Neoadjuvant Trastuzumab, Pertuzumab, and Chemotherapy Versus Trastuzumab Emtansine Plus Pertuzumab in Patients with HER2-Positive Breast Cancer (KRISTINE): A Randomised, Open-Label, Multicentre, Phase 3 Trial
Hurvitz et al., Lancet Oncol. 2018 Jan;19(1):115-126.
PubMed ID: 29175149
HER2 positive breast cancer is a more aggressive subtype and carries a risk of recurrence after 8-10 years despite HER2 targeted therapy. Dual HER2 treatment with trastuzumab and pertuzumab in combination with chemotherapy has emerged as standard of care treatment in the neoadjuvant setting. Trastuzumab emtansine is an antibody–drug conjugate with a more tolerable safety profile compared to traditional chemotherapy. Hurvitz and colleagues investigated the efficacy and safety of trastuzumab emtansine with pertuzumab vs standard of care treatment in early stage HER2 positive breast cancer.
- Patients: Histologically confirmed Her2 positive stage I-III breast Ca, no previous treatment, ECOG 0-1
- Study design: phase III, open-label RCT
- Trastuzumab emtansine 3.6 mg/kg IV
- Pertuzumab 840 mg LD then 420 mg IV
- Control (Standard TKI):
- Trastuzumab 8mg/kg LD then 6mg/kg IV
- Petuzumab 840 mg LD then 420 mg IV
- Docetaxel 75 mg/m2 IV
- Carboplatin AUC 6 IV
- Primary:PCR (ypT0/is, ypN0)
- Secondary: Proportion without inflammatory breast Ca who underwent breast-
conserving surgery, EFS, IDFS, OS, QOL, safety
- 443 patients randomized to TeP (n=223) and DCTP (n=221)
- Baseline patient characteristics: 99.5% female, median age 49.5 yrs., 38% Western Europe, 38% rest of the world, 62% ER/PR+, 83% stage IIA-IIIA, 67% white race, 95% ECOG 0, median time from breast Ca diagnosis – 5 yrs.
Table 1: Efficacy Outcomes
Table 2: Adverse events and treatment summary
- Most common adverse events leading to dose reductions: lab anomalies (9% for TeP) v GI disorders (11% for D) and blood/lymphatic disorders (11% for C)
- Most common grade ≥3 adverse event with TeP: thrombocytopenia, fatigue, increased ALT, hypokalemia
- Most common grade ≥3 adverse event with DCTP: neutropenia, diarrhea, febrile neutropeniaGrade 4 adverse event (<1%) with TeP: peripheral neuropathy, thrombocytopenia, platelet count decreased, acute kidney injury, bacteremia, respiratory failure
- Most common grade 4 adverse event with DCTP: neutropenia (16%), neutropenia (6%), febrile neutropenia (5%)
- Neoadjuvant targeted therapy with trastuzumab emtansine and pertuzumab failed to demonstrate superiority over conventional trastuzumab, pertuzumab docetaxel and carboplatin in terms of improving PCR in early stage HER-2 positive breast Ca. Furthermore, standard therapy was associated with higher rates of breast conserving surgery.
- Exploratory analysis revealed lower PCR rates with trastuzumab emtansine plus pertuzumab (OR= 0.62) and in patients who were hormone receptor positive (OR=0.43). In this study, 62% were hormone receptor positive at baseline. This is similar to findings from the TRYPHAENA study (Ann Oncol 2013; 24: 2278–84). Women with early stage breast cancer were randomized to neoadjuvant FEC with trastuzumab and pertuzumab, FEC followed by docetaxel, trastuzumab and pertuzumab or docetaxel, carboplatin, trastuzumab and pertuzumab. 84% of who received docetaxel, carboplatin, trastuzumab and pertuzumab with hormone negative disease achieved PCR and was consistently higher than the hormone positive subgroup in all three treatment arms. The evidence suggests that in HER-2 positive, hormone negative disease, chemotherapy with targeted therapy provides better clinical outcomes.
- Trastuzumab emtansine with pertuzumab provided a more favourable safety profile. Higher rates of adverse events, treatment interruption/discontinuation occurred in patients on standard therapy. Side effects for both standard therapy and target combination therapy were consistent with that previously reported in the literature. Trastumuzab emtansine with pertuzumab provided the advantage of delayed time to deterioration in HRQOL and physical function.
- Central pathology review was not conducted. PCR was the primary study endpoint. Previous literature found PCR to be a good surrogate for long-term survival. However, residual disease may have been overlooked in this study.
- Whether neoadjuvant trastuzumab emtansine alone (without pertuzumab) is sufficient as neoadjuvant therapy was not addressed in this study and would have provided more insight into the use of targeted therapy in HER-2 positive breast Ca. In the absence of new and compelling evidence, docetaxel, carboplatin, trastuzumab with pertuzumab remains standard of care neoadjuvant treatment in HER-2 positive early stage breast Ca.
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Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair–Deficient/Microsatellite Instability–High Metastatic Colorectal Cancer
Overman MJ et al., J Clin Oncol. 2018 Mar 10;36(8):773-779.
PubMed ID: 29355075
DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC) occurs in around 4% of patients and responds poorly to conventional therapy compared to MMR-proficient/microsatellite stable mCRC. Preliminary studies showed that dMMR/MSI-H status predicts response to PD-L1 therapy. In the CheckMate-142 trial, nivolumab provided objective responses in 31%, with PFS of 50% at 12 mos. and 12-mo. OS of 73% in dMMR/MSI-H mCRC (Lancet Oncol 18:1182-1191, 2017).
Ipilimumab, a cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) inhibitor was found to enhance the activity of nivolumab when given in metastatic melanoma. Based on this, researchers investigated the efficacy and safety of this combination in dMMR/MSI-H mCRC in the CheckMate-142 trial. Results from this cohort are summarized below.
- Patients: Histologically confirmed recurrent CRC or mCRC assessed as dMMR and/or MSI-H per local guidelines, progressed on ≥1 one prior systemic treatment (fluoropyrimidine + oxaliplatin or irinotecan) or refused chemotherapy, ECOG 0-1, no active brain or leptomeningeal metastases.
- Study design: Phase III, open-label RCT
- Nivolumab 3mg/kg IV + ipilimumab 1 mg/kg IV q3w x 4 then nivolumab 3 mg/kg q2w
- Primary: ORR (investigator-assessed)
- Secondary: ORR (blinded independent central review [BICR], DCR, PFS, OS, HRQOL, safety
- 119 patients with dMMR/MSI-H mCRC were treated in stages 1 and 2.
- Baseline patient characteristics: median age 58 yrs., 92% white race, 55% ECOG 1, 45% stage IV at diagnosis, 55% right colon as primary tumor location, 40% with ≥ 3 prior therapies, 99% prior fluoropyrimidines (5-fluorouracil or capecitabine), 93% prior oxaliplatin, 73% prior irinotecan, 57% prior VEGF inhibitors, 37% KRAS mutation, 24% BRAF mutation, 55% with <1% tumor PD-L1 expression at baseline, 29% with clinical history of Lynch syndrome.
- Median doses for nivolumab and ipilimumab were 24 and 4, respectively.
Table 1: Efficacy Outcomes
Table 2: Adverse events and Treatment Summary
- Most common any grade adverse events: diarrhea (22%), fatigue (18%), pruritus(17%)
- Causes of treatment discontinuation in >1 patient: autoimmune hepatitis and acute kidney injury (2% each)
- Among patients who discontinued treatment due to TRAE (n=16), ORR and DCR were similar with ITT population.
- Most of the immune-related TRAEs resolved except for endocrine TRAEs which resolved in 40%.
- Median time to resolution of non-endocrine TRAEs was 1.5 to 9 wks.; for endocrine TRAEs, median time was not reached.
- QOL was maintained in ≥ 60% of patients during the study.
- QOL statistically improved with nivolumab + ipilimumab and was maintained during treatment after adjusting for baseline score.
- Statistically significant improvement was observed for nausea or vomiting, dyspnea, diarrhea, cognitive functioning, and physical functioning although change from baseline was not ≥ 10 points at most time points
- Nivolumab with ipilimumab yielded durable tumor responses in previously treated dMMR/MSI-H mCRC. At least 54% achieved tumor responses as early as 2.8 mos. Seventy one percent were free from disease progression at 1 year while 85% were still alive at 12 mos. PFS and OS were not reached at a median follow-up of 13.4 mos. Anti-tumor activity was observed regardless of mutation status, level of tumor PD-L1 expression or history of Lynch syndrome.
- The combination of nivolumab with ipilimumab was safe and well tolerated. Diarrhea was the most common TRAE. TRAEs were mostly low grade and resolved with protocol-specified management algorithms. Patients who discontinued therapy due to TRAEs had similar clinical outcomes as those who did not discontinue therapy. No treatment-related deaths were reported during the trial.
- The two-drug regimen did not appear to compromise QOL, despite adverse events. In at least 60% of patients, QOL was maintained.
- CheckMate-142 trial was not designed to elicit formal comparisons between combination therapy and nivolumab monotherapy. Median follow-up was short at 13.4 mos. and 63% were still receiving treatment at data cut-off.
- In the phase II KEYNOTE-164 trial, 28% of patients (n=61) with previously treated MSI-H mCRC achieved ORR with pembrolizumab (Ann Oncol 28, 2017 (suppl 5; abstr 386P). Median DOR and OS was not reached for MSI-H CRC, with 6-mo. OS and PFS rates of 87% and 43%, respectively.
- In summary, immunotherapy with nivolumab and ipilimumab is a promising treatment option in previously treated dMMR/MSI-H mCRC based on durable tumor responses, prolonged survival and manageable safety profile.
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