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Immune Therapy to Fight Cancer

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123Donna View Drop Down
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 29 2018 at 9:47pm

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.)

https://www.nejm.org/doi/full/10.1056/NEJMoa1809615


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

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Dec 10 2018 at 7:50am

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

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jul 13 2019 at 12:18pm

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.

https://www.cancernetwork.com/immuno-oncology/promising-combo-triple-negative-breast-cancer-only-brca-mutation

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

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sophie View Drop Down
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Post Options Post Options   Thanks (0) Thanks(0)   Quote sophie Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 5:18pm
Has anyone heard of keynote 522? Which just come out this week which is related to immunization therapy shall we get benefit ?
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Kellyless Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 10:54pm
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!
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Kellyless Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 11:07pm
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!!
https://www.pharmaceutical-business-review.com/news/keytruda-keynote-522-trial/ 

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!
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Post Options Post Options   Thanks (0) Thanks(0)   Quote sophie Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 11:19pm
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?


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Post Options Post Options   Thanks (0) Thanks(0)   Quote Kellyless Quote  Post ReplyReply Direct Link To This Post Posted: Aug 02 2019 at 1:09am
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!
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