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ONCAlert | Upfront Therapy for mRCC

Oncology Experts Select Top Abstracts Ahead of 2019 ASCO Annual Meeting

Danielle Ternyila
Published Online: 9:20 PM, Tue May 28, 2019
Pashtoon M. Kasi, MD, MBBS, MS
Ahead of the 2019 Annual ASCO Meeting, several oncology experts spoke with Targeted Oncology to highlight the top abstracts from this year’s meeting that they feel will have the biggest impact on clinical practice.

“ASCO is the super bowl for oncology where we network with our friends and colleagues from all over the place,” said Vivek Subbiah, MD, assistant professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center. “We learn a lot in this meeting, so I am very excited.”

Many of the top abstracts are investigating the role of PARP inhibitors across various fields. Several PARP inhibitors have already gained FDA approval for the treatment of patients with breast cancer, ovarian cancer, and pancreatic cancer, among others. New data will be presented during the meeting for PARP inhibitors across several tumor types.

“I think in gastrointestinal (GI) cancers as a whole, there are many studies that revolve around major themes at ASCO,” said Pashtoon M. Kasi, MD, MBBS, MS, assistant professor of oncology and senior associate consultant in the Division of Hematology/Oncology at the University of Iowa, Holden Comprehensive Cancer Center. “I think PARP inhibitors are the most exciting where you have many abstracts that are incorporating its use; it’s already been approved in ovarian cancer and germline patients with breast cancer or the BRCA gene, but it’s not just limited to those.”

Maurie Markman, MD, president of medicine and science at the Cancer Treatment Centers of America, added, “It’s been a dead year [in gynecologic oncology], about as bad as it has been in a long time in terms of interesting and new things. However, you know, it’s all about PARPs. I am excited to see 3 oral presentations here.”

In an interview with Targeted Oncology, experts in gynecology, GI, genitourinary (GU), lung, and breast cancers spoke to the significance of the abstracts they are most looking forward to at the 2019 ASCO Annual Meeting. 
 

Gynecologic Cancers

 
Maurie Markman, MD
Maurie Markman, MD

Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.

“One randomized phase II trial is looking at olaparib (Lynparza) monotherapy versus chemotherapy in platinum-resistant ovarian cancer. It’s a small study, but it’s an interesting study,” said Markman. “Patients were randomized to single-agent olaparib or standard of care, which was defined as physician’s choice of pegylated liposomal doxorubicin, topotecan (Hycamtin), paclitaxel (Abraxane), or gemcitabine (Gemzar), with the primary endpoint as objective response rate (ORR).”

One hundred patients were randomized 2:1 to receive olaparib or chemotherapy. According to the abstract, the ORR was 18% in the olaparib arm versus 6% with chemotherapy. The median duration of response (DoR) and progression-free survival (PFS) were similar between the 2 arms.

“It is a small study with 67 [patients] receiving olaparib and 33 on chemotherapy. The DoR was similar between the 2 arms, and they basically concluded that they saw olaparib showed a favorable response in platinum-resistant ovarian cancer compared to chemotherapy, including in the wild-type patients. This relatively small study was able to suggest single-agent olaparib might actually be useful in platinum-resistant disease.”

Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial.

“This is a randomized phase III trial looking at single-agent olaparib versus chemotherapy specifically in germline mutated BRCA patients. Patients were randomized 2:1 to olaparib versus chemotherapy that could have been paclitaxel, topotecan, gemcitabine, or pegylated liposomal doxorubicin. This study has 266 patients and was specifically in the BRCA-mutated population,” said Markman.

The SOLO3 trial had a primary endpoint of ORR, with secondary endpoints including PFS and safety. Of the 266 patients randomized to either olaparib or chemotherapy, the ORR was 72% versus 51%, respectively. In addition, the PFS was 13.4 months versus 9.2 months. Investigators concluded this PARP inhibitor led to a significant and clinically relevant improvement in ORR and PFS in this patient population with no additional safety signals.

“Bottom line here is that patients who had germline mutations and received olaparib had an improvement in ORR and PFS compared to chemotherapy,” said Markman. “They did show hazard ratio and PFS by independent review; the PFS was 13.4 months versus 9.2 months and the median hazard ratio of 0.62 favoring olaparib. This an important study.”

Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24.

“This small study [enrolled] 97 patients, 48 randomized to niraparib (Zejula) alone and 49 randomized to combination [niraparib plus] bevacizumab (Avastin),” Markman said. “The idea was to look at a nonchemotherapy-containing regimen. This trial demonstrated that compared to niraparib alone, the use of niraparib plus bevacizumab significantly improved PFS. Median PFS was 11.9 months versus 5.5 months with the single agent; the hazard ratio was 0.35.”

This randomized, open-label phase II trial had a primary endpoint of PFS; 97 patients with platinum-resistant ovarian cancer were randomized to receive either single-agent niraparib or the combination of niraparib plus bevacizumab. The PFS was significantly improved in the combination arm while there was also no difference in treatment-emergent grade 3 or 4 adverse events (AEs) besides hypertension, seen in 26.5% of patients with the combination versus 0% with the monotherapy.

“The problem here is that they didn’t have a chemotherapy control. Although bevacizumab plus niraparib demonstrated improvement in PFS compared to niraparib, we don’t know what it would have done compared to chemotherapy. That’s my criticism on this study,” said Markman.

Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta-analysis (NMA).

“This is actually an attempt to compare the relative benefits of bevacizumab and PARP inhibitors in ovarian cancer. They concluded, as 1 would expect, that in the BRCA-mutated patients, PARP inhibitors were substantially better than bevacizumab,” said Markman.

This meta-analysis compared the 1563 patients with platinum-sensitive recurrent ovarian cancer who were treated with bevacizumab to 1839 patients treated with a PARP inhibitor as a maintenance therapy. Overall, the analysis showed an improvement in PFS for patients in the PARP arm. However, in those patients harboring a BRCA mutation, the PARP inhibitor induced an event higher PFS compared to bevacizumab.

“They also compared bevacizumab to chemotherapy alone, but we already had those trials showing us bevacizumab compared directly to chemotherapy. It’s the PARP inhibitors versus bevacizumab that is of interest. I think these are some interesting data to support the argument that in the mutated BRCA patients, if you are using bevacizumab, it’s not unreasonable to switch to a PARP. If the patient is wild-type, there is no reason to switch, though, as the data do not suggest any favoring there,” Markman concluded.
 

Lung Cancer

 
H. Jack West, MD
H. Jack West, MD

Randomized phase II study of adjuvant afatinib for three months versus two years in patients with resected stage I-III EGFR mutant NSCLC.

“Looking at a short course of 3 months to 2 years of adjuvant afatinib (Gilotrif) in patients who have undergone surgery for EGFR mutation-positive stage I/II/III non–small cell lung cancer (NSCLC), I think we will be looking at what’s currently a very active question,” said H. Jack West, MD, director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington, “the question of should we be giving adjuvant targeted therapy to people who have a driver mutation. Does it impact overall survival (OS)? More importantly, how longitudinally feasible is it, and how much is necessary?”

Patients with completed resected stage I, II, or III NSCLC with an EGFR mutation were randomized to receive either 3 months or 2 years of adjuvant afatinib, starting with an oral dose of 30 mg daily and increased to 40 mg after 28 days with toxicity. Overall, only 46 patients were accrued. At a median follow-up of 38 months, there were 10 recurrences and 3 deaths in the 3-month arm compared to 5 recurrences and 2 deaths in the 2-year arm.

In conclusion, recurrences at 2 years were 14% less common in patients who received afatinib for 2 years versus 3 months, and the study did not meet its primary endpoint. However, failure to meet significance could have been influenced by both the low accrual and early drug discontinuation.

“This will be instructive just for giving us a glimpse of if it is possible we are eradicating disease after giving [afatinib] for just a few months or if it is just suppressive,” West concluded.

RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC).

“This is largely looking at a question we have been intrigued by before for EGFR-positive patients, which is whether there is benefit to adding a VEGFR antagonist therapy to EGFR TKI (tyrosine kinase inhibitor) therapy. This trial is with ramucirumab (Cyramza) plus placebo added to erlotinib (Tarceva) as first-line treatment for these patients,” said West.

Overall, 449 patients were randomized between the 2 arms of erlotinib plus either ramucirumab or placebo. The primary endpoint was investigator-assessed PFS. Patients in the erlotinib plus ramucirumab arm experienced a significantly prolonged PFS, as well as duration of response and PFS2.

“What we have seen historically with these patients is we get an improvement in PFS but not necessarily OS, so it hasn’t changed practice yet. It certainly has improved in PFS as a signal, so it’s still considered an interesting approach.”

Randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine /cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small-cell lung cancer (Ns-NSCLC): The JIPANG study.

“This is a trial of interest in the adjuvant setting, comparing 2 different regimens: pemetrexed (Alimta) and cisplatin versus vinorelbine (Navelbine) plus cisplatin. That’s for patients with stage II–IIIA nonsquamous NSCLC,” said West.

In the phase III JIPANG trial, 804 patients were randomized to either 1 of the 2 treatments; 784 patients were evaluated for efficacy. At a median follow-up of 45.2 months, the median recurrence-free survival (RFS) was 38.9 months in the pemetrexed/cisplatin arm compared to 37.3 months, and the OS at 3 years was 83.5% versus 87.2%, respectively.

“I think we have our favored regimens in the adjuvant setting, but we largely consider them interchangeable. I think we are taking a closer look with this trial at whether there are incremental benefits to 1 regimen over the other,” said West.

Although this trial did not meet its primary endpoint, both regimens had similar efficacy, but the pemetrexed/cisplatin arm had a better tolerability as postoperative adjuvant chemotherapy. In addition, a significant correlation was found for RFS between treatment and EGFR mutation status.

Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001.

“A poster will be presenting the 5-year data from the KEYNOTE-001 trial, which is a phase I largely expanded trial of nearly 500 patients,” West said. “[These] patients were mostly previously treated with pembrolizumab. [We] will see 5-year outcomes in a setting where we would have expected almost every patient to have died. It’s going to give us some new information.”

The open-label, phase I KEYNOTE-001 trial investigated the role of pembrolizumab in treatment-naïve or previously treated patients with locally advanced or metastatic NSCLC. This poster presentation will share the 5-year OS outcomes.

“Although checkpoint inhibitors have been around for years, we know they have activity to improve survival in the short-term. Getting a clearer idea of if it is possible long-term is really going to add something. There is a lot of interest in seeing how sustained some of these responses can be,” West concluded.
 

Genitourinary Cancers

 
Sumanta Kumar Pal, MD
Sumanta Kumar Pal, MD

Biomarker analyses from JAVELIN Renal 101: Avelumab + Axitinib versus sunitinib in advanced RCC

“This is exciting biomarker data from the JAVELIN Renal 101 study,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope. “This is a trial looking at patients with metastatic kidney cancer. It’s a targeted therapy with an immunotherapy. That trial was positive, and there’s going to be some biomarker data at the meeting that may shed some light on who the most appropriate candidates for treatment are.”

The JAVELIN Renal 101 is a phase III trial for patients with previously untreated advanced renal cell carcinoma (RCC). Patients demonstrated a PFS benefit and higher ORR with the avelumab (Bavencio) plus axitinib (Inlyta) combination compared to sunitinib (Sutent). In this study, efficacy was correlated with the results of a molecular analysis from tissue samples in all 886 patients.

“That trial was positive, and there’s going to be some biomarker data at the meeting now that may shed some light on who the most appropriate candidates for treatment are. I think that will be quite helpful.”

The findings from this study have defined molecular features associated with therapy-specific outcomes for the frontline treatment of patients with advanced RCC. This may help in determining the right treatment strategies for the right patients in the future.

CALGB 90601 (Alliance): Randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma. 

“This is a trial we have been waiting a long time for. This study will shed some light on whether or not bevacizumab will be useful in combination with gemcitabine/cisplatin in patients with advanced bladder cancer. I think this will be an important study,” said Pal.

In this phase III trial, 506 patients were randomized to receive gemcitabine and cisplatin plus either bevacizumab or placebo. The median OS was 14.5 months in patients treated with bevacizumab compared to 14.3 months with placebo after median follow-up of 46.2 months. Grade 3 or higher AEs were more common in the bevacizumab arm at a rate of 83.5% versus 80.7% for placebo.

The addition of this agent did not appear to improve survival as per the primary endpoint, but these data were consistent with OS rates of prior phase III trials for cisplatin-based chemotherapy regimens.

First results from TITAN: A phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).

This phase III double-blind, randomized trial investigated whether a next-generation androgen receptor inhibitor, apalutamide (Erleada), could improve radiographic PFS and OS in patients with mCSPC when combined with ADT. In total, 525 patients were randomized to receive either apalutamide or placebo, regardless of the extent of disease.

“They demonstrate significant benefit in the setting of mCSPC; it’s really the first-time we are seeing benefit in that particular setting,” Pal noted.

The addition of apalutamide significantly improved both the radiographic PFS and the OS, while also demonstrating a tolerable toxicity profile. These data support the use of this therapy in addition to ADT for patients with mCSPC.
 

Gastrointestinal Cancers

 
Mark A. Lewis, MD
Mark A. Lewis, MD

Olaparib as maintenance therapy following first-line platinum-based chemotherapy (PBC) in patients with a germline BRCAmutation and metastatic pancreatic cancer: phase III POLO trial

In the phase III POLO trial, PARP inhibitor olaparib is investigated as a maintenance therapy option following frontline treatment with a platinum-based chemotherapy regimen in patients with BRCA-mutated metastatic pancreatic cancer.

“The one I’m really excited about is the plenary session, which is embargoed. I have nothing else to tell you except that I am intrigued and I’m hopeful they aren’t putting it up as plenary for no finding,” said Mark A. Lewis, MD, of Intermountain Healthcare. “There’s a lot of interest in pancreas cancer this year because a lot of people felt that last year, pancreas cancer didn’t get enough attention. Pancreatic cancer is colloquially known as a very deadly disease that has been hard to make progress in.”

“I think this is timely because it’s really become the standard of care to check all pancreatic patients for the BRCA mutation. That’s now a formal recommendation from the NCCN, so I think that is going to fit in nicely if indeed there is going to be a new treatment recommended for BRCA-mutated tumors. That’s actually going to be meaningful for a group of patients that may have fallen under the radar. BRCA is traditionally associated with breast and ovarian cancer, but I think it’s important for public awareness forpeople to know BRCA can be a driver mutation and that pancreas cancer should be a tumor associated with BRCA,” said Lewis.

NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC) – 1st experimental arm (EA) initial results.

“We’re just hitting the tip of the iceberg in the changing of our understanding of rectal cancer. In GI oncology, I often think of rectal cancer as the most inherently multidisciplinary cancer. I honestly don’t think that the care of the person with locally advanced rectal cancer is complete or appropriate until it involves a surgeon, a radiation oncologist, and a medical oncologist,” said Lewis.

“We have known for a while that getting chemotherapy to sensitize the radiation improves outcomes in terms of reducing local recurrence and also in protecting, to some degree, against distant metastases,” Lewis added. “This abstract is part of the ongoing study of total neoadjuvant therapy (TNT) where patients with bulky, locally advanced tumors are going to get all of their treatment, systemic chemotherapy followed by radiation and then surgery in that order, so there is no role for neoadjuvant therapy.”

This phase II trial looked at 178 patients with locally advanced rectal cancer; patients were randomized to receive a TNT including neoadjuvant FOLFOX, radiation and chemotherapy of capecitabine (Xeloda) with or without the PARP inhibitor veliparib (ABT-888), followed by surgery. Results showed that the addition of veliparib was safe with no unexpected short-term toxicities. However, this failed to improve the neoadjuvant rectal cancer score.

“What I find interesting about this abstract that other people might look at as a negative study is that this is really our first glimpse of outcomes. This is just our first sighting of more findings to come from this trial. It’s like a ‘stay tuned’ abstract, and we will see what the formal presentation tells us.”

APACT: phase III, multicenter, international, open-label, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma

“A lot of oncologists felt like last year the PRODIGE 24 study got slighted and should have been a plenary presentation because it showed us the longest ever survival reported after surgery for pancreas cancer. I feel like this abstract this year may partly be readdressing that balance with a new study looking at the doublet gemcitabine and paclitaxel,” Lewis said.

The phase III APACT trial randomized 866 treatment-naïve patients with metastatic pancreatic cancer to either paclitaxel plus gemcitabine or gemcitabine alone. The primary endpoint was disease-free survival (DFS), which was not significantly longer in the experimental arm. However, DFS by investigator (sensitivity analysis) and interim OS were improved with the combination regimen as compared to gemcitabine alone.

“At least by independent review, disease-free survival didn’t actually seem any better for that doublet over gemcitabine alone. The authors are taking a very optimistic view of the OS benefit in that this is progress; we don’t have the final analysis yet, but I think any improvement that we can make in pancreatic cancer is desirable. I’m quite curious to see what’s to come.”

Results of KEYNOTE-240: phase 3 study of pembrolizumab vs best supportive care (BSC) for second-line therapy in advanced hepatocellular carcinoma (HCC).

The phase III KEYNOTE-240 followed the phase II KEYNOTE-224 in which patients with advanced hepatocellular carcinoma (HCC) received pembrolizumab (Keytruda) as a second-line therapy. In the phase III trial, 413 patients were randomized to either pembrolizumab or placebo. Primary endpoints were OS and PFS, which were both improved by pembrolizumab. However, the results were not statistically significant.

“This trial is interesting because it’s negative, in my opinion. This is a little bit of a cautionary tale of what happens when you shift from phase II work to phase III. Pembrolizumab had looked very promising in the second-line setting of HCC in KEYNOTE-224, but this is a follow-up phase III trial where pembrolizumab was compared to placebo. There was a response signal probably around what you would expect for immunotherapy in the high teens, but it did not meet their quite stringent, prespecified mark of statistical significance for improved survival,” Lewis said.

“I think a lot of people are going to find this disappointing because, just like pancreas cancer, liver cancer is a disease that until recently had a dearth of treatment options. There has been a promising explosion of drugs in this space, but none of them are having the survival benefit we were hoping. I think a lot of people pinned their hopes on immunotherapy. In this particular patient population, pembrolizumab didn’t quite pan out the way a lot of us had hoped,” Lewis concluded.

Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (CARC) (Alliance A021202).

“The neuroendocrine tumors (NETs), until a decade ago, really had a scant number of treatments,” Lewis said. “Thankfully in the last few years we have had a relative increase of options, including TKIs. This study looks at low- to intermediate-grade NETs that are progressing radiographically within a year of enrollment on this study. This was looking at pazopanib versus placebo.”

This multicenter, randomized, double-blind phase II trial enrolled 171 patients with progressive carcinoid tumors. The primary endpoint was PFS, in addition to secondary endpoints of OS, ORR, and safety. The median PFS was 11.6 months in the arm that received pazopanib versus 8.5 months in those who received placebo. The OS was 41 months versus 42 months, respectively.

“I think there was a modest but real benefit in PFS. The principal investigator promised to discuss response rates at the ASCO meeting, which I think will be interesting. In the meantime, I think this is evidence that there are other treatment pathways and biology that we can exploit in NETs,” Lewis said.
 

Precision Medicine 

 
Vivek Subbiah, MD
Vivek Subbiah, MD

Identification of targetable molecular alterations in the NCI-COG Pediatric MATCH trial

“What we have seen now was supported by almost 25% of patients in the NCI-COG Pediatric MATCH trial,” said Subbiah. This trial aimed to determine whether precision medicine would be beneficial to pediatric patients with cancer.

Patients between the ages of 1 and 21 years old with treatment-refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders were investigated in this study; patients were screened for targetable alterations and directed toward a treatment able to target that specific alteration.

The trial included 2 steps; investigators aimed to first find if patients could be matched to targeted therapies based on their molecular alterations. Second, they tested how effective the targeted therapies would be in this set of pediatric patients.

“This is pretty exciting for the pediatric oncology world. This opens up the doors for precision oncology in pediatrics.”

Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.

“This is an early phase II that showed several responses across tumor types in pediatric patients. The medicine seems to be tolerated pretty well. A total of 12 patients had an objective response, meaning the tumor shrank or disappeared with entrectinib (Ignyta) with a median treatment duration of 208 days,” said Subbiah.

Pediatric and young adult patients 20 years or younger with recurrent/refractory solid tumors were enrolled on the trial to receive entrectinib; patients were recommended to disease-specific expansion cohorts of CNS and solid tumors harboring NTRK1/2/3, ROS1, or ALK aberrations, and neuroblastoma. This drug was well tolerated among the 28 patients evaluated for response.

“We have many drugs that are now working in children, especially in precision oncology. It’s very encouraging.”

Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial.

“This is an ATR kinase inhibitor. That is interesting. Small cell lung cancer (SCLC) has always been a challenge, so this is a trial with an agent called lurbinectedin.”

This is a multicenter phase II basket trial investigating the safety and efficacy of lurbinectedin in SCLC with a primary endpoint of confirmed ORR by RECIST v.1.1 criteria. Overall, 105 patients with an ECOG status of 0-2 who had received 1 prior line of chemotherapy received lurbinectedin treatment.

Lurbinectedin is active in the second-line setting for patients with SCLC in both resistant and sensitive disease, according to investigators. The toxicity profile was manageable, demonstrating its potential as a new agent for this patient population.

“That is exciting because for the first time in a long time, we have something that is not a chemotherapy drug that is working in SCLC,” said Subbiah.

ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS).

“Another session I am really looking forward to is the plenary session for sarcoma,” said Subbiah. “It’s a late-breaking abstract, so the final data are not out yet. Earlier in a press release, however, they had eluded that the trial was negative, and the FDA withdrew the previous approval for this drug.”

This is a randomized double-blind phase III trial investigating doxorubicin plus olaratumab compared to doxorubicin plus placebo in patients with advanced soft tissue sarcoma (STS).

“This has implications in STS, but this is surprisingly the plenary session. It’s very important for investigators involved in the study and the patients that were enrolled on the clinical trial; it’s important to showcase the negative studies as well as positive studies at a meeting like ASCO,” Subbiah concluded.
 

Breast Cancer

 
Matteo Lambertini, MD, PhD
Matteo Lambertini, MD, PhD
Safety of pregnancy following breast cancer (BC) in patients (pts) carrying a BRCA mutation (mBRCA): Results of an international cohort study.
 
“This abstract addresses a very important and unmet medical need: future conception in BRCA-mutated breast cancer survivors, including maternal safety and pregnancy outcomes, risk of congenital malformations, and breastfeeding patterns,” said Matteo Lambertini, MD, PhD, lead author and medical oncologist at the Ospedale Policlinico San Martino and adjunct professor at the University of Genova. “Concerns around this topic are particularly important for [patients with] BRCA-mutated breast cancer considering the lack of evidence before this study to properly counsel these women.”
 
In this international retrospective analysis, 1252 patients with metastatic breast cancer with the BRCA mutation were included from 30 centers. Following their breast cancer diagnosis, 195 patients had a pregnancy after a 4.5-year range. Among the 150 patients who conceived, 13 (11.6%) and 2 (1.8%) experienced pregnancy complications and congenital anomalies, respectively.
 
“Results from this large study are of paramount importance for counseling young patients with BRCA-mutated breast cancer inquiring about the feasibility and safety of future conception. The study showed that pregnancy after breast cancer in women carrying a germline BRCAmutation does not appear to worsen fetal outcomes or maternal prognosis, thus providing reassurance to BRCA-mutated breast cancer patients interested in future family planning. Main take-home message is that, after adequate treatment and follow-up, this study provides solid data not to contraindicate anymore pregnancy after breast cancer also among BRCA-mutated patients,” said Lambertini.
 
A randomized phase II study of palbociclib plus exemestane with GNRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer (KCSG-BR 15-10, CT02592746).
 
In a prospective, 2-arm randomized, multicenter, open-label phase II study, 184 patients were randomly assigned to receive chemotherapy or endocrine therapy exemestane (Aromasin) with palbociclib (Ibrance). The combination showed clinical benefit in terms of PFS compared to chemotherapy in patients with premenopausal estrogen receptor (ER)–positive metastatic breast cancer.
 
“This important study (and very difficult trial to be conducted) addresses a very relevant medical question for everyday clinical practice: the need to prefer chemotherapy or the possibility to postpone it after endocrine therapy in women with advanced hormone receptor–positive disease,” said Lambertini. “The study showed that the combination of endocrine therapy plus CDK 4/6 inhibitors (palbociclib [Ibrance] plus exemestane) was superior to single agent chemotherapy (capecitabine). Hence, the study results confirm and reinforce the current indication of all major guidelines that, in the absence of visceral crisis, endocrine therapy should be always the preferred approach in women with advanced hormone receptor-positive disease.”
 
Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: overall survival (OS) results.
 
“Convincing overall survival data from the trials of CDK4/6 inhibitors and endocrine therapy are very much awaited considering the concerns of whether the important benefit in progression-free survival observed in all the trials translates into an overall survival benefit,” said Lambertini. “The results from this randomized phase III trial are not yet available (this is a late-breaking abstract); nevertheless, they would be of crucial importance if they show for the first time a clear and significant improvement in OS with the combination of a CDK4/6 inhibitor with endocrine therapy in patients with metastatic hormone receptor–positive/HER2-negative disease in the first-line endocrine-sensitive setting.”
 
“In this case, these results would strongly suggest once again that the combination of CDK4/6 inhibitor and endocrine therapy should become widely available for women with metastatic hormone receptor–positive disease. A better understanding on how to optimize the sequencing of the available treatment options and the identification of patients who may benefit from endocrine therapy alone should be considered research priority in this setting,” Lambertini said.
 
SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx).
 
“Despite the availability of very effective anti-HER2 targeted therapies for women with HER2-positive metastatic disease (including dual blockade with pertuzumab and trastuzumab, and T-DM1), treatment resistance occurs,” Lambertini said. “Therefore, additional active treatment options in the later lines are urgently needed also considering that patients with HER2-positive metastatic disease have long survival and tend to receive several lines of treatment in the advanced setting.”
 
The randomized, open-label phase III SOPHIA trial randomized patients with HER2-positive metastatic breast cancer 1:1 to chemotherapy with either margetuximab or trastuzumab (Herceptin). Overall, patients in the margetuximab arm saw an improvement in PFS with comparable safety. Median PFS was 5.8 months in the margetuximab arm versus 4.0 months in the trastuzumab arm.

“The SOPHIA trial shows very convincing data on this regard with the use of margetuximab plus chemotherapy in pre-treated patients with HER2-positive metastatic disease that showed to be superior to our current standard of care in this setting (trastuzumab plus chemotherapy). Notably, the research in this area remains very active with several other important compounds that have already shown promising preliminary data for the treatment of these patients,” Lambertini added.
 
Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: A randomized, phase III study of the Gruppo Italiano Mammella (GIM).
 
“Patients with hormone receptor–positive early-stage breast cancer remain at high risk of late recurrence beyond the first 5 years after diagnosis. It is known that extended endocrine therapy with an aromatase inhibitor after initial 5 years of tamoxifen improves their disease-free survival. However, it remains controversial the benefit of extended endocrine therapy in patients that receive aromatase inhibitor in the first 5 years,” said Lambertini. “The GIM4 trial addressed this question and showed that extended adjuvant aromatase inhibitor with letrozole (Femara) after 5 years of sequential tamoxifen plus aromatase inhibitor improves disease-free survival.”
 
The GIM4 LEAD was a prospective randomized multicenter trial in Italy. From August 2005 to May 2010, 2065 patients were randomized to receive either 2-3 years or 5 years of letrozole.
 
“These results, in line with prior findings, suggest that tamoxifen for 2 to 3 years followed by an aromatase inhibitor for 5 to 6 years can be considered a proper strategy of extended endocrine treatment in postmenopausal breast cancer patients at residual risk of recurrence,” Lambertini concluded.
 

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