Ryan McDonald

The addition of pembrolizumab (Keytruda) and trastuzumab (Herceptin) to the combination cisplatin plus capecitabine was able to effectively treat HER2-positive advanced gastric and gastroesophageal junction (GEJ) cancer, regardless of PD-L1 expression in the phase 1b/2 PANTHERA trial (NCT02901301), according to updated clinical and molecular findings presented during the 2021 ASCO Gastrointestinal Cancers Symposium.

The study results also showed that alterations to the 

 pathway in patients with HER2 amplifications were associated with a statistically significant improved duration of survival in patients.

At a median follow-up of 18.2 months, patients who were administered the triplet therapy regimen (n = 43; median age, 63 years; 76.6% male) achieved a median overall survival (OS) of 19.3% (95% CI, 16.5-NR) and a median progression-free survival (PFS) of 8.6 months (95% CI, 7.2-16.4). The regimen also conferred an overall response rate (ORR) of 76.7% (95% CI, 61.4-88.2) and disease control rate (DCR) of 97.7% (95% CI, 87.7-99.9).

“Clinical parameters including PD-L1 expression were not related to survival,” Sun Young Rha, MD, PhD, a medical oncologist in the Division of Medical Oncology at Yonsei Cancer Center in Seoul, South Korea, said in a recording of the presentation.

As a result, Rha said the researchers decided to evaluate the genomic profiling of patients using targeted next-generation sequencing (NGS).

The phase 1 portion of the trial indicated that the recommended dosing schedule for the phase 2 portion of the trial should be delivered to the patient every 3 weeks with 200 mg of pembrolizumab via IV on day 1, 6 mg/kg of trastuzumab on day 1, 1000 mg/m2 of capecitabine twice a day (BID) on days 1 through 14, and 80 mg/m2 of cisplatin on day 1.

The primary end point of the phase 2 portion of the trial, per RECIST v1.1, was ORR. Additional secondary end points were PFS, OS, duration of response, safety, and predictive biomarker analysis by targeted NGS. At the time of data cutoff (Aug. 31, 2020), 6 patients had completed 2 years of treatment without any disease progression and 3 remained on treatment.

At baseline, more than half of the patients (72.1%) had not received a gastrectomy. Of the organs where the disease progressed to, the most frequent included the lymph nodes (83.7%), liver (48.8%) and peritoneum (25.6%). Using Combined Positive Score (CPS) at baseline to identify PD-L1 protein expression, 39.5% of patients had a CPS of < 1%, 48.8% had a CPS of ≥ 1%, 11.6% had a CPS of ≥ 10% and 11.6% of patients did not undergo a primary tumor PD-L1 status at diagnosis. Using an ImmunoHistoChemistry test, 69.8% of patients had a score of 3+ (indicating a presence of HER2) at baseline and the remaining patients had a score of 2+ (indicating borderline presence of HER2).

More than half of the patients (56.6%) experienced a more than 50% reduction in tumor burden. Patients with HER2 which was amplified (22 months) by NGS had a statistically significant longer median PFS than those without an amplified HER2 (7.7 months) (

=.0275). The same was determined in patients with altered RTK/RAS pathways (median PFS, 13.8 months) vs. patients with wild-type RTK/RAS (4.9 months; 

“In summary first-line triplet regimen pembrolizumab, trastuzumab, and chemotherapy showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in advanced gastric cancer,” concluded Rha. “Correlative biomarkers found from our study need to be validated through ongoing trials.”

Rha SY, Lee C-K, Kim HS, et al. A multi-institutional phase Ib/II trial of first-line triplet regimen (Pembrolizumab, Trastuzumab, Chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): Molecular profiling and clinical update. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; January 15-17, 2021; Virtual. Abstract 218.

Articles

The addition of pembrolizumab and trastuzumab to the combination cisplatin plus capecitabine was able to effectively treat HER2-positive advanced gastric and gastroesophageal junction cancer, regardless of PD-L1 expression in the phase 1b/2 PANTHERA trial.

Pembrolizumab/Trastuzumab Regimen Effective in Treating HER2-Positive Advanced Gastric, GEJ Cancer

Patients with radiation-associated breast angiosarcoma may have an effective treatment option with the combination of oral paclitaxel with encequidar (oPac+E), according to study results presented during the 2020 San Antonio Breast Cancer Symposium.

The researchers assessed activity, safety and tolerability of oPac 205 mg/m2 plus E 12.9 mg once daily for 3 consecutive days weekly in patients with unresectable cutaneous angiosarcoma. The primary outcome of the study was tumor response to therapy every 6 weeks.

From August 2018 to May 2020, 7 patients (median age, 66 years; range, 49-76) were diagnosed with breast cutaneous angiosarcoma. All patients had previously been diagnosed with breast cancer and received a mastectomy and radiotherapy and/or adjuvant chemotherapy.

Three patients (43%) achieved a complete response on the combination, and also achieved stable disease (43%). One patient achieved a partial response to therapy. Forty-three percent of patients crossed over to receive curative surgical resection.

The combination was generally well tolerated, with grade 3 treatment-related adverse events (TRAEs) occurring in 5 patients. The most common grade 3 TRAEs included fatigue (2 cases), diarrhea, dyspnea, dehydration, pneumonitis and neutropenia (one case each). Three patients needed dose reductions, however there were no treatment discontinuations as a result of AEs. No patient deaths have been reported to date.

The authors concluded that the combination may be an effective oral treatment for patients with radiation-associated breast angiosarcoma, with limited toxicities, which could offer patients the potential to avoid intravenous chemotherapy at a hospital.

Ravi V, Wagner M, Chen TWW, et al. A phase 2 study of oral paclitaxel and encequidar (oPac+E) in the treatment of cutaneous angiosarcoma: The breast angiosarcoma subgroup. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster PS13-05.

Patients with radiation-associated breast angiosarcoma may have an effective treatment option with the combination of oral paclitaxel with encequidar.

Oral Paclitaxel Plus Encequidar Produces Responses as Treatment of Radiation-Associated Breast Angiosarcoma

Data from a 29-practice consortium shows that oncologists tend to under-recognize substantial symptoms among patients with breast cancer receiving radiotherapy (RT) after they have undergone a lumpectomy, according to a presentation during the 2020 San Antonio Breast Cancer Symposium. The data underscore a need for improvement in symptom detection.

“Understanding whether physicians detect whether patients are experiencing substantial toxicity is important, both because recognition of symptoms is necessary for appropriate supportive care and because clinical trials investigating new treatment options often rely on physician assessments using common toxicity criteria for adverse events,” Reshma Jagsi, MD, DPhil, deputy chair of the Department of Radiation Oncology at University of Michigan, said during a virtual presentation of the data.

Using a large multicenter consortium of 29 practices in Michigan, Jagsi and colleagues aimed to compare physician and patient reports of acute toxicity during breast RT, and specifically analyze if under-recognition of toxicities were pronounced in certain subgroups.

Between January 2012 and March 2020, 13,725 patients completed RT at one of the practices included in the Michigan Radiation Oncology Quality Consortium. Among those who completed RT, 9,941 completed at least one patient-reported outcome (PRO) questionnaire while receiving RT.

Where physician assessments via Common Terminology Criteria for Adverse Events (CTCAE) reporting of patient toxicity were available within 3 days of PRO evaluations, Jagsi and colleagues compared the difference in ratings on four symptoms: pain, pruritis, edema and fatigue. The main symptom the researchers wanted to evaluate was pain, which was defined using the Brief Pain Inventory rating pain within the past 24 hours as worst, least, average and “right now.” If patients reported their pain as a 4 to 6 on a 10-point scale, they were considered to have under-recognized pain if the physician graded it as absent or 0.

For patients who reported severe pain as a score of 7 or more, they were deemed to have under-recognized pain if the physician graded it as less than or equal to grade 1 mild pain.

In measuring the frequency of bother from pruritis and edema, symptoms were considered under-recognized if physicians graded those symptoms as absent when patients graded them as bothered often or all the time.

As for fatigue, a patient’s symptoms were deemed under-recognized if they reported experiencing fatigue most of the time and their physician said the condition was absent.

Approximately 1/3 of patients reported moderate or severe pain (34.5%; 3,433 of 9,940) and frequent both from pruritis (30.6%; 3,039 of 9,923). Less than 1/4 of patients reported frequent bother from edema (23.9%; 2,363 of 9,906) or severe fatigue (24.9%; 2,209 of 8,860).

Under-recognition of at least 1 of the 4 symptoms occurred at least once during in the treatment course of 53.2% of patients who reported at least 1 substantial symptom while receiving RT.

Patients aged under 50 years (OR = 1.35; 95% CI, 1.15-1.58; 

 < .001), as well as 50 to 59 years (OR = 1.21; 95% CI, 1.06-1.39; 

 = .006) were more likely to be under-recognized versus patients aged 60 to 69 years. Moreover, Black (OR = 1.92; 95% CI, 1.65-2.23; 

 < .001) or other race (OR = 1.82; 95% CI, 1.24-2.66; 

 = .002) were also associated with under-recognition of symptoms.

“We concluded that patient-reported outcome collection is essential for trials, because relying on the common toxicity criteria for adverse events to detect adverse events based on physician record will miss important symptoms. And prior work has actually suggested this for acute gastrointestinal symptoms associated with radiation treatment, and this work shows that it's also true for the acute symptoms associated with breast radiotherapy,” Jagsi concluded. “Moreover, this work reveals that physicians systematically miss substantial symptoms in certain patients, including patients who are younger, or who have Black or other race, and therefore, improving symptom detection may actually be a targetable mechanism to reduce disparities in radiation therapy, experiences and outcomes.”

Following the presentation of the data, SABCS Co-Director Virginia Kaklamani, MD, DSc, said it was surprising to see that 30% of cases of what patients were reporting as issues associated with their radiation therapy were underrecognized by physicians. Moreover, she said, it was surprising to see those cases higher in young women and racial minorities.

“We need to do a better job,” said Kaklamani, leader of the Breast Oncology Program at the University of Texas Health San Antonio’s MD Anderson Cancer Center. “That's really what it is, we need to conduct studies where patient-reported outcomes are being reported, and we as physicians need to listen more to our patients.”

Jagsi R, Griffith KA, Vicin F, et al. Identifying patients whose symptoms are under-recognized during breast radiotherapy: Comparison of patient and physician reports of toxicity in a multicenter cohort. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract GS3-07

Data from a 29-practice consortium shows that oncologists tend to under-recognize substantial symptoms among patients with breast cancer receiving radiotherapy after they have undergone a lumpectomy, according to a presentation during the 2020 San Antonio Breast Cancer Symposium. The data underscore a need for improvement in symptom detection.

Better Symptom Detection Needed for Patients with Breast Cancer Who Receive Radiotherapy After Lumpectomy

Placebo following a fixed-treatment duration of ibrutinib (Imbruvica) combined with venetoclax (Venclexta) achieved similar 1-year disease-free survival (DFS) results compared with patients who remained on ibrutinib following confirmed undetectable minimal residual disease (MRD) in patients with previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, according to a presentation at the 2020 American Society of Hematology Annual Meeting.

The results, according to lead study investigator William G. Wierda, MD, PhD, professor, D.B. Lane Cancer Research Distinguished Professor, section chief of chronic lymphocytic leukemia and center medical director of the department of leukemia at The University of Texas MD Anderson Cancer Center, support a fixed duration treatment of ibrutinib and venetoclax in this patient population.

“The one-year disease-free survival rate of 95% in patients randomized to placebo is similar to the rate for patients randomized to ibrutinib, supporting a fixed duration treatment with 12 cycles of combined ibrutinib plus venetoclax and treatment discontinuation for patients who achieved confirmed undetectable MRD,” said Wierda during a virtual presentation of data from the MRD cohort of the phase 2 CAPTIVATE trial.

Wierda stated that preclinical data supported the use of ibrutinib and venetoclax in this situation, as each treatment alone demonstrated complementary clinical activity and did not have overlapping toxicities.

The aim of this cohort of the CAPTIVATE trial, according to Wierda, was to assess if deep remissions could be achieved following a 1-year fixed duration of ibrutinib plus venetoclax, and if patients could discontinue treatment and reasonably remain off treatment.

The primary goal of the study was to compare 1-year DFS between the continued administration of ibrutinib or a switch to placebo in patients who achieved a confirmed undetectable MRD, which was defined as undetectable serially over 3 or more cycles of therapy, and noticeable in peripheral blood (PB) and bone marrow (BM).

The CAPTIVATE trial is a multicenter, international phase 2 study of first line ibrutinib and venetoclax across 2 cohorts: one involving MRD and the other fixed duration. In this cohort, patients received 3 cycles of ibrutinib followed by 12 cycles of the combination. Patients were then randomized to receive placebo or further ibrutinib treatment depending on their MRD status.

Among 149-evaluable patients (median age, 58 years; range, 28-69), 58% achieved confirmed undetectable MRD and were randomized to either continued ibrutinib alone (n = 43) or placebo (n = 43). The remaining 63 patients who did not reach confirmed undetectable MRD were randomized to continue receiving ibrutinib (n = 31) or the combination (n = 32).

Results showed that continued ibrutinib following a confirmed undetectable MRD resulted in a 1-year DFS of 100% compared with 95.3% in the placebo group (

After a median follow-up of 31.3 months, all evaluable patients achieved a 30-month progression-free survival (PFS) of 95.3% (95% CI, 90.4-97.8). Each randomized arm in both the confirmed undetectable MRD and unconfirmed undetectable MRD group achieved a 30-month PFS of 95% or greater.

Increases in undetectable MRD were greater with continued combination therapy compared with ibrutinib alone in patients who had unconfirmed undetectable MRD following the 12 cycles of the combination. Following additional randomized treatment with ibrutinib, undetectable MRD in BM increased from 32% to 42% compared with 31% to 66% in patients who continued to receive the combination. Moreover, undetectable MRD in PB remained at 45% for patients who received additional ibrutinib and increased from 50% to 69% in patients who received the combination.

Very few patients in each arm required dose reduction or dose discontinuation, according to Wierda. In the group with confirmed undetectable MRD, 4 patients (3 in the ibrutinib arm and 1 in the placebo arm) experienced adverse events (AEs) that led to dose reduction after randomization. Four patients in the unconfirmed undetectable MRD group — 2 each for ibrutinib alone and the combination — experienced AEs that led to dose reduction after randomization. There were no treatment discontinuations as a result of AEs in the confirmed undetectable MRD group compared with 3 (1 for ibrutinib alone and 2 for the combination treatment) in the group with unconfirmed undetectable MRD.

The most common AEs of interest over time, meaning grade 3 or 4, were neutropenia and hypertension. Occurrences varied across the treatment arms.

“There were no safety concerns with this highly active combination of first line ibrutinib and venetoclax an all-oral, once-daily, fixed-duration regimen that achieves undetectable MRD in blood or bone marrow in three quarters of patients after 12 cycles of combined treatment,” concluded Wierda.

Wierda WG. Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease-Free Survival (DFS) Results From the MRD Cohort of the Phase 2 CAPTIVATE Study. Presented at: the 2020 ASH Annual Meeting and Exposition; December 5-8, 2020. Abstract #123.


Placebo following a fixed-treatment duration of ibrutinib combined with venetoclax achieved similar 1-year disease-free survival results compared with patients who remained on ibrutinib following confirmed undetectable minimal residual disease in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma.

Ryan McDonald | Authors

Articles

Pembrolizumab/Trastuzumab Regimen Effective in Treating HER2-Positive Advanced Gastric, GEJ Cancer

Oral Paclitaxel Plus Encequidar Produces Responses as Treatment of Radiation-Associated Breast Angiosarcoma

Better Symptom Detection Needed for Patients with Breast Cancer Who Receive Radiotherapy After Lumpectomy

Similar 1-Year DFS Observed With Continued Ibrutinib, Following Fixed-Duration of Ibrutinib/Venetoclax Vs Placebo in CLL/SLL