to other reasons (n = 41). Discontinuation in the placebo cohort was due to progressive disease (70.4%; n = 252), worsening of clinical symptoms due to disease progression (6.1%; n = 22), unacceptable toxicities (2.5%; n = 17), investigator decision (4.7%; n = 15), or other reasons (12.3%; n = 44).

“The nivolumab arm showed a greater PFS all [patient subsets],” Boku noted.

The ORR was 57.5% (n = 208) in the nivolumab arm (95% CI, 52.2-62.6) versus 47.8% (n = 173) in the placebo arm (95% CI, 42.5-53.1; 

 = .0088). Of the patients who received nivolumab plus chemotherapy, 19.3% achieved complete responses (CRs; n = 70), 38.1% had partial responses (PRs; n = 138), 14.4% experienced stable disease (SD; n = 52), and 6.9% had progressive disease (n = 25). Among those who were given placebo plus chemotherapy, 13.3% had CRs (n = 48), 34.5% experienced PRs (n = 125), 20.7% achieved SD (n = 75), and 12.7% had disease progression (n = 46).

Additionally, the disease control rate (DCR) was 71.8% in the nivolumab arm (n = 260; 95% CI, 66.9-76.4) versus 68.5% (n = 248; 95% CI, 63.4-73.3) in the placebo arm. The median TTR was 1.4 months in both arms (nivolumab, 95% CI, 1.0-8.3; placebo, 95% CI, 1.0-15.3). Additionally, the median DOR was 12.91 months (95% CI, 9.89-16.56) in the nivolumab/chemotherapy cohort versus 8.67 months (95% CI, 7.2-11.37) in the placebo/chemotherapy cohort.

Any grade of any adverse effect (AE) was reported in 99.7% (n = 358) of patients who received nivolumab with chemotherapy. Among this cohort, 37.6% (n = 135) experienced any grade of any serious AEs, while 69.4% (n = 249) had grade 3 and 4 of any AE and 2.2% (n = 8) had grade 5 of any AE. In the placebo cohort, 99.7% (n = 357) experienced any grade of any AE, 33.5% (n = 120) experienced any grade of any serious AEs, 63.1% (n = 226) had grade 3-4 of any AE, and 1.7% (n = 6) had grade 5 of any AE.

Patients who received nivolumab plus chemotherapy most frequently experienced any grade of skin (37.3%) and gastrointestinal (35.9%) AEs. Gastrointestinal (5.8%), hepatic (3.9%), and skin (3.9%) were the most commonly reported grade 3 or 4 AEs, with only 1 case of a grade 5 hepatic AE reported with this regimen. The most common any-grade AEs reported in the placebo arm were gastrointestinal (31.6%) and skin (24%). This regimen also led to grade 3 or 4 gastrointestinal (5.3%) and hepatic (3.4%) AEs in patients who received it. No grade 5 AEs were reported in this cohort.

“Nivolumab plus chemotherapy could be considered a new first-line treatment option for patients with unresectable, advanced or recurrent gastrointestinal GEJ cancer,” concluded Boku.

1. Boku N, Ryu MH, Oh DY, et al. Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; virtual. Accessed September 21, 2020. Abstract LBA7_PR.

2. Kang YKm Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2017; 390(10111):2461-2471. doi:10.1016/S0140-6736(17)31827-5.

3. Boku N, Ryu MH, Chung HC, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). 

. 2019;30(2):250-258. doi: 10.1093/annonc/mdy540.

In the phase 3 ATTRACTION-4 study, nivolumab added to chemotherapy led to a statistically significant improvement in progression-free survival and induced higher overall response rates in patients with previously untreated advanced or recurrent gastric and gastroesophageal junction cancer, according to results presented during the 2020 ESMO Virtual Congress.

Nivolumab Plus Chemotherapy Extends PFS With Durable Responses in Gastric/GEJ Cancers

Patients with completely resected stage IIIAN2 non–small cell lung cancer (NSCLC) should not be recommended for post-operative radiotherapy (PORT), according to results from the phase 3 LungART trial (NCT00410683) that were presented during the ESMO Virtual Congress 2020, due to nonstatistically significant increase in disease-free survival (DFS) versus those treated in the control group.

Results showed that the median DFS in the control arm where patients did not receive PORT was 22.8 months (95% CI, 17-37) versus 30.5 months (95% CI, 24-49) in those who received PORT (HR, 0.85; 95% CI, 0.67-1.07; 

 = .016). The 3-year DFS rates were estimated to be 43.8% (95% CI, 37-51) in the control arm versus 47.1% in the PORT arm (95% CI, 40-54).

A total of 152 DFS events occurred in the control arm, while 144 events were reported in the PORT arm. Mediastinal relapse occurred in 46.1% of patients in the control cohort (n = 70) versus 25.0% of patients in the PORT cohort (n = 36). Additionally, 17.8% of those in the control arm had brain metastases (n = 27), and 46.7% had other metastases (n = 71). In the PORT cohort 23.6% of patients (n = 34) had brain metastases and 49.3% experienced other metastases (n = 71).

Overall survival (OS) rates at 3 years were 68.5% (95% CI, 61-75) in the control arm and 66.5% (95% CI, 59-73) in the PORT arm. Death was reported in 5.3% of patients in the control arm (n = 8) compared with 14.6% of those in the PORT arm (n = 21).

“The differences in [3-year DFS] were not statistically significant,” lead author of the study Cecile Le Péchoux, MD, of the Institut de Cancérologie Gustave Roussy, said during the press conference. She also added, “Regarding the OS curve, there is really no difference between the [arms], but these are very good results in terms of outcome, since these patients are at high risk. More than two-thirds of these patients are living at 3 years; this is also due to the modalities of treatment on relapse that have come out over the past few years.”

The trial enrolled 500 patients with completely resected NSCLC with N2 histology and cytologically-proven nodal involvement. Patients were randomized 1:1 to either the control arm or the PORT arm, where they received 54 gy/5 for 5 weeks. Patients were stratified based on the administration of chemotherapy histology, extent of mediastinal lymph node involvement, and the use of pre-treatment PET scans. The primary end point of the trial was DFS, and key secondary end points included OS, patterns of relapse, local failure, second cancers, and treatment-related toxicity.

Three months after undergoing randomization, 15.0% of patients in the control arm (n = 37) and 23.7% of patients in the PORT arm (n = 57) experienced at least 1 grade 3 or 4 toxicity. At least 1 early grade 3 or 4 toxicity occurred in 7.7% of those in the control group (n = 19) and 8.9% experienced at least 1 late grade 3 or 4 toxicity (n = 22). In the PORT cohort, 11.6% (n = 28) experienced at least 1 early grade 3 or 4 toxicity and 14.6% (n = 36) had at least 1 late grade 3 or 4 toxicity.

While no patients in the control group experienced early grade 5 toxicities, 1.2% (n = 3) of those in the PORT cohort did. These toxicities included cardiopulmonary arrest, pneumonitis, and infectious pneumonitis. Late grade 5 toxicities additionally occurred in 0.8% (n = 2) of those in the control arm, and included depression and respiratory failure. Late grade 5 toxicity was reported in 1.2% (n = 3) of those in the PORT arm and included acute pulmonary edema, respiratory failure. Once unspecified death was reported in the investigational arm.

“The use of PORT was associated with a 15% increase in DFS that was determined to be nonstatistically significant, with no difference in 3-year overall survival; it was also associated with more toxicities that need to be explored further, especially cardiopulmonary events,” Le Péchoux concluded. “At the moment, conform PORT cannot be recommended as a standard of care in all patients who have been completely resected and were stage III and II.

Investigators plan to further analyze patterns of failure, predictive factors of efficacy and toxicity, radiotherapy quality, and surgery quality.

Rafal Dziadziuszko, MD, PhD, of Medical University of Gdansk, commented on the LungART trial during the press conference.

“It has been over 20 years that [thoracic oncologists] have been debating on the issue as to whether or not [radiation should be used on] patients with mediastinal lymph node involvement after surgery.” Dziadziuszko said. He went on to say, “Physicians around the world hesitated whether to provide this service for patients or not. The arguments in favor were that you can increase local control…. The arguments against were that we did not have significant evidence that this treatment prolonged survival. There is also an argument of potential harm.”

Le Péchoux C, Pourel N, Barlesi F, et al. An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement. Primary end-point analysis of Lung ART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Presented at: 2020 ESMO Virtual Meeting; September 19-21, 2020; Virtual. Abstract: LBA3_PR

Patients with completely resected stage IIIAN2 non–small cell lung cancer should not be recommended for post-operative radiotherapy, according to results from the phase 3 LungART trial that were presented during the ESMO Virtual Congress 2020, due to nonstatistically significant increase in disease-free survival versus those treated in the control group.

Phase 3 Trial Results Do Not Support PORT in Resected Stage IIIAN2 NSCLC

Abemaciclib (Verzenio) in combination with tamoxifen led to an improvement in overall survival (OS) compared with abemaciclib alone in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer. Notably, the benefit of the combination was observed across all subgroups in the study, according to findings from the final OS analysis of the nextMONARCH trial presented during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.

The OS analysis was performed 24-months after the last patient entered treatment, with a median follow-up time of 27.2 months. Despite not being powered for testing OS superiority with strong Type 1 error control, results showed a median OS of 24.2 months with the combination versus 17.0 months with 200 mg of abemaciclib (HR, 0.62; 95% CI, 0.40-0.97; 

 = .0341). The 150-mg dose of abemaciclib showed a longer median OS than the 200-mg dose of the agent, at 20.8 months versus 17.0 months, respectively (HR, 0.96; 95% CI, 0.64-1.44; 

“The final OS analysis showed a 7.2-month improvement in OS with the addition of tamoxifen to abemaciclib—24.2 months compared to 17.0 months—when compared to 200 mg of abemaciclib monotherapy,” Erika Hamilton, MD, principal investigator and director of Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute said in a presentation during the congress.

The updated median progression-free survival (PFS) was determined to be 9.07 months in the combination therapy arm compared with 7.43 months with the 200-mg dose of abemaciclib (HR, 0.81; 95% CI, 0.56-1.16; 

 = .2493). The median PFS was 7.2 months with the 150-mg dose versus 7.43 months with the 150-mg dose (HR, 1.06; 95% CI, 0.74, 1.53; 

 = .7400). The median PFS, although longer in the combination arm, was not determined to be statistically significant.

The addition of CDK4/6 inhibitors to endocrine therapy has emerged as the current standard of care for patients with HR-positive, HER2-negative advanced/metastatic breast cancer, said Hamilton. Currently, abemaciclib is the only continuously-dosed CDK4/6 inhibitor monotherapy drug in its class to be 

 for patients who have progressed after endocrine therapy or chemotherapy in the metastatic setting.

In the randomized, open-label phase 2 trial, investigators set out to evaluate abemaciclib, either as a monotherapy or in combination with tamoxifen in heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer. Additionally, they wanted to examine how effective the combination would be in overcoming endocrine resistance. In a randomized setting, investigators assessed 2 monotherapy doses as well as the use of prophylactic loperamide to reduce the incidence and severity of diarrhea and dose adjustments.

The study population was the same as that of the 

,3 but without prior taxane mandation. To be eligible for participation, patients needed to have previously received 2 or more chemotherapy regimens and 1 or 2 of these therapies must have been received in the metastatic setting. Patients also needed to have measurable disease and an ECOG performance status of 0 or 1. Patients were stratified based on the presence of liver metastases or previous treatment with tamoxifen in the advanced or metastatic setting.

A total of 234 patients were enrolled on the study and they were randomized 1:1:1 to receive either abemaciclib at 150 mg every 12 hours plus tamoxifen at 20 mg once daily (arm A; n = 78), 150 mg of abemaciclib every 12 hours (arm B; n = 79), or 200 mg of abemaciclib every 12 hours plus prophylactic loperamide (arm C; n = 77).

The primary end point of the study was investigator-assessed PFS, and key secondary end points included response rates, OS, and safety. Additional exploratory end points of the trial included understanding the association between biomarkers and clinical outcomes, as well as the relationship between tamoxifen and abemaciclib exposure and response. The time of the data cutoff was June 28, 2019.

Additional results showed that the overall response rate (ORR) was consistent with what had been observed in the primary PFS analysis of the trial. In arm A, the confirmed ORR was 34.6% and the clinical benefit rate was 61.5%. In arm B, these rates were 24.1% and 49.4%, respectively; in arm C, they were 33.8% and 51.9%, respectively.

OS by prespecified subgroup analyses showed a clear trend favoring the combination arm, according to Hamilton. Two arms, however, weren’t shown to favor either regimen or were roughly equal; these included those without liver metastases and those who had less organs involved at baseline.

“I also want to call out that prior tamoxifen in advanced breast cancer, whether that was present or absent, seemed to favor the combination of tamoxifen with abemaciclib,” Hamilton added.

Of the patients who received the combination therapy, 93.6% (n = 73) experienced any grade of treatment-related adverse effects (TRAE), with 43.6% (n = 34) experiencing grade 3 toxicities and 9% (n = 7) experiencing grade 4. Slightly fewer TRAEs were observed in those who received the combination arm compared with those who were given the 150-mg dose of abemaciclib (any grade, 97.5%; grade 3, 45.6%; grade 4, 5.1%) and those given the 200-mg dose plus prophylactic loperamide (any grade, 98.7%; grade 3, 61.0%; grade 4, 10.4%).

The most common any-grade TRAE reported in the combination arm was diarrhea (53.8%; n = 42), although no grade 4 diarrhea was reported across the arms. Additionally, neutropenia was commonly reported in the combination arm (any grade, 42.3%; n = 33), with 20.5% (n = 16) of patients experiencing grade 3 toxicity and 2.6% (n = 2) experiencing grade 4. Patients also experienced anemia on the combination regimen (any grade, 43.6%; grade 3, 12.8%; grade 4, 1.3%).

TRAEs of special interest included venous thromboembolism, a known AE of tamoxifen; this toxicity was experienced at any grade in 10.3% (n = 3) and at grade 3/4 5.1% (n = 4) in the combination arm. These rates were 5.1% and 2.5%, respectively, in the 150-mg abemaciclib arm, as well as 3.9% and 2.6%, respectively, in the 200-mg abemaciclib arm.

Pneumonitis, which has been widely recognized as a risk associated with CDK4/6 inhibitors, was another TRAE of special interest. While no patients in the combination arm experienced this AE, incidences of any grade (1.3% and 1.3%) and grade 3/4 (0% and 1.3%) were reported in the 150 mg cohort and 200 mg cohorts, respectively.

“AEs were consistent with those observed in the primary analysis of the trial and the known safety profile of abemaciclib in practice,” concluded Hamilton. “Incidence and severity of treatment-emergent diarrhea was improved in nextMONARCH, with 9% grade 3 toxicities reported compared with 20% grade 3 toxicity previously reported in MONARCH-1.”

1. Hamilton E. nextMONARCH : Final overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with HR+, HER2-metastatic breast cancer. Virtual 2020 ESMO Congress; September 19-21, 2020; virtual. Accessed September 19, 2020. Abstract 273O.

2. Rugo, HS. Achieving improved survival outcomes in advanced breast cancer. 

 2019;381(4):371-372. doi:10.1056/NEJMe1906236

3. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. 

. 2017;23(17):5218-5224. Doi: 10.1158/1078-0432.CCR-17-0754

Abemaciclib in combination with tamoxifen led to an improvement in overall survival compared with abemaciclib alone in patients with hormone receptor–positive, HER2-negative metastatic breast cancer. Notably, the benefit of the combination was observed across all subgroups in the study, according to findings from the final OS analysis of the nextMONARCH trial presented during the 2020 European Society of Medical Oncology Virtual Congress.

Author | Hayley Virgil

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