04/29/2018: Articles Summaries - Breast & Hematologic Cancers

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 BREAST CANCERS HEMATOLOGY

BREAST CANCERS

Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial
Wapnir IL et al., J Clin Oncol. 2018 Apr 10;36(11): 1073-1079.
PubMed ID: 29443653 


Introduction:

The phase III CALOR trial was designed to determine whether adjuvant chemotherapy after surgery for isolated locoregional recurrence (ILRR) could improve clinical outcomes (Lancet Oncol 15:156-163, 2014). Interim analysis at a median follow-up of 4.9 yrs. revealed that significant improvement in DFS (5-yr. DFS 69% vs. 57%) and OS (5-yr. OS 88% vs. 76%) was achieved with chemotherapy vs. no chemotherapy. The effect of chemotherapy was as expected, more pronounced in the ER negative subgroup. Long-term follow-up results are summarized below, with focus on ER status.

 

Methods:

  • Patients: Histologically/pathologically confirmed breast cancer who underwent complete unilateral breast surgery (mastectomy or BCT) for ILRR.
  • Study design: phase III, open-label RCT
  • Intervention
    • Experimental: Chemotherapy (physician’s choice)
      • RT required for positive margins and those without previous RT during primary treatment

      • Endocrine therapy required for ER positive tumors, anti-HER2 therapy for HER2 positive tumors was optional (HER2 testing was not required)

    • Control: No chemotherapy
  • Endpoints
    • Primary: DFS
    • Secondary: OS, breast cancer–free interval (BCFI), safety

 

Results:

  • 162 patients randomized and analyzed by ITT
     
  • On multivariable analysis, statistically significant interaction for DFS and BCFI was observed between chemotherapy and ER status.


Table 1: Baseline patient characteristics by ER status*


Table 2: Efficacy Outcomes


Table 3: Sites of First Failure

 

Discussion:

  • Analysis of long-term clinical outcomes in the phase III CALOR trial at a median follow-up of 9 yrs. confirmed an advantage in terms of DFS and BCFI but not OS in women with ER negative breast cancer who received chemotherapy after surgery for ILRR compared to no chemotherapy. No benefit was observed for the ER positive group, suggesting that endocrine therapy is adequate for most of these patients. Significant interaction between ER status and chemotherapy was noted. The study seemed to suggest that ILRR and not ER status was a better predictor of benefit with chemotherapy.
  • Visceral metastasis was the most common site of distant failure. The highest incidence occurred in the ER negative group that did not receive chemotherapy.
  • In this pragmatic trial, treatment was based on physician’s choice where 64% administered polychemotherapy, mostly anthracycline-based (45%) and only 1% used anthracycline-taxane combination. Anti-HER2 therapy was given to 6% of the study population and was optional; today it is standard of care treatment for HER2 positive breast cancer. The study closed early due to slow accrual and the statistical plan was amended due to small sample size, which unfortunately limits the interpretation of study results.
     
  • In summary, chemotherapy (physician’s choice) reduced the absolute risk of a DFS and BCFI event by 36% in women with ER negative breast cancer after complete resection for ILRR. Endocrine therapy appeared to be adequate treatment for the ER positive group, whose outcomes did not improve with the addition of chemotherapy after surgery for ILRR.
     
  • The large majority of patients enrolled in this study had a local relapse >=2 years post-original diagnosis.  It is possible that local recurrences that occur before this could have a different biology that what was described in this study and could possibly be more chemotherapy resistant.  As a result, whether or not chemotherapy would be helpful for tumors that recur locally before 2 years is uncertain.

More Breast Cancer Updates

 

HEMATOLOGY CANCERS

Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial
Armand P et al., J Clin Oncol. 2018 Mar 27:JCO2017760793.
PubMed ID: 29584546

 

Introduction:

Patients with relapsed/refractory classic Hodgkin lymphoma (cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) have very poor prognosis. Although brentuximab vedotin (BV) has shown clinical activity in this setting, treatment options are limited.

Overexpression of programmed death 1 (PD-1) ligands 1 (PD-L1) and 2 (PD-L2) on the surface of tumor cells were found in cNHL. Nivolumab is a PD-1 inhibitor that provided objective tumor response in heavily pretreated relapsed/refractory cNHL. Based on this finding, researchers conducted the CheckMate 205 trial to further investigate its efficacy and safety in this population.

 

Methods:

  • Patients: Biopsy confirmed relapsed/refractory cNHL after failure with auto-HCT.
    • Cohort A:  no prior BV

    • Cohort B: failure of post-auto BV

    • Cohort C: BV prior and/or after auto-HCT failure
       

  • Study design: Phase II single-arm trial
     
  • Intervention: Nivolumab 3 mg/kg IV every 2 weeks
    *Cohort C to discontinue nivolumab after 1 year in persistent CR or resume treatment if relapsed within 2 years of the last dose
     
  • Endpoints
    • Primary: Overall response rate (ORR) by independent radiology review committee (IRC)
    • Secondary: Duration of response (DOR) by IRC, frequency and duration of partial remission (PR) and CR by IRC, investigator-assessed ORR and DOR, progression-free survival (PFS) by IRC, overall survival (OS), tumor change with treatment beyond progression (TBP), time to next treatment (TTNT)

 

Results:

  • 119 patients with dMMR/MSI-H mCRC were treated in stages 1 and 2.
     
  • Overall, 69% achieved IRC-assessed ORR of which 16% achieved CR and 53% achieved PR. ORR for cohorts A, B and C were 65%, 68% and 73%, respectively, with corresponding CR rates of 29%, 13% and 12%.
     
  • More than 95% of patients achieved reductions in target lesion burden. Patients in cohort C and those refractory to previous therapy or BV pre or post auto-HCT had similar response rates.
     
  • Objective responses were observed as early as 2.1 mos., lasted for 16.6 mos. (IRC-assessed DOR) overall and for 20.3, 15.9 and 14.5 mos. in cohorts A, B and C, respectively.
     
  • Patients remained free from disease progression at a median of 14.7 mos. overall and 18.3, 14.7 and 11.9 mos. in cohort A, B and C. Patients who received BV before or after auto-HCT had similar median PFS (11.9 vs. 11.5 mos.). Median TTNT was not reached in cohorts A and B and was 19.4 mos. in cohort C. Median OS was not reached for the study population and all cohorts. 1-yr OS was 92% overall and 93%, 95% and 90% for cohorts A, B and C, respectively.
     
  • In the group with TBP (n-=70), these patients had better performance status, were less likely to have B symptoms but more likely to have new lesions (radiographic progression) compared to not TBP. CR and PR were achieved in 7% and 44%, respectively, with a median duration of TBP of 5.2 mos. It took a median of 8.8 mos. to initiate next systemic therapy after initial progression in the TBP group vs. 1.5 mos. in not TBP group. Corresponding median OS was not reached vs. 13.2 mos. and 1-yr. OS was 84 vs. 61%, respectively.
     
  • Grade 3-4 elevated lipase (5%), neutropenia (3%), elevated ALT (3%) as well as any grade fatigue (23%), diarrhea (15%) and infusion-related reactions (14%) were the most common adverse events. Most of the deaths were due to disease progression and none were related to nivolumab. 17% discontinued treatment due to adverse events (pneumonitis 2%, immune hepatitis 1%) while 12% experienced serious adverse events (infusion-related reactions 2%, pneumonitis 1%). Hypothyroidism/thyroiditis and rash were the most common immune mediated adverse events, majority of which resolved.
     
  • Among 44 patients who received allo-HCT after a median of 13 nivolumab doses, 77% received non-myoablative conditioning. 6-month cumulative incidences of TRM and disease progression were 13% and 7%, respectively. Five patients with TRM underwent transplant and died 36-96 days post transplant; 4 had acute graft vs. host disease (aGVHD). aGRVD occurred in 20% (grade 3-4) while chronic GVHD (cGVHD) was reported in 15.3%. Median PFS and OS were not reached; 6-mo. PFS and OS were 82% and 87%, respectively.

 

Discussion:

  • In relapsed and refractory cNHL, nivolumab provided clinically meaningful benefit in terms of tumor response and survival even among patients who received allo-HCT. These results, together with a favourable safety profile support further investigation of nivolumab in this treatment setting.

More Hematologic Cancer Updates