A combined attack on hepatocellular carcinoma (HCC) with the PD-L1 inhibitor atezolizumab (Tecentriq) plus the anti-VEGF monoclonal antibody bevacizumab (Avastin) resulted in clinically meaningful and durable objective responses as first-line therapy for patients with previously untreated, unresectable disease, according to findings presented at the 2019 International Liver Cancer Association Annual Conference.

The results of the phase IB GO30140 study may provide patients in this setting with a new treatment option, investigator Kyung-Hun Lee, MD, said in reporting the f indings. He said the regimen was well tolerated.

Approximately 80% of patients with HCC present with unresectable cancer requiring treatment with therapies other than surgery. Receptor tyrosine kinase inhibitors that inhibit VEGF are the first-line systemic standard of care for patients with unresectable or metastatic HCC. These are associated with modest survival benefits but considerable toxicities. A phase III noninferiority trial demonstrated unconfirmed overall response rates per RECIST 1.1 criteria of 18.8% for lenvatinib (Lenvima) and 6.5% for sorafenib (Nexavar).

In randomized studies, single-agent PD-L1/ PD-1 immune checkpoint inhibitors have shown clinical activity against HCC but not superiority over standards of care, noted Lee, of the Department of Hemato Oncology, Medical Oncology Center, Seoul National University Hospital, South Korea.

“Many HCC tumors are hypervascularized and overexpress VEGF and PD-L1, and we know that the anti-VEGF monoclonal antibody bevacizumab has shown modest single-agent activity in HCC,” said Lee. “In addition to antiangiogenic activity, bevacizumab also showed immunomodulatory effects. We also know that PD-L1 with VEGF has shown clinical benefit in other tumor types.”

GO30140 (NCT02715531) included cohorts for patients with HCC, gastric, pancreatic, and esophageal cancers. Eligibility included measurable disease assessed per RECIST 1.1 criteria, EGOG performance status of 0 or 1, and adequate hematologic and organ function. Patients with HCC were required to have metastatic or unresectable disease and no prior systemic therapy.

Arm A, the HCC study arm, enrolled 104 patients with unresectable HCC with a ChildPugh score up to B7. Patients were given atezolizumab 1200 mg intravenously every 3 weeks plus bevacizumab 15 mg/kg intravenously every 3 weeks.

The primary endpoints in arm A were treatment safety and independent review facility (IRF)—assessed objective response rate (ORR) per RECIST 1.1 criteria. Key secondary endpoints included duration of response (DOR) and progression-free survival (PFS) per IRF RECIST, ORR, DOR, and PFS per IRF HCC modified RECIST criteria (HCC mRECIST). Lee said data on some key secondary endpoints will be available at upcoming conferences.

The majority of patients enrolled were male (81%) with a median age of 62 and 57% from Asia, excluding Japan. Forty-nine percent of patients had hepatitis B, and 30% had hepatitis C. Extrahepatic spread or macrovascular invasion was present in 88% of patients.

In the study arm, 36% of patients had a confirmed ORR, with 12% of patients achieving complete response. “We had duration response with this study ranging from 1.6 months to 31.0 months. More than half of the patients [54%] enjoyed a duration of response of more than 9.0 months,” said Lee.

He said that DOR was consistent across analyses: HCC mRECIST (61% of patients) and investigator (INV)—assessed RECIST (62%). In addition, 76% of responses per IRF-assessed RECIST 1.1 are ongoing, and the median duration of response was not reached, noted Lee.

The combination of atezolizumab and bevacizumab resulted in a median PFS also consistent across the 3 analyses: Both RECIST and HCC mRECIST showed 66% of patients with a median PFS of 7.3 months. INV RECIST showed 72% of patients with a median PFS of 7.4 months. Median overall survival, measured by HCC mRECIST, was 17.1 months, with a 6-month overall survival rate of 82% and a 12-month OS of 63%.

“The benefits of atezolizumab and bevacizumab were generally consistent among patient subgroups, with clinical activity observed irrespective of PD-L1 status,” said Lee.

Median treatment duration was 8.3 months on atezolizumab and 8.2 months on bevacizumab. Eighty-eight percent of patients experienced any-grade treatment-related adverse events (TRAEs), with 39% having grade 3/4 TRAEs and 3% having grade 5. The most common AEs were proteinuria (37%), decreased appetite (35%) and fatigue (28%). The most common grade 3/4 AE was hypertension (14%), Lee noted. In addition, 24% of patients had serious TRAEs, including pyrexia (5%), cholangitis (3%), and upper gastrointestinal hemorrhage (3%).

The most common AE of special interest (AESI) related to atezolizumab was rash (23%), and the most common AESI related to bevacizumab was proteinuria (37%). Grade 3/4 bleeding AESIs associated with bevacizumab included 2% of patients with upper gastrointestinal bleeding and 2% of patients with esophageal varices hemorrhage.

“Fifteen patients [14%] required systemic corticosteroids within 30 days of experiencing an adverse event on atezolizumab,” said Lee. Increased aspartate aminotransferase and alanine aminotransferase levels (3% of patients each) were the most common hepatic events requiring systemic steroids within 30 days of an AE. No new safety signals were identified beyond the established single-agent safety profiles, said Lee.

“In conclusion, this combination of atezolizumab and bevacizumab may become a promising treatment option for patients with unresectable HCC,” said Lee. Investigators are further evaluating the combination in the IMbrave150 phase III study (NCT03434379).

Lee KH, Ryoo BY, Hsu C-H, et al. Phase IB study results: safety and efficacy of atezolizumab + bevacizumab versus atezolizumab in patients with previously untreated, unresectable, or advanced hepatocellular carcinoma. Presented at: 13th Annual Conferences of the International Liver Cancer Association; September 20-22, 2019; Chicago, IL. Abstract 0-32. ilca-online.org/wp-content/uploads/2019/09/ABSTRACTS-2019-min.pdf

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. 

. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.

Articles

Atezolizumab (Tecentriq) plus bevacizumab (Avastin) resulted in clinically meaningful and durable objective responses as first-line therapy for patients with previously untreated, unresectable disease.

Early Findings Support Novel Regimen for Unresectable HCC

Using dual checkpoint inhibitors in patients with hepatocellular carcinoma (HCC) is demonstrating activity with a manageable safety profile in both second-line and perioperative settings, according to findings presented at the International Liver Cancer Association Annual Conference (ILCA 2019).

In updated data from the CheckMate-040 study, the combination of nivolumab (Opdivo), a PD-1 inhibitor, plus ipilimumab (Yervoy), a CTLA-4 inhibitor, demonstrated a favorable benefit—risk profile in patients previously treated with sorafenib (Nexavar).

 In patients with resectable HCC, use of the combination before surgery was associated with a pathologic complete response (pCR) rate of 29% in a phase II study.

The findings add to the growing body of data about the immunotherapy duo, which has been approved for patients with unresectable or metastatic melanoma; intermediate- or poor-risk, previously untreated renal cell carcinoma; and microsatellite instability—high or mismatch repair deficient metastatic colorectal cancer that has progressed after chemotherapy. In HCC, nivolumab monotherapy is approved for patients who have been previously treated with sorafenib.

CheckMate-040 Findings in Advanced Disease

In advanced, unresectable, or progressive HCC, the first findings from CheckMate 040 were presented at the 2019 American Society of Clinical Oncology Annual Meeting (

). Further analysis of the results indicated that the combination can also yield a favorable safety profile, said Anthony B. El-Khoueiry, MD, in his presentation at ILCA 2019, held September 20 to 22 in Chicago, Illinois.

Investigators focused on the primary endpoints of safety and tolerability using National Cancer Institute Common Terminology Criteria for Adverse Events. They reported results for 148 patients with advanced HCC who had previously been treated with first-line therapy with sorafenib, were sorafenib intolerant, or had disease progression after sorafenib.

Patients were randomized 1:1:1 between 3 arms with different dosing combinations and schedules until unacceptable intolerability or disease progression. Fifty patients in arm A were given 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for 4 cycles. Forty-nine patients in arm B received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks times 4. Patients in both of these arms were then given nivolumab 240 mg intravenously as a flat dose every 2 weeks. Forty-nine patients in arm C received just nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks.

The majority of patients—88%, 85%, and 79% in arms A, B, and C, respectively&mdash;had discontinued sorafenib due to disease progression. Also, most patients across the treatment arms had either hepatitis B or C virus (74%-82%).

The median follow-up across all 3 arms was 31 months. As is the nature with systemic therapies and HCC, disease progression halted treatment. It was the most common reason for treatment discontinuation in all 3 arms, occuring among 51% of patients in arm A versus 69% in both B and C.

In contrast, arm A, with the higher dose of ipilimumab, had 22% of patients discontinue treatment due to toxicity versus 6% in B and 2% in C. Despite the higher toxicity, arm A had the longest median duration of therapy, with patients lasting 5.1 months on therapy, compared with 2.3 months and 4 months for arms B and C, respectively.

“This may be associated with the efficacy seen in that arm,” said El-Khoueiry, associate professor of clinical medicine in the Division of Medical Oncology and director of the phase I drug development clinical program at Keck Medicine of the University of Southern California (USC), as well as medical director of the Clinical Investigations Support Office at the USC Norris Comprehensive Cancer Center, both in Los Angeles.

The objective response rate was 31% in arms B and C and 32% in A. Arm A had the highest pCR rate, at 8%, versus 6% in B and 0% in C. Partial responses were achieved by 24% of patients in arm A, 24% in B, and 31% in C.

“The greatest survival benefit was also observed in arm A, with a median overall survival [OS] of 22.8 months and the highest OS rate of 44% through 30 months,” El-Khoueiry said. The median OS in arm B was 12.5 months; in arm C, 12.7 months. The median durations of response were 17.5, 22.2, and 16.6 months in arms A, B, and C, respectively.

In terms of treatment-related adverse events (TRAEs), El-Khoueiry said the data brought no surprises. “It’s similar to what’s seen in other tumor types,” he said. The most common TRAEs involved skin and subcutaneous tissue, investigations (including liver laboratory abnormalities), general and administration site events, gastrointestinal events, and endocrine-related effects.

“Although rates of any-grade TRAEs were higher in arm A [94%], the types of TRAEs observed were similar across treatment arms. No new safety signals were observed, and most TRAEs were manageable and reversible,” El-Khoueiry said.

Overall, the incidence of grade 3/4 TRAEs was also higher in arm A, at 53%, compared with 29% in arm B and 31% in C. Among hepatic investigations, the most common abnormalities were increased aspartate aminotransferase  (AST) and alanine aminotransferase (ALT).

“There were several serious events, 4 of which were hepatic related and required steroid therapy,” El-Khoueiry said. “None of the hepatic events required anything besides corticosteroids.”

Five patients experienced hepatobiliary events: 3 in arm A, 1 in B, and 1 in C. Of these, 4 patients—2 each in A and B&mdash;had to discontinue their therapy. “The patient labeled as ‘drug-induced liver injury’ was labeled as such by the investigator. However, that patient did not meet the protocol prespecified; specifically, the patient did not have a bilirubin above the upper limits of normal,” El-Khoueiry said.

Select hepatic events were also reported in 27% of patients in arm A versus 24% in B and 17% in C. Among all select TRAEs, systemic corticosteroids were used to treat 51% of patients in arm A, 24% in B, and 23% in C. With the exception of endocrine events, the vast majority of select TRAEs were resolved across all arms.

The study also looked at immune-mediated adverse events (imAEs), a subset of select TRAEs, in which patients had to be placed on either immunosuppressive agents or other corticosteroids. These events could have happened up to 100 days after the last dose of therapy, El-Khoueiry said. The most common imAEs were rash, hepatitis, adrenal insufficiency, diarrhea/colitis, and pneumonitis. As expected, these were more common in arm A, specifically for hepatitis, he said, which occurred in 10 patients versus 5 in B and 3 in C.

Ninety percent of imAEs resolved. Of the 10 patients in arm A who had hepatitis, 7 received glucocorticoids for a median of 2 weeks. Of patients experiencing hepatic adverse effects, roughly 60% to 70% were rechallenged across arms. “No patients experienced a recurrence of any category of imAEs upon rechallenge with either therapy,” El-Khoueiry said.

Across all arms and all organs—skin, endocrine, hepatitis&mdash;the median time to onset was short, between 3 and 8 weeks. “Generally, across tumor types, that’s going to happen in the first 3 to 5 months anyway,” El-Khoueiry said.

With hepatic events, the median time to onset was from 4.1 to 5.3 weeks. Resolution took 3.1 to 12 weeks, with similarly high rates of resolution among arms: 92% for arms A and B and 88% for C.

Table. Key Findings From CheckMate-040 Study

Given the favorable OS and risk profile of this combination, further investigation is warranted, El-Khoueiry said. The phase III CheckMate 9DW study will undertake the task of comparing nivolumab plus ipilimumab against the standard of care with either sorafenib or lenvatinib (Lenvima). The trial, which has not yet started recruiting patients, has a target enrollment of 1084 participants (NCT04039607).

In the first interim analysis of a phase II study, pCRs were seen in 29% of patients with resectable HCC treated with a perioperative immunotherapy regimen, Yehia I. Abugabal, MD, reported in a presentation at ILCA 2019. The randomized, open-label study evaluated nivolumab alone versus nivolumab plus ipilimumab.

“[Although] surgical resection is associated with a very high recurrence rate, we currently do not have any effective neoadjuvant or adjuvant therapy despite the fact that hepatocellular carcinoma is a very immunogenic tumor. In fact, low intratumoral CD8 T cells and ratio Teff:Treg cells [effector T cells:regulatory T cells] has been shown repeatedly to be related to a high incidence of recurrence and low survival after hepatocellular carcinoma resection,” said Abugabal, of The University of Texas MD Anderson Cancer Center in Houston. “Recently, PD-1 antagonists have shown significant activity in hepatocellular carcinoma and have been granted conditional approval.”

The study design was a randomized 1:1 trial of patients with resectable HCC, determined by surgeons as good candidates for either conservative hepatic resection or liver resection with curative intent. Thirty patients were expected to be enrolled and randomized between arms A and B. The primary endpoints were safety and tolerability, and the secondary endpoints included overall response rate and time until recurrence. Additional exploratory objectives focused on immunological/biomarker changes in the tumor tissue and peripheral blood.

Patients in arm A received neoadjuvant nivolumab alone at 240 mg intravenously (IV) every 2 weeks for 3 doses. Surgery took place at the 6-week mark, followed by adjuvant nivolumab starting at week 10 at 240 mg IV every 2 weeks until recurrence or up to 2 years. Surveillance, including imaging, blood samples, insulinlike growth factor-1 score, and magnetic resonance elastography, occurred every 12 weeks.

Arm B followed the same surgical timeline but with a neoadjuvant combination therapy of nivolumab 240 mg IV plus ipilimumab 1 mg/kg IV every 2 weeks for 3 doses. Adjuvant chemotherapy included nivolumab alone at 240 mg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for up to 2 years or until recurrence, with surveillance completed every 12 weeks.

Among 14 evaluable patients, 4 achieved a pCR, with a 50/50 split between the 2 study arms. One patient in each arm who achieved pCR had hepatitis C virus, 1 in the nivolumab-alone arm had hepatitis B virus, and 1 in the combination arm did not have hepatitis.

Two patients in arm A experienced grade 3 or higher TRAEs post operatively, including possible lipase and amylase increases. In arm B, 2 patients experienced grade 3 or higher events prior to surgery of possible increases in ALT/AST, and 1 had a grade 3 TRAE post operatively of definite colitis.

Treatment was deemed safe, and surgical resec-tion was not delayed. Just 1 patient did not undergo planned resection due to reasons that were unrelated to the study treatment.

Blood sampling and tumor sampling also took place prior to treatment, as well as prior to surgery. “Imaging showed that prior to surgery, the tumor looked very vascular, typical of HCC. At the time of surgery, there was no enhancement in the tumor,” Abugabal said.

“Further analysis identified very specific highly cytotoxic tumors in CD8 T cells,” he said. “These are a reflection of the activity of cytotoxic T cells.”

The observation of pCR was associated with a significant increase in 2 specific clusters of CD8 T cells and in the Teff:Treg ratio after therapy.

Two more patients have since been enrolled, Abugabal noted.

“After validation, the study may contribute to a paradigm shift in the perioperative treatment of resectable HCC,” he concluded.

El-Khoueiry AB, Hsu C, Kang YK, et al. Safety profile of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 40 study. Presented at: 2019 International Liver Cancer Association Annual Conference; September 20-22, 2019; Chicago, IL. Abstract O-13. ilca-online.org/wp-content/uploads/2019/09/ABSTRACTS-2019-min.pdf.

Kaseb AO, Carmagnani R, Vence LM, et al. Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC. Presented at: 2019 International Liver Cancer Association Annual Conference; September 20-22, 2019; Chicago, IL. Abstract O-02. ilca-online.org/wp-content/uploads/2019/09/ABSTRACTS-2019-min.pdf.

Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/125554s075lbl.pdf. Accessed October 1, 2019.

Yau T, Kang YK, Kim, TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. Poster presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Poster 4012. meetinglibrary.asco.org/record/173194/poster.

Using dual checkpoint inhibitors in patients with hepatocellular carcinoma is demonstrating activity with a manageable safety profile in both second-line and perioperative settings.

Immunotherapy Combo Shows Signs of Efficacy in 2 HCC Settings

While tomosynthesis has been described by the oncology community as one of the biggest improvements in breast cancer screening, the technology that renders 3D-like images of the breast does carry limitations. The implementation of tomosynthesis, however, has allowed for more accurate detection of breast cancers—especially in patients with dense breasts, explains Sarah M. Friedewald, MD, division chief, Breast and Women’s Imaging, and medical director, Lynn Sage Comprehensive Breast Cancer Center, Northwestern Memorial Hospital.

Additionally, tomosynthesis has proven to be useful in an era where radiologists are challenged by the ever-changing recommendations of when breast cancer screening should begin and the frequency of screening, she noted during a presentation at the 2016 Lynn Sage Breast Cancer Symposium.

Tomosynthesis makes the malignancy more apparent. Friedewald described tomosynthesis screening as visually “peeling back” the breast tissue and being able to dissect the image slice by slice. The number of images a tomosynthesis machine takes is based on the individual manufacturer recommendations, explained Friedewald, and not a radiologist’s decision. “For example, if a breast has a 5% compression, the tomosynthesis scan might result in 54 images; but not to be confused, there’s not 54 images of the breast taken for us to look at.”

Tomosynthesis received FDA approval in 2011. At the end of 2015, there was a 20% adoption rate in the United States, said Friedewald. In January 2015, Medicare approved it for use. As of June 2016, Cigna, one of the country’s largest insurers, approved it as a mammogram option because of the NCCN guidelines, said Friedewald. All of these factors led tomosynthesis to be adopted much more quickly than the adoption rate of digital over film.

What is commonly referred to as tomosynthesis screening is not actually just a 3D image alone, explained Friedewald, but actually combined data using both 2D and 3D images. The radiologist receives 3 sets of data from a tomosynthesis scan—the raw data, which are not used by most radiologists, a 2D scan, and the reconstituted 3D images, said Friedewald. The 3D images can be further dissected into 1 mm slices to distinguish abnormalities, she said.

There are numerous clinical data supporting the use of tomosynthesis, said Friedewald. It has been evaluated in 2 radiologist reader studies. In one study, every radiologist reading improved when tomosynthesis was added. These were the studies presented to the FDA that led to the approval of tomosynthesis.

In a retrospective analysis of 454,850 examinations at 13 different institutional sites that were early adopters of tomosynthesis, conducted by Friedewald and her team, there was a decrease in the overall rate of recall by a relative difference of 15%.

 There was also an increase of 41% in invasive cancer detection.

In the 13 sites, most moved from a decrease in recall rate to an increase in cancer detection with tomosythesis use, noted Friedewald. Only 2 sites went in the opposite direction. In one, the sample size was too small to be statistically significant, she concluded. The other site only had 6 months of use with tomosythesis, and Friedewald explained that there’s a learning curve with using tomosynthesis that may have contributed to that outcome.

Friedewald provided real life imaging examples of the benefits of tomosynthesis. In one example, tomosynthesis detected a bilateral invasive carcinoma that 2D imaging had missed. “If she had only had the 2D image, she would’ve been dismissed home and would come back in a year.” In another case, tomosynthesis differentiated that what appeared to be a speculated tissue was actually a blood vessel turn. With a 2D image, that may have led to further biopsy, noted Friedewald.

“Overall, with tomosynthesis, there’s an increase in cancer detection and a simultaneous decrease in recall,” said Friedewald of the technology’s major benefits.

Friedewald admitted that there are limitations to tomosynthesis. Of particular note, there are significant variabilities based on breast densities, said Friedewald. This is important, explained Friedewald, because women defined as having dense breasts can have either heterogeneously dense breast tissue or extreme dense breast tissue.

“Still more studies need to be done to recognize the benefits in each of those categories,” she argued.

“It isn’t perfect. A lot of people think tomosynthesis is the answer and that they don’t need to do anything else. That’s simply not true,” cautioned Friedewald. “There are some things

it misses but it’s still a big improvement over 2D alone.”

Friedewald provided examples of where an ultrasound after tomosynthesis imaging provided additional information the new technology had missed. In one case a large mass detected a year after the initial tomosynthesis screening showed no cause for concern.

Friedewald also cautioned against a limited use of tomosynthesis, for example 3D imaging with MLO view only, as more views may be needed to detect the widest range of abnormalities. “Some cancers are still only seen in one projection,” explained Friedewald.

Also, for all sites reporting on tomosynthesis use, there was no change in ductal carcinoma in situ detection with tomosynthesis, said Friedewald.

Perhaps the biggest plus for tomosynthesis is the role it plays in boosting the recommendation for annual mammograms, an area of continued controversy in the breast cancer care community. “With tomosynthesis, we are really able to drop that false-positive rate, which is part of the major concern with annual cancer screenings,” concluded Friedewald.

Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. 

In traditional, 2D mammography, Friedewald explained, there’s a high sensitivity on identifying invasive abnormalities in fatty breasts, but that sensitivity drops significantly in women with dense breast tissue, who account for half of the screening population. “2D mammography can hide an abnormality and it can also make it appear there’s a lesion there when it doesn’t really exist, resulting in false-negatives and recall,” said Friedewald.

While tomosynthesis has been described by the oncology community as one of the biggest improvements in breast cancer screening, the technology that renders 3D-like images of the breast does carry limitations.

Expert Discusses Importance of Tomosynthesis in Breast Cancer

PARP inhibitors still have a place in the treatment paradigm of triple-negative breast cancer (TNBC), but the role of these agents are significantly evolving, according to Patricia Mucci LoRusso, DO. 

The agents are part of potential treatment strategies against triple-negative tumors, which account for about 15% of all breast cancers in the United States, said LoRusso. Of these, 70% harbor the 

This drug class targets poly (ADP-ribose) polymerase, a pivotal protein in the repair of strand breaks in DNA. “DNA repair is really quite important in breast cancer cells in general because that’s what allows them to continue to grow and metastasize and obviously kill the host,” explained LoRusso. In patients with 

-mutated cells, PARP inhibitors increase DNA double-strand breaks and the death of homologous recombination—deficient cells, contributing to cell death. In normal cells, noted LoRusso, even with PARP inhibitors present, the cells can repair by homologous recombination and the tumor cells goes on to survive and do further damage.

The scientific relevance of PARP inhibitors may extend beyond TNBC with 

“When we give PARP inhibitors, we’re not only probably impacting the mechanism or the function we thought in terms of DNA repair, but there are other functions that are probably also being impacted with the utilization of PARP inhibitors,” said LoRusso. “This is especially important when we start to look at mechanisms of resistance and mechanisms of response in patients who do not harbor 

LoRusso said she’s currently interested in a clinical trial of patients with TNBC without 

 mutations, looking at whether hypoxia induction could induce what is called 

, a phenomenon first identified by researchers in 2005.

 “It isn’t necessarily the development of the 

 gene mutation, but rather with chronic exposure to hypoxia, many of these cells had decreased homologous recombination repair, thus not allowing them to restore their double-stranded DNA, as well as a decrease in MMR repair which leads to genetic instability and potentially an altered therapeutic response to PARP inhibitors.”

PARP inhibitors have moved beyond olaparib, the first FDA-approved PARP inhibitor and considered the “gold standard,” said LoRusso, with many being investigated in ongoing clinical trials—among them cediranib, veliparib, and olaparib.

In patients with TNBC, LoRusso said she’s interested in a clinical trial which looked at giving these patients cediranib as a sensitizer to olaparib, to induce hypoxia and thus create BRCA-ness.

Platinum agents also can cause intragenic mutations, explained LoRusso, another mechanism of resistance to PARP inhibitors; these secondary 

 mutations pose another challenge for this class of drugs. “One of the primary mechanisms of resistance is restoration of the functionality of the 

gene, wherein treating these patients, you get a secondary mutations in 

 that restore the mechanism of this gene and then prevent the drugs from working because now these genes can work in homologous recombination, overriding the mechanism of the PARP inhibitor.”

Combination therapies of irinotecan and veliparib have also received significant sustained responses in patients with 

 mutations, even in those with platinum resistance, said LoRusso.

LoRusso suggested that monotherapy sequencing may not be as important as combination interventions for patients with TNBC, but, she added, “We have to be cautious as to how we use PARP inhibitors and how we sequence drug combinations and drug therapies in 

-mutant patients in hopes of maximizing the effect of these drugs.”

The main question going forward, posited LoRusso, is how can PARP inhibitor activity be enhanced? 

To this end, said LoRusso, the I-SPY2 trials testing combinations of talazoparib and CPT11, and veliparib and carboplatin,

 have proved themselves in the neoadjuvant settings. “These two combinations in this trial are going to be extremely informative in how we enhance PARP inhibitors.”

“When these agents were being developed, nobody thought of using them in the adjuvant or neoadjuvant setting. And perhaps this is the absolute best place to personalize this class of drugs before their tumors have been poisoned by platinums and developed resistance to other therapeutic interventions. Perhaps in this select small group of patients, we can make a difference in terms of a cure, with the use of PARP inhibitor therapy,” said LoRusso, who argued for the continued development of this class of agents.

“The best data, the most informative data, and the greatest probability of benefit for our patients will be in forthcoming studies and hopefully they, too, will make a difference in the personalized approach to cancer therapy.”

Bindra, RS, Crosby, RE, Glazer, PM, Regulation of DNA repair in hypoxia cancer cells. 

Sonnenblick A, deAzambuja E, Azim HA Jr, Piccart M. An update on PARP inhibitors—moving to the adjuvant setting. 

Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. 

“PARP inhibitors are alive and well, and we’ve just begun to understand where they fit into the arsenal of treatment, with not only triple-negative breast cancer (TNBC), but other types of breast cancer as well,” said LoRusso, a professor of medicine and associate director of innovative medicine at Yale University, during a presentation at the 2016 Lynn Sage Breast Cancer Symposium. 

PARP inhibitors still have a place in the treatment paradigm of triple-negative breast cancer, but the role of these agents are significantly evolving.

Role of PARP Inhibitors Evolving in Triple-Negative Breast Cancer

Despite its substantial progress, much remains unknown about endocrine therapy as a treatment for breast cancer, according to William J. Gradishar, MD. This type of treatment has come a long way since tamoxifen ruled the adjuvant therapy landscape in 1989, but oncologists still have much to learn about newer therapies and combating endocrine resistance mutations.

The current NCCN guidelines call for continuation of endocrine therapy until disease progression or unacceptable toxicity levels, noted Gradishar, deputy director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine. “We try to continue patients on endocrine therapy because of the quality of life issues and because it’s better tolerated than chemotherapy,” said Gradishar at the 2016 Lynn Sage Breast Cancer Symposium.

Sixty percent to 70% of breast cancers are hormone receptor-positive, and current treatments aim to decrease estrogen levels or block ER. While some cancer are initially resistant to such therapies (de novo resistance), others become resistant over time (acquired resistance), highlighting the need for novel therapeutics to combat endocrine therapy resistance.

In order to prolong effective treatment with these therapies, research should now focus on overcoming resistance mechanisms to endocrine therapy, he said, by exploring estrogen receptor (ER) mutations, CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, and HDAC inhibitors.

“Biologic information may influence the choice of therapy we offer the patient, but we just don’t know enough about yet,” he said. “When estrogen receptors stop working, it’s usually the factor that one or more molecular pathways becomes more important.”

To delay or prevent resistance, endocrine therapy is now being given in various combinations. In most instances, it is no longer considered a monotherapy, Gradishar noted.

Palbociclib, which targets CDK4/6, was first FDA approved in 2015 in combination with the endocrine therapy letrozole. It is now also approved for use with fulvestrant. Gradishar explained that in response to mitogenic signals, cyclin D1 complexes with CDK4/6, leading to the phosphorylation of RB protein, causing the protein to no longer serve as a tumor suppressor, which results in uncontrolled cell proliferation.

Two other CDK 4/6 inhibitors, ribociclib and abemaciclib, are also in development for patients with breast cancer and other malignancies. Gradishar expects these agents to be approved soon. Both abemaciclib and ribociclib have received breakthrough therapy designations from the FDA and are in phase III studies; however, abemaciclib appears unique, as it has single-agent activity.

In May, a phase III study exploring ribociclib plus letrozole was stopped, after demonstrating an improvement in progression-free survival. For abemaciclib, the agent is also being explored in phase III studies. The phase III MONARCH-2 study is looking at the agent with fulvestrant. As a single-agent, the phase II MONARCH-1 study showed a response rate of nearly 20% in heavily pretreated patients with refractory, hormone-receptor—positive, HER2-negative advanced breast cancer.

Patients given palbociclib plus letrozole showed significant improvement in progression-free survival. Unfortunately, neutropenia is one of the common side effects seen with this dual treatment, said Gradishar, adding that while it doesn’t necessarily cause a problem for the patient it can be a headache for the treating physician to monitor and manage.

Uniquely, most significant side effects of abemaciclib appear to be gastrointestinal issues, said Gradishar, with no neutropenia. “Abemaciclib seems to have some ability to benefit Cyclin D1, which may be important, but it may also have some toxicity,” said Gradishar.

Another approach once resistance has developed is the addition of an mTOR inhibitor endocrine therapy. TOR regulates metabolism in times of plenty and not, explained Gradishar, which is why it’s so prevalent in mammals.

The phase III BOLERO-2 study was instrumental in the FDA approval of the mTOR inhibitor everolimus in combination with exemestane for patients with postmenopausal advanced breast cancer following resistance to a non-steroidal aromatase inhibitor. Blocking mTOR with everolimus improved progression-free survival by 55% compared with exemestane alone; however, survival was not significantly improved.

Studies are now assessing the addition of an mTOR inhibitor in the frontline setting. The phase III SWOG S1222 trial is looking at fulvestrant with or without everolimus or exemestane with or without everolimus for untreated patients with ER-positive metastatic breast cancer.

Several other options are also under exploration, although these have been met with mixed results. A primary reason for the lack of conclusive findings for these therapies may be the lack of a biomarker to select patients. With many new therapies, it’s difficult to define a biomarker for who would benefit, argued Gradishar. With PIK3 inhibition, for example, not many studies have been successful, he said.

As an example, the phase III FERGI study exploring fulvestrant with or without the PI3K inhibitor pictilisib was met with uncertain results. Progression-free survival was not significantly improved with the addition of pictilisib, and results were similar in those with PIK3CA-mutated and wild-type tumors.

The phase III BELLE-2 study was able to show efficacy for the combination of fulvestrant and the PI3K inhibitor buparlisib; however, it was too small a benefit to warrant a regulatory submission. In this study, the PI3K inhibitor improved progression-free survival by just 1.9 months across the full population. Furthermore, the improvement was not statistically significant in a PI3K activated group.

There was hope for a biomarker from this study, however, as patients with PIK3CA mutations in circulating tumor DNA showed a 44% reduction in progression or death with buparlisib. This finding will still need to be confirmed in other studies.

HDAC inhibitors are also of interest as a combination approach with endocrine therapy. Chief among these therapies is entinostat, which has received a breakthrough designation from the FDA in September 2011. The designation was based on significant improvements in survival experienced by patients in the phase II ENCORE 301 study, in which entinostat was administered in combination with exemestane. A phase III study is exploring entinostat and exemestane versus exemestane alone for patients with resistance to non-steroidal aromatase inhibitors, Gradishar noted.

Looking across the numerous studies of these newer targeted therapies, it is easy to say they are superior to their monotherapy counterparts, he said. “But these therapies are increasingly complex, potentially toxic, and certainly more expensive, so it’s yet to be determined."

Even with successful targeting, Gradishar said there is still a long way to go to understand the use of endocrine and endocrine resistance mutations more globally.

Despite its substantial progress, much remains unknown about endocrine therapy as a treatment for breast cancer.

Rita Colorito

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