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25 februari 2022: Uit de Keynote 522 studie blijkt dat het toevoegen van Atezolizumab (een vorm van immuuntherapie met anti-PD medicijnen) met neoadjuvante carboplatine/nab-paclitaxel bij borstkankerpatiënten met triple negatieve tumoren ongeacht PD-L1 expressie, geen statistisch significant verschil uitmaakte van het percentage pathologische complete remissies (pCR) vergeleken met alleen neoadjuvante chemotherapie in een vroeg stadium en bij lokaal gevorderde hoogrisico-triple negatieve borstkanker. Er traden maar 4 procent meer complete remissies op bij totaal 280 borstkankerpatiënten die 1 op 1 gerandomiseerd waren ingedeeld.

Echter de onderzoekers stellen dat de verbeterde overall overleving die in andere studies wel werd gezien (zie ook verderop in dit artikel) niet afhankelijk is van de complete remissies. Zie het studieverslag waarvan het abstract onderaan dit artikel staat:

Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIP Michelangelo randomized study

Kernpunten uit de studie:

In het gerandomiseerde NeoTRIP-onderzoek was atezolizumab met neoadjuvant carboplatine/nab-paclitaxel haalbaar in TNBC zonder de immuuntoxiciteit te beperken, maar leidde het tot een bescheiden, statistisch niet-significante toename van de pCR-snelheid, die hoger was voor PD-L1-positief dan voor PD-L1-negatief tumoren.
Toevoeging van ICI's aan neoadjuvante chemotherapie verbeterde de pCR-snelheid significant in andere onderzoeken (KEYNOTE-522, IMpassion031). KEYNOTE-522 en een derde studie (GeparNUEVO) toonden echter aan dat event-free-survival (EFS) onafhankelijk was van pCR. De eerste analyse van NeoTRIP ondersteunt het idee dat pCR mogelijk niet het meest geschikte surrogaateindpunt is om de rol van ICI's in vroege TNBC te meten.
Het primaire eindpunt van NeoTRIP is EFS, en het ontbreken van pCR-verbetering kan misleidend zijn wat betreft de impact van atezolizumab op de werkzaamheid op lange termijn bij TNBC met een hoog risico.

7 augustus 2019: Bron: Future Medicine

Wanneer patienten met snel een recidief van borstkanker met triple negatief maar wel PD-L1-positieve expressie naast eerstelijns chemo met nab-paclitaxel ook atezolizumab wordt toegevoegd dan hebben zij grotere kans om de 2 jaar te overleven dan alleen met chemotherapie. (overall overleving 25 maanden versus 15,5 maanden). Atezolizumab is een vorm van immuuntherapie met een anti-PD medicijn.

De combinatiebehandeling verminderde ook het risico op ziekteprogressie of overlijden met ongeveer 40% in vergelijking met degenen die alleen met chemotherapie werden behandeld. Van de patiënten die met de combinatie werden behandeld, overleefde 54% ten minste twee jaar in vergelijking met slechts 37% van de met chemotherapie behandelde patiënten.
Bovendien leidde de combinatie tot een veel betere progressievrije overleving (mediaan van 7,4 maanden versus 4,8 maanden) en responspercentages (59% versus 43%) bij de PD-L1-positieve patiënten. Bijwerkingen traden met vergelijkbare percentages op tussen de twee groepen, waarbij 23% van de combinatiebehandelde patiënten en 18% van de met chemotherapie behandelde patiënten ernstige bijwerkingen meldden, met als meest voorkomende hypothyreoïdie, die optrad bij 17% van de met de combinatie behandelde patiënten

Dit blijkt uit een fase III studie IMpassion132 bij totaal 902 patienten met een recidief van triple negatieve gevorderde borstkanker met een PD-L1-positieve expressie. De FDA gaf op basis van deze studie toestemming voor gebruik van deze combinatiebehandeling bij deze groep van patienten. Zie daarvoor ook het persbericht op de website van de producent.

Voor het studierapport: IMpassion132 Phase III trial: atezolizumab and chemotherapy in early relapsing metastatic triple-negative breast cancer moet betaald worden.

Het abstract geeft summiere informatie zodat ik niet meer details kan toevoegen:

CLINICAL TRIAL PROTOCOL normal

IMpassion132 Phase III trial: atezolizumab and chemotherapy in early relapsing metastatic triple-negative breast cancer

Published Online: 12 Apr 2019 https://doi.org/10.2217/fon-2019-0059

The PD-L1 inhibitor atezolizumab received US FDA accelerated approval as treatment for PD-L1-positive metastatic triple-negative breast cancer (TNBC). In IMpassion130, combining atezolizumab with first-line nab-paclitaxel for metastatic TNBC significantly improved progression-free survival and showed a clinically meaningful effect on overall survival in patients with PD-L1-positive tumors. The placebo-controlled randomized Phase III IMpassion132 (NCT03371017) trial is evaluating atezolizumab with first-line chemotherapy (capecitabine [mandatory in platinum-pretreated patients] or gemcitabine/carboplatin) for inoperable locally advanced/metastatic TNBC recurring ≤12 months after completing standard (neo)adjuvant anthracycline and taxane chemotherapy. Stratification factors are: visceral metastases, tumor immune cell PD-L1 status and selected chemotherapy. Patients are randomized to atezolizumab 1200 mg or placebo every 3 weeks with the chosen chemotherapy, continued until progression, unacceptable toxicity or withdrawal. The primary end point is overall survival.

Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIP Michelangelo randomized study

Highlights

•
In the randomized NeoTRIP study atezolizumab with neoadjuvant carboplatin/nab-paclitaxel was feasible in TNBC without limiting immune toxicity, but led to modest, statistically non-significant increase of pCR rate, which was higher for PD-L1 positive than for PD-L1 negative tumors.
•
Addition of ICIs to neoadjuvant chemotherapy significantly improved pCR rate in other trials (KEYNOTE-522, IMpassion031). However, KEYNOTE-522 and a third trial (GeparNUEVO) showed that event-free-survival (EFS) was independent of pCR. The first analysis of NeoTRIP supports the notion that pCR may not be the most appropriate surrogate endpoint to measure the role of ICIs in early TNBC.
•
The primary endpoint of NeoTRIP is EFS, and lack of pCR improvement may be misleading as to the impact of atezolizumab on long-term efficacy in high risk TNBC.

Background

High-risk triple negative breast cancers (TNBC) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need of new therapeutic approaches. PD-L1 expression is an adaptive mechanism of tumour resistance to tumour infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/PD-1 check-point may improve efficacy of classical chemotherapy.

Patients and methods

Two-hundred-eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin AUC 2 and nab-paclitaxel 125 mg/m2 iv on days 1 and 8, without (N = 142) or with (N = 138) atezolizumab 1200 mg iv on day 1. Both regimens were given q3 weeks for 8 cycles before surgery and 4 cycles of an adjuvant anthracycline regimen. The primary aim of the study is to compare event-free survival, an important secondary aim was the rate of pathological complete remission (pCR defined as absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat population.

Results

The intention-to-treat analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab [44.4%: odds ratio (OR) 1.18; 95% CI 0.74-1.89; P = 0.48]. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminases abnormalities with atezolizumab.

Conclusions

The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis the presence of PD-L1 expression was the most significant factor influencing rate of pCR (OR 2.08). Continuing follow up for the event-free survival is ongoing, and molecular studies are under way.

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Article Info

Publication History

Accepted: February 8, 2022

Received: January 18, 2022

Publication stage

In Press Journal Pre-Proof

Footnotes

Presented in part at the San Antonio Breast Cancer Symposium, December 12, 2019.

Contributors:The study was designed by LG and PV in collaboration with the sponsor, Fondazione Michelangelo. Data were collected via an electronic data capture system located in Milano and analyzed by the biostatistician IM. Analyses were discussed with LG and PV and then presented to all the authors. GV assessed all biomarkers required for the study. LG and PV prepared the initial draft of the manuscript. All authors made substantial contributions to the intellectual content of this work via data acquisition and interpretation, in addition to critical revision of the manuscript. All authors provided their final approval of the manuscript.

Data sharing:Qualified researchers can request the datasets generated during and/or analyzed during the current study to the corresponding author or to segreteria@fondazionemichelangelo.org and the request will be examined by the members of the Protocol Steering Committee.