Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer
Background
Unresectable
locally advanced or metastatic triple-negative
(hormone-receptor–negative and human epidermal growth factor receptor 2
[HER2]–negative) breast cancer is an aggressive disease with poor
outcomes. Nanoparticle albumin-bound (nab)–paclitaxel may enhance the
anticancer activity of atezolizumab.
Methods
In
this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with
untreated metastatic triple-negative breast cancer to receive
atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel;
patients continued the intervention until disease progression or an
unacceptable level of toxic effects occurred. Stratification factors
were the receipt or nonreceipt of neoadjuvant or adjuvant taxane
therapy, the presence or absence of liver metastases at baseline, and
programmed death ligand 1 (PD-L1) expression at baseline (positive vs.
negative). The two primary end points were progression-free survival (in
the intention-to-treat population and PD-L1–positive subgroup) and
overall survival (tested in the intention-to-treat population; if the
finding was significant, then it would be tested in the PD-L1–positive
subgroup).
Results
Each
group included 451 patients (median follow-up, 12.9 months). In the
intention-to-treat analysis, the median progression-free survival was
7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5
months with placebo plus nab-paclitaxel (hazard ratio for progression or
death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002);
among patients with PD-L1–positive tumors, the median progression-free
survival was 7.5 months and 5.0 months, respectively (hazard ratio,
0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat
analysis, the median overall survival was 21.3 months with atezolizumab
plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel
(hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among
patients with PD-L1–positive tumors, the median overall survival was
25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI,
0.45 to 0.86). No new adverse effects were identified. Adverse events
that led to the discontinuation of any agent occurred in 15.9% of the
patients who received atezolizumab plus nab-paclitaxel and in 8.2% of
those who received placebo plus nab-paclitaxel.
Conclusions
Atezolizumab
plus nab-paclitaxel prolonged progression-free survival among patients
with metastatic triple-negative breast cancer in both the
intention-to-treat population and the PD-L1–positive subgroup. Adverse
events were consistent with the known safety profiles of each agent.
(Funded by F. Hoffmann–La Roche/Genentech; IMpassion130
ClinicalTrials.gov number, NCT02425891.)
Two of these studies were highlighted at SABCS 2018:
The first is a scientifically complex study aimed at determining which patients will have the highest response rates to an immunotherapy agent known as atezolizumab, the same agent in the IMPASSION study. That trial showed patients with a marker called PD-L1 benefit from treatment with atezolizumab. This will help researchers both design future trials and personalize treatment for TNBC patients.
The second study is a phase I trial of CAR-T therapy for patients that have a specific targetable mutation, including TNBC patients. CAR-T is a technically complex form of treatment in which cells are removed from the patient, genetically re-engineered and then injected back into the patient where the goal is to stimulate an ongoing immune response to the tumor. It has been used in clinical trials with patients who have a range of leukemias, lymphomas, non small cell lung cancer and other tumors, but this is the first trial to include TNBC patients.
This is a phase I study with small numbers of patients and very early results. Only four TNBC patients were included in the data presented at SABCS, Three of them had responses to their treatment, but it is still far too soon to draw conclusions about the future of CAR-T therapy for TNBC.
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09) 11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15
Promising Combo for Triple-Negative Breast Cancer, but Only With a BRCA Mutation
Combination therapy with niraparib, a poly (ADP-ribose) polymerase
(PARP) inhibitor, and pembrolizumab had clinical activity in
triple-negative breast cancer (TNBC), according to the results of the
TOPACIO trial. However, that activity appeared limited to patients with BRCA-mutated
tumors, a finding that aligns with PARP inhibitor activity seen to
date. The two PARP inhibitors olaparib and talazoparib are currently
approved for TNBC patients with BRCA mutations. Results of this study were published in JAMA Oncology.
OPACIO is an open-label, single-arm, multicenter, phase II clinical
trial that included 55 women with advanced or metastatic TNBC from 34
sites across the United States, all of whom received niraparib in
combination with pembrolizumab on day 1 of each 21-day cycle. Patients
were eligible for the trial regardless of BRCA mutation status or programmed death ligand 1 (PD-L1) expression.
In terms of the safety profile, 32 patients (58%) had a grade 3 or
higher treatment-related adverse event. The most common grade 3 or
higher events were anemia (18%), thrombocytopenia (15%), and fatigue
(7%). “These are typical class effects from PARP inhibitors,” said Yuan Yuan, MD, PhD, a medical oncologist specializing in breast cancer at City of Hope, during an interview with Cancer Network, who was not involved in the current study. “Totally not surprising,” she added.
As for immune-related adverse events, the most frequent any-grade
events were adrenal insufficiency (2%), hyperglycemia (2%),
hyperthyroidism (2%), hypothyroidism (7%), pneumonitis (2%), and
polymyalgia rheumatica (2%). There were only 2 grade 3 immune-related
adverse events, one of which was adrenal insufficiency and the other
polymyalgia rheumatica. Yuan said the immune toxicities were “very
consistent” with what’s been seen for pembrolizumab.
For the entire study population, the overall response rate (ORR) was
21% (10 of 47 evaluable patients), which included 5 confirmed complete
responses and 5 confirmed partial responses. In addition, 13 patients
had stable disease, yielding a disease control rate (DCR) of 49% (23 of
47 evaluable patients). Seven patients were still on treatment.
“I definitely think there is a signal for the combination,” said Yuan. That
said, she cautioned, the study is a single-arm trial without a control.
“There would need to be a confirmatory study comparing the PARP
inhibitor plus immune checkpoint inhibitor vs single agent,” she said.
She added that the response rate “appears” to be higher in the
single-arm trial than the historical data using the PARP inhibitor
alone.
For patients with BRCA mutations, the clinical activity was
even more pronounced, with an ORR of 47% (7 of 15 evaluable patients), a
DCR of 80% (12 of 15 evaluable patients), and a median progression-free
survival (PFS) of 8.3 months (95% CI, 2.1 months–not estimable).
However, the opposite was true for patients without a BRCA
mutation; the ORR dropped to 11% (3 of 27 evaluable patients), DCR to
33% (9 of 27 evaluable patients), and the median PFS to 2.1 months (95%
CI, 1.4–2.5 months).
“There is a good scientific rationale to do this combination,” said Yuan. “But when you look at the patients without BRCA
tumors, the overall response rate is a little bit disappointing.” She
said the ORR for these patients—that is, 11%—is “almost comparable” with
a single-agent immune checkpoint inhibitor.
It's the Keytruda trial that's been going a while that my friend did I think. It's Taxol for 12 weeks with Carboplatin every 3 or 4, followed by the usual dose dense A.C. Every 2 weeks times 4, while doing doses of Keytruda every...few weeks the whole time. Then surgery of your choice 4-6 weeks after chemo ends, keep doing the Keytruda after surgery every few weeks for like...6-8 months? My friend got sick as a dog, but did get a pCR. She had a mastectomy because of a positive BARD gene mutation. It was a loooong year, but she's a year out from the whole thing and doing well.
IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads 6/1/16 Local recurrence same breast, same spot 1.8cm Carb.4x every 3 wks, Taxol 12x once wk. Dbl Mast. PCR!! Reconstruction fail, NED!
I just googled, it's the same trial. They are reporting preliminary results show an increase in pCR, so the study will continue as is.
FYI - if you enter the study you may get a placebo. My friend had major Keytruda specific side effects so she knew she was getting it. If she'd figured out she was on a placebo she'd have bailed on those last 6-8 months of treatments so she could move the hell on to completing reconstruction. Because skin expanders are evil!!
Keytruda plus chemotherapy meets co-primary endpoint in KEYNOTE-522 trial
Merck said that Keytruda in combination with chemotherapy has met one of the two primary endpoints of a phase 3 trial in triple-negative breast cancer (TNBC).
n the late-stage trial called KEYNOTE-522, Keytruda and chemotherapy combination achieved pathological complete response (pCR) following the neoadjuvant part of the neoadjuvant/adjuvant study regimen.
pCR is defined as an absence of all signs of cancer in tissue samples that are analysed after completion of neoadjuvant therapy and definitive surgery.
As per an interim analysis carried out by the independent data monitoring committee (DMC), Keytruda and chemotherapy combination delivered a statistically significant improvement in pCR rates, in comparison to chemotherapy alone, irrespective of PD-L1 status.
Merck said that based on the DMC’s recommendation, the KEYNOTE-522 trial will go on without changes to study the other dual-primary endpoint of event-free survival (EFS), as per its design.
Keytruda’s safety profile in the late-stage trial was on par with previously reported studies with no new safety signals observed.
Merck Research Laboratories president Roger Perlmutter said: “These findings from this innovatively designed trial with Keytruda mark the first time an anti-PD-1 therapy plus chemotherapy has demonstrated a statistically significant improvement in pathological complete response rate as a neoadjuvant, or pre-surgical, segment of treatment for triple-negative breast cancer.
“TNBC is an aggressive malignancy with a high rate of recurrence within the first five years of diagnosis. We are encouraged by these results and plan to discuss these data with health authorities and to present these findings at an upcoming medical congress.”
Keytruda, which has been approved in the US, European Union and in other countries for multiple indications, is an anti-PD-1 therapy that functions by enhancing the ability of the body’s immune system to help detect and fight tumour cells. The humanised monoclonal antibody prevents the interaction between PD-1 and its ligands, PD-L1 and PD-L2 to help in the activation of T lymphocytes that may impact tumour cells and healthy cells.
Earlier this month, the anti-PD-1 therapy in combination with Eisai’s Lenvima has been granted breakthrough therapy designation from the US Food and Drug Administration (FDA) for unresectable hepatocellular carcinoma (HCC).
IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads 6/1/16 Local recurrence same breast, same spot 1.8cm Carb.4x every 3 wks, Taxol 12x once wk. Dbl Mast. PCR!! Reconstruction fail, NED!
Hi Kelly, thank you for your input on 522 trail... I am not sure I understand how to declare PCR after sugery is over and continue taking drugs ... is it the same after surgery taking taxol and carboplatin and then declare PCr?
To get the full Keytruda immunotherapy effect it has to be taken that long. And that's the trial - if you're in a trial you really really really need to stay in it unless there's a health issue. If she'd dropped out her whole participation in the trial is worthless to the trial - it's ruined. Placebo or no, pCR or not - it's an important commitment. And pCR is in no way a YAY I'm cured forever for sure Thing, it's just better odds, so not a reason to quit the treatment. I don't understand why they put such a brutal chemo regimen with it, it's a LOT, and Keytruda can be a lot more on top of it. She did it because of the mutation, she had a higher risk factor. But then she also did a diep flap reconstruction so tummy tuck! And to cap off a helluva lot of tough stuff she did the hysterectomy because BARD1 is also ovarian risk so dayum - it was a medical odyssey.
I have another friend with Colon cancer mets to the lungs. He's doing Keytruda every 3 weeks or so and it's working. The first time he tried it he had a huge flare up of rheumatoid arthritis that he didn't know he had! So bad and painful he called an ambulance and spent time in hospital. He had to quit Keytruda and get that under control, but 3-4 months later went back in Keytruda and is doing ok with it. Immunotherapy is very promising, but it's not a chemo replacement and it's not an easy, small thing.
I would LOVE to see a trial with the standard AC-T plus Keytruda trial. Is the Carboplatin necessary to get the pCR advantage? If it's not then YAY! Skip it, and do the A.C. First cuz it is easier that way.
IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads 6/1/16 Local recurrence same breast, same spot 1.8cm Carb.4x every 3 wks, Taxol 12x once wk. Dbl Mast. PCR!! Reconstruction fail, NED!
FDA: Novel Breast Ca Drugs Linked to Severe Lung Illness
Reports of ILD, pneumonitis in patients on CDK4/6 inhibitors
The FDA issued a warning
Friday that CDK4/6 inhibitors for advanced breast cancer may cause rare
but severe lung inflammation, and said fatalities had been reported.
Package warnings have been added to the three approved agents in the
class -- palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib
(Verzenio) -- and breast cancer patients taking these agents should be
monitored for pulmonary symptoms indicative of either pneumonitis or
interstitial lung disease (ILD).
"The overall benefit of CDK4/6 inhibitors is still greater than the
risks when used as prescribed," the agency said in the statement
announcing the move. But clinicians should suspend treatment in patients
"who have new or worsening respiratory symptoms, and permanently
discontinue treatment in patients with severe ILD and/or pneumonitis."
Data from completed and ongoing postmarketing trials involving CDK4/6
inhibitors were reviewed and revealed the connection, the FDA said, but
factors to identify at-risk patients have not been found.
Signs and symptoms of ILD and pneumonitis can include "hypoxia,
cough, dyspnea, or interstitial infiltrates on radiologic exams in
patients in whom infectious, neoplastic, and other causes have been
excluded."
CDK4/6 inhibitors are used in combination with hormone therapies for
patients with advanced or metastatic hormone receptor-positive,
HER2-negative breast cancer. The first of these agents, palbociclib,
received FDA approval for women in 2015. This was followed by the 2017 approvals of ribociclib and abemaciclib. Most recently, palbociclib's indication was expanded to include men.
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