A study of treatment patterns in adult patients with mantle cell lymphoma (MCL) revealed a discrepancy between actual patterns of care and recommendations based on clinical trials, according to lead investigator Peter Martin, MD, in a poster presented at the European Hematology Association 2021 Virtual Congress.

MCL is most commonly treated in younger patients (≤65) with chemoimmunotherapy with or without autologous stem cell transplantation (SCT), and in older patients (≥65) with bendamustine-rituximab (Rituxan; BR) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

“Our understanding of how clinical study findings are reflected in routine clinical practice is limited,” Peter Martin, MD, associate professor of medicine and chief of the Lymphoma Program at Weill Cornell Medicine, New York, said. “These data highlight the need to develop treatment regimens that can be delivered effectively in routine and community practices, and treatments may not need to be centered around SCT intent in young patients.”

The retrospective analysis included patients (n = 4216) with a confirmed MCL diagnosis in the Flatiron Health de-identified database between January 2011 and January 2021 by the Flatiron Health database; 3614 had a record of frontline treatment for MCL. All the patients were 18 years or older and had at least 2 recorded clinic visits. Data originated from 280 cancer clinics representing 800 sites of care; most patients (86.6%) were treated in community oncology settings.

Patient characteristics, treatment patterns, real-world time-to-next treatment (rwTTNT), and real-world overall survival (rwOS) were evaluated. rwTTNT was defined as the time from start of first-line treatment to subsequent treatment or death, whichever came first; rwOS as time from start of first-line treatment to death.

“This was a retrospective analysis,” Martin said. “There were missing data in the baseline characteristics. The tumor response and disease progression data were not available to evaluate overall response rate or progression-free survival. And the intention for choosing treatments (eg, transplantation or maintenance) was not captured in the database.”

Still, significant data were revealed: in patients under 65 years, only 30.5% received a cytarabine-containing regimen; 23.3% received SCT. In patients over 65 years, about 65% received BR or R-CHOP. Median rwTTNT was 28 months in patients under 65 and 22.3 months in patients 65 years or older, which, according to Martin, “appears worse than what has been reported with standard therapies in this population. Older age and high-risk disease features were predictive of worse outcome in the real world, while [rituximab] maintenance appeared to be associated with better outcome. Among the SCT-eligible patients, there was no clear rwTTNT or rwOS benefit associated with receipt.”

Median follow-up in patients with documented first-line MCL treatment was 45.5 months (range, 0.033-119.4) and median rwTTNT was 24 months (28 months in patients <65 years and 22.3 months in patients ≥65 years). At 36 months, the rwTTNT was 41% (95% CI, 39%-43%) for all patients, 46% (95% CI, 43%-49%) for patients <65 years, and 38% (95% CI, 36%-41%) for patients ≥65 years. The 36-month rwOS rate was 68% (95% CI, 66%-69%) in all patients, 78% (95% CI, 75%-81%) in younger patients, and 62% (95% CI, 60%-65%) in older patients.

The 36-month rwTTNT rate was comparable for patients under 65 years treated with SCT (65%; 95% CI, 59%-71%) compared with those did not receive SCT (59%; 95% CI, 55%-64%; log-rank 

= .082). At 3 years, the rwOS rate was 87% (95% CI, 83%-92%) in younger patients who received SCT and 84% (95% CI, 81%-88%) in those who did not receive SCT (log-rank 

= .387). For patients 65 years or older who were not treated with SCT, the 36-month rate of rwTTNT was 37% (95% CI, 35%-40%).

Among eligible patients with a record of treatment, 2340 patients (64.7%) were 65 years or older and 1274 (35.3%) were under age 65. Of the younger group, 971 patients were SCT eligible and 291 received SCT. A total of 23.1% received rituximab maintenance therapy.

Overall, the median age for the study was 69.4 years (range, 27.7-84.6), with 64.7% of patients over age 65, 71.5% male, and 86.6% treated in a community oncology setting. Patients treated with cytarabine-containing regimens (n = 514) and SCT (n = 291) were younger (median, 60.1 and 59.6 years, respectively) than those treated with R-CHOP (n = 636; median age, 66.3) or BR (n = 1502; median age, 72.7) and were less likely to be treated in the community. Patients treated with cytarabine-based regimens were also more likely to have blastoid/pleomorphic morphology (20%) than the overall patient group (10%) but had a low-risk MCL International Prognostic Index (MIPI) score. Those treated with SCT were more likely to have a lower MIPI score than the overall population as well as those treated with BR or R-CHOP.

Martin P, Wang M, Kumar A, et al. Real-world treatment patterns and outcomes of 4216 previously untreated mantle cell lymphoma patients in US routine clinical practice. Presented at: European Hematology Association 2021 Congress; June 9-12, 2021; Virtual. Abstract EP798.

Articles

A study of treatment patterns in adult patients with mantle cell lymphoma revealed a discrepancy between actual patterns of care and recommendations based on clinical trials.

Real-World Treatment Reveals Discrepancy Between Actual Care and Clinical Trial Recommendations in MCL

The combination of pyrotinib plus trastuzumab (Herceptin), docetaxel, and carboplatin (TCbH) significantly improved the total pathological complete response (pCR) rate over TCbH alone in the neoadjuvant treatment of patients with HER2-positive breast cancer, according to data from a phase 2 trial (NCT03756064) presented during the 2021 ASCO Annual Meeting.

“In this study, TCbH plus pyrotinib neoadjuvant therapy significantly improved the total pCR rate of HER2-positive breast cancer patients for about twice [that of] TCbH with a manageable safety [profile],” the study authors, led by Xiaowen Ding, MD, of the Department of Breast Surgery, Zhejiang Cancer Hospital in Hangzhou, China, wrote in their poster.

The randomized, double-blind multicenter study evaluated the efficacy and safety of the addition of pyrotinib, an irreversible second-generation HER2-targeted tyrosine kinase inhibitor (TKI), to TCbH versus TCbH alone given as neoadjuvant treatment in patients with stage II-III HER2-positive breast cancer and invasive carcinoma. pCR, the primary end point, was defined in the study as no invasive or in situ disease in the breast or axilla. Secondary end points included toxicity, event-free survival, disease-free survival, distant disease-free survival, and objective response rate (ORR).

From 2019 to 2021, 67 patients with HER2-positive breast cancer were randomized equally into the treatment and control groups. Investigators hypothesized that patients treated in the investigational group (pyrotinib+TCbH) could have a higher pCR rate than the control group (TCbH). Their hypothesis proved true with the total pCR rate in the treatment group measuring 71.4% (15/21) versus 36.7% (11/30) in the control group; a significant difference was found between the 2 groups (

In the treatment group (n = 34) patients received 6 cycles of 400 mg pyrotinib plus 6 mg/kg trastuzumab with a loading dose of 8 mg/kg, 75 mg/m docetaxel, and carboplatin at area under the curve 6. As of data cutoff, 21 patients had undergone surgery, 7 had not competed treatment (6 had not finished neoadjuvant therapy and 1 had not received surgery), and 6 withdrew consent and discontinued treatment. In the control group (n = 33), patients received the same 6 cycles of TCbH. Thirty patients had undergone surgery and 3 had not completed neoadjuvant therapy.

All patients (n = 21, 100%) in the treatment group achieved a response, while the control group showed an ORR of 83.3% (25/30). Four patients showed stable disease and 1 was evaluated as progressive disease in the control group.

The most common adverse event was diarrhea, with grade 3 events occurring in 6 cases (28.6%) in the treatment group, most of which were limited to the first treatment cycle. In the control group, 3 patients (10%) experienced grade 3 diarrhea.

Eligibility for the study included patients aged 18-70 years with stage II-III HER2-positive breast cancer, invasive carcinoma, and an ECOG performance status of 0-1. In the investigational group, at baseline, 22 patients (65%) were older than 50, and 12 (35%) were 50 or younger; 29 patients (85%) exhibited tumor size >2 cm, 5 patients (15%) ≤2 cm; 22 patients (64%) had about 1 to 2 positive lymph nodes, 6 (18%) had about 3 to 4, and 6 (18%) were node negative; and 21 patients (62%) had a negative hormone receptor (HR) status, while 13 patients (38%) were positive for HR.

In the control group, 18 patients (55%) were older than 50, 15 patients (45%) were 50 or younger; 30 patients (91%) showed a tumor size of >2 cm, 3 patients (9%) ≤2 cm; 21 patients (64%) had about 1 to 2 positive nodes, 9 (27%) had about 3 to 4 positive nodes, and 3 (9%) were node negative; and 17 patients (52%) had negative HR status, 16 patients (48%) reported positive.

Ding X, Mo W,Xie X, et al. Pyrotinib as neoadjuvant therapy for HER2+ breast cancer: a multicenter, randomized controlled phase II trial. 

 2021;39(suppl 15):574. doi:10.1200/JCO.2021.39.15_suppl.574

The combination of pyrotinib plus trastuzumab, docetaxel, and carboplatin (TCbH) significantly improved the total pathological complete response rate over TCbH alone in the neoadjuvant treatment of patients with HER2-positive breast cancer.

Neoadjuvant Pyrotinib Quadruplet Significantly Improves pCR in HER2+ Breast Cancer

Tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine maintained and even improved overall survival (OS) over placebo in pretreated patients with HER2-positive breast cancer, according to the updated results of the phase 2 HER2CLIMB trial (NCT02614794) which were presented during the 2021 ASCO Annual Meeting.

“Tucatinib in combination with trastuzumab and capecitabine continues to improve progression-free and overall survival in patients with HER2-positive breast cancer,” Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milano and the head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy, said during a presentation on the findings. “This combination has the potential to become a new standard of care in this patient population.”

Significantly, OS benefit with tucatinib was maintained with an additional 15.6 months of follow-up (total of 29.6 months), a 5.5-month improvement in median OS was seen in the total population. The median OS in the tucatinib arm was 24.7 months (95% CI, 21.6-28.9) versus 19.2 months (95% CI, 16.4-21.4) in the placebo arm (HR, 0.73; 95% CI, 0.59-0.90; 

= .004). Tucatinib also significantly reduced the risk of disease progression or death by 40% in patients with brain metastases and by 30% in patients with visceral metastases.

Curigliano presented the updated findings from the randomized, double-blind, placebo-controlled HER2CLIMB trial. A total of 612 patients with unresectable, locally advanced or metastatic HER2-positive breast cancer were enrolled in the study. All had been previously treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadycla); had an ECOG performance status of 0 or 1; and a brain MRI at baseline. Patients with treated stable brain metastases, untreated metastases not needed immediate treatment, previously treated progressing metastases not needed immediate therapy, and patients with no evidence of brain metastases were all eligible.

Patients were divided into 2 arms: tucatinib (n = 410) and placebo (n = 202). Over a 21-day cycle, patients in the tucatinib arm were given 300 mg tucatinib orally twice daily (PO BID), 6 mg trastuzumab every 3 weeks (loading dose 8 mg on day 1 of cycle 1), and 1000 mg capecitabine PO BID (days 1-14). The placebo arm received the same regimen of trastuzumab and capecitabine. As of the post-analysis cut-off date, February 8, 2021, 404 (98.5%) patients had received at least 1 dose of tucatinib, and 35 patients (8.5%) are continuing treatment in the tucatinib arm. In the placebo arm, 197 (97.5%) patients received at least 1 dose of placebo, and 1 patient (0.5%) is continuing treatment in the placebo arm. Twenty-six patients (12.9%) crossed over from the placebo arm to the tucatinib arm, 9 (4.5%) of whom remain on treatment.

The primary end point of the study was progression-free survival according to RECIST v1.1 by blinded independent central review. Secondary end points included OS and PFS in patients with metastases and confirmed overall survival in patients with measurable disease.

PFS in the tucatinib arm was consistent with the primary analysis; its benefit was maintained with longer follow-up (HR, 0.57; 95% CI, 0.47-0.70; 

< .00001), with the median PFS being 7.6 months in the tucatinib arm compared with 4.9 months in the placebo arm.

Regarding safety, “the tucatinib regimen continues to be safe and well tolerated with additional follow-up,” Curigliano said. “In the 15.6 months since the primary analysis, only 1 additional patient discontinued tucatinib due to an adverse event.”

The most common adverse events (AEs) in the tucatinib arm included diarrhea (n = 331, 81.9%), palmar-plantar erythodysesthesia syndrome (n = 264, 65.3%), nausea (n = 243, 60.1%) fatigue and vomiting (n = 193, 47.8%). Grade 3 or higher AEs included palmar-plantar erythodysesthesia syndrome (n = 57, 14.1%), diarrhea (n = 53, 13.1%), and fatigue (22, 5.4%), which were more common in the tucatinib arm versus the placebo arm.

Curigliano G, Mueller V, Borges V, et al. Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with or without brain metastases, 

 2021;39(suppl 15; abstr 1043). doi:10.1200/JCO.2021.39.15_suppl.1043

Tucatinib plus trastuzumab and capecitabine maintained and even improved overall survival over placebo in pretreated patients with HER2-positive breast cancer.

Tucatinib Plus Trastuzumab/Capecitabine Maintain Survival Benefit in HER2-Positive Breast Cancer

Pembrolizumab (Keytruda) plus concurrent chemoradiation therapy (cCRT) induced antitumor effects in patients with unresectable, locally advanced, stage III non–small cell lung cancer (NSCLC) irrespective of PD-L1 expression or tumor histology, according to updated findings from the phase 2 KEYNOTE-799 (NCT0363178) that were presented virtually during the 2021 ASCO Annual Meeting.

“[Historically] the standard of care for patients with resectable, locally advanced stage III NCSLC includes concurrent chemoradiation therapy followed by consolidation therapy with durvalumab [Imfinzi],” said Salma K. Jabbour, MD, professor and vice chair of clinical research and faculty development at The Rutgers Cancer Institute of New Jersey, during a presentation of the data. “However, approximately 20% to 30% of patients who begin chemoradiation therapy experience disease progression or toxicity and are ineligible to receive durvalumab as consolidated therapy, representing an unmet clinical need. Pembrolizumab plus concurrent chemoradiation therapy represents a promising therapy [for these patients].”

Jabbour presented findings from the nonrandomized, open-label phase 2 KEYNOTE-799 study, with 3 additional months of follow-up. A total of 216 patients, 18 years or older, were enrolled in the study. All patients had previously untreated, unresectable, pathologically confirmed stage IIIA-C NSCLC, with measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, adequate pulmonary function, and no prior systemic immunosuppressive therapy within 7 days.

Patients were divided into 2 cohorts: A consisted of patients with both squamous and nonsquamous NSCLC (n = 112); cohort B included patients with nonsquamous NSCLC only (n = 102). Jabbour’s presentation focused on median follow-up of 18.5 months (range, 13.6-23.8) in cohort A and 13.7 months (range, 2.9-23.5) in cohort B, with a cutoff date of October 28, 2020.

All patients in the study received up to 17 cycles of pembrolizumab, administered in a dose of 200 mg every 3 weeks. Patients in cohort A also received one cycle of carboplatin and paclitaxel followed by added standard thoracic radiology for cycles 2 and 3, and subsequent pembrolizumab monotherapy. Patients in cohort B received the same dosing for pembrolizumab, with the addition of cisplatin and pemetrexed, plus thoracic radiotherapy in cycles 2 and 3, followed by single-agent pembrolizumab for cycles 4 through 17.

Primary end points were overall response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR) and incidence of grade 3 or higher pneumonitis. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Both cohorts reported an ORR of 70%: cohort A, 70.5% (95% CI, 61.2%-78.8%); cohort B, 70.6% (95% CI, 60.7%-79.2%). Complete responses were reported in 3.6% of patients in cohort A and in 4.9% of cohort B. Neither cohort reached a median duration of response (DOR), PFS, or OS. More than three-quarters of patients in each arm had a DOR of at least 1 year (cohort A, 79.7%; cohort B, 75.6%). The 12-month PFS rate for cohort A was 67.1% and 71.6% for cohort B. The 12-month OS rate for cohort A was 81.3% and 87% for cohort B.

Responses were observed regardless of PD-L1 expression level and tumor histology. In cohort A, for those with negative PD-L1 expression (tumor proportion score [TPS] <1%) the ORR was 66.7% and 75.8% for those with positive expression (TPS ≥1%). In cohort B, ORRs were 71.4% and 72.5% for negative and positive PD-L1 expression, respectively. Patients with nonsquamous disease had an ORR of 69.2% in cohort A and squamous patients in cohort A had an ORR of 71.2%. All patients in cohort B had nonsquamous disease.

“Toxicity was manageable,” said Jabbour, noting that incidence of grade 3 or higher pneumonitis occurred in 9 patients (8.0%) in cohort A and in 7 patients (6.9%) in cohort B, which she considered to be “consistent with studies of anti–PD-1 or PD-L1 therapy with concurrent chemoradiation in stage III NSCLC.” Grade 3-5 treatment-related adverse events occurred in 72 patients (64.3%) in cohort A and in 51 patients (50.0%) in cohort B. Grade 3-5 immune-mediated adverse events and infusion reactions were observed in 16.1% of patients in cohort A and in 9.8% of cohort B patients.

Results of phase 2 KEYNOTE-799 study will now help guide phase 3 testing, which is currently ongoing in KEYLYNK-012 (NCT04380636).

 The KEYLYNK study will look at the earlier incorporation of pembrolizumab with concurrent chemoradiotherapy with or without olaparib (Lynparza) and will compare it to the standard of care, which is to receive immunotherapy after the completion of chemoradiotherapy for patients with stage III NSCLC.

Jabbour SK, Lee KH, Frost N, et al. KEYNOTE-799: phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 NSCLC. 

. 2021;39(suppl 15):8512. doi:10.1200/JCO.2021.39.15_suppl.8512

Jabbour SK, Cho BC, Bria E, et al. Phase 3 study of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib versus concurrent chemoradiation therapy followed by durvalumab in unresectable, locally advanced, stage III non-small cell lung cancer: KEYLYNK-012. 

 2021;39(suppl 15):TPS8580. doi:10.1200/JCO.2021.39.15_suppl.TPS8580

Pembrolizumab plus concurrent chemoradiation therapy induced antitumor effects in patients with unresectable, locally advanced, stage III non–small cell lung cancer irrespective of PD-L1 expression or tumor histology. 

Shari Mycek

Articles

Real-World Treatment Reveals Discrepancy Between Actual Care and Clinical Trial Recommendations in MCL

Neoadjuvant Pyrotinib Quadruplet Significantly Improves pCR in HER2+ Breast Cancer

Tucatinib Plus Trastuzumab/Capecitabine Maintain Survival Benefit in HER2-Positive Breast Cancer

Concurrent Pembrolizumab Plus Chemoradiation Therapy Elicits Antitumor Activity in NSCLC