Platinum and taxane chemotherapies remain standard first-line treatments for epithelial ovarian cancer. The treatment of recurrent ovarian cancer has historically been based on how a patient responded to the first-line regimen. Patients whose cancer recurred 6 months or more after the last platinum infusion are categorized as 

, whereas patients whose cancer recurred within 6 months of the last infusion are classified as 

. Greater understanding of ovarian cancer biology and the emergence of new targeted therapies is diminishing the importance of platinum response in determining how to treat recurrent disease.

 titled “Expert Views on Therapy for Ovarian, Fallopian Tube, and Peritoneal Cancers,” a panel of gynecologic oncology specialists discussed novel agents for the second, third, fourth, and even fifth lines of therapy and the growing importance of molecular signature, histology, and time to recurrence in treatment decisions. As panel moderator 

 summarized, “We have had 3 new FDA approvals for targeted therapies in the last 2 years, and I anticipate within the next year, we’ll have 3 more. Our armamentarium is growing, and our paradigms are changing.”

Ovarian cancer, like cancers that affect other organs, comprises many subtypes. Approximately 90% are epithelial, 80% of which are subcategorized as serous carcinomas.

 Serous carcinomas are further divided into high grade and low grade, with high grade accounting for 90% of serous tumors.

 “High-grade serous patients tend to have the worst prognosis compared to those with low-grade serous cancers,” said Angeles 

 She said high-grade serous tumors are further classified according to whether they harbor a homologous recombination deficiency (HRD), such as a germline or somatic 

 gene helps repair DNA and suppresses tumor growth, and current guidelines recommend all women with epithelial ovarian cancer have a blood test for a germline 

alteration. Monk said it surprises him when he meets a new patient who has had epithelial ovarian cancer for a long time but never had a 

 said some experts recommend clinicians also test the tumor for a somatic 

mutation, which a blood test would not detect. 

 reminded everyone that HRD testing is another option. She said although an HRD test does not identify specific somatic mutations, it does indicate whether a patient has an important somatic mutation in the DNA repair pathway.

 said it is important to know whether the “machinery is messed up,” because the cancer cell may have a vulnerability able to be exploited with drugs that induce DNA damage. Secord called the process

 mutation—whether it’s germline or somatic&mdash;or they have another defect that’s causing loss of homologous recombination, then the cells can’t repair themselves once they’re subjected to a DNA-damaging event,” Secord said. Coleman said synthetic lethality explains why patients with high-grade serous ovarian cancers who have a 

 mutation have better outcomes than patients without a

mutation. The same gene that predisposes their cells to malignant transformation makes those malignant cells vulnerable to DNA-damaging drugs.

The poly(ADP-ribose) polymerase (PARP) protein plays a significant role in repairing DNA damage. Monk described how the class of drugs known as PARP inhibitors are designed to block PARP’s enzymatic activity, thereby disrupting DNA repair and causing an accumulation of single-stranded breaks.“If you can’t repair single-stranded breaks, you get a double-stranded break. And if you have a 

-like mutation, you can’t repair the double- stranded break [and] the cell dies,” he said.

The FDA has approved 2 PARP inhibitors for women with ovarian cancer. In 2014, olaparib (Lynparza) received accelerated approval for women with advanced ovarian cancer who have a germline 

 mutation and used at least 3 prior lines of chemotherapy. Approval was based on data from a phase II trial that included 193 heavily pretreated patients with ovarian cancer and a germline 

 The overall response rate (ORR) in this cohort was 31%, and median progression-free survival (PFS) was 7 months.

 Herzog said the most common adverse events (AEs) in the phase II trial were fatigue and anemia. Some patients also experienced gastrointestinal issues, which Herzog said may have been because the formulation of olaparib used in the trial required patients to take 16 capsules per day.

Moore said the phase III SOLO-2 trial, which is meant to be a confirmatory study, uses a new tablet formulation of olaparib. Patients will require fewer tablets than capsules, and Monk speculated the new formula might reduce gastrointestinal toxicity. SOLO-2 recruited women with platinum-sensitive, 

-mutated recurrent ovarian cancer and randomly assigned them to olaparib tablets or placebo. “That study has been reported to be positive in a press release but without any accompanying hazard ratio as of yet, so we’re awaiting data,” Moore said. SOLO-3 is another ongoing trial, which is comparing olaparib with physician’s choice of standard chemotherapy in recurrent ovarian cancer.

 Peer Exchange® panel, Monk accurately predicted that the FDA would soon approve a new PARP inhibitor, rucaparib (Rubraca). On December 19, the FDA granted accelerated approval to rucaparib and to a companion diagnostic test, the FoundationFocus CDxBRCA, which screens ovarian tumor tissue for 

 Rucaparib is indicated for women with advanced ovarian cancer who have received 2 or more lines of chemotherapy and whose tumor harbors a germline or somatic 

Approval was based on findings from 2 single-arm clinical trials (ARIEL2 and Study 10), which included women with 

-mutated advanced ovarian cancer. “They particularly were interested in looking at those patients who had a germline or a somatic 

 mutation and had received greater than 2 lines of prior chemotherapy,” Moore said. At the 2016 European Society for Medical Oncology Congress, Rebecca Kristeleit, PhD, presented a pooled efficacy analysis for 106 women in the studies, which showed an investigator ORR of 53.8% and a median PFS of 9.2 months.

 Moore praised the remarkable outcomes and the safety profile; she said most AEs observed in the studies were common class effects of PARP inhibitors.

Coleman and his colleagues recently published additional findings from ARIEL2, which showed rucaparib was more effective in patients with a

 mutation who had a high degree of genomic loss of heterozygosity (LOH), or what Coleman called“genomic scarring.”

 Coleman said, “Rather than going through and trying to pick off which genes are actually the vulnerable ones...it was just easier to look across all of the genes.”

Table. Progression-Free Survival for Niraparib Versus Placebo in the NOVA Ovarian Cancer Trial

Niraparib is another PARP inhibitor the panel predicted was likely to earn FDA approval. Niraparib was evaluated in the phase III NOVA trial (n = 553) as maintenance therapy for women with platinum-sensitive, recurrent ovarian cancer.6 The authors stratified the women into 3 cohorts: those with a germline 

 mutation, those without one, and those without one who were HRD positive. “The maintenance niraparib approach resulted in improved PFS in all 3 groups,” Secord said (Table). She added that when she first learned of the results, she assumed patients with a somatic tumor mutation accounted for the positive results in the niraparib cohort of women with no germ- line mutation. She was pleasantly surprised to find niraparib also benefited women who carried neither a germline nor a somatic 

“I’m still confused about this maintenance idea,” Monk said. “In the NOVA trial, maintenance is in the title, but half the patients still have cancer. How can I call that maintenance if they had partial responses until their last treatment?” The experts agreed the terminology was imperfect, and Herzog suggested the NOVA trial was more like a switch study.

Veliparib is a fourth PARP inhibitor, which is being evaluated in an ongoing phase 3 trial as an addition to standard frontline chemotherapy for ovarian cancer and as maintenance therapy after chemotherapy. “Myelosuppression becomes a very real issue with DNA-damaging chemotherapy, but veliparib is probably less potent [than the other PARP inhibitors] on that specific angle,” Coleman said.

No trials have compared the PARP inhibitors head- to-head for ovarian cancer, and the panel agreed on the need for caution when making cross-trial comparisons. “You need to be aware of what the methodology was—it’s very important,” Herzog said. He suggested clinicians look at the toxicities observed with each PARP inhibitor and the labels once they are all approved.

“There are some differences between these drugs and how they bind to the different PARP receptors,” Secord said. She pointed out that niraparib is associated with a higher risk of thrombocytopenia than other PARP inhibitors. Herzog noted that the PARP inhibitors also have differences in bioavailability.

Moore said it was too early to know whether one PARP inhibitor was better than another. “Certainly they have differences in the Petri dish in terms of potency, but even the 3 we’re talking about are all pretty potent PARP inhibitors, and they all work in the studies that they have been tested in,” she said.

Ongoing trials of the various PARP inhibitors should provide more data to guide clinicians’ choices once they are all available for use in practice. Some studies are assessing outcomes by HRD score, others are assessing PARP inhibitors as frontline therapy or in combination with other classes of agents, such as VEGF inhibitors. Herzog predicted future trials would likely combine them with immune checkpoint inhibitors and other immunotherapies. The panelists expressed excitement about the many new options available for their patients. “We’ve had a real change—a paradigm shift,” Herzog said.

The group agreed that despite the advances, many challenges remain, such as drug resistance. Herzog said he expects the recent evolution in clinical trial design will lead to data-driven answers to critical questions, such as how to sequence PARP inhibitors with other agents or which combinations work best for which patients. “We have a light at the end of the tunnel,” Coleman concluded.

Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 

Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline 

 2015;33(3):244-250. doi:10.1200/JCO.2014.56.2728.

US Food and Drug Administration. FDA grants accelerated approval to new treatment for advanced ovarian cancer [press release]. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm533873.htm. Published December 19, 2016. Accessed January 16, 2017.

Kristeleit RS, Shapira-Frommer R, Oaknin A, et al. Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high-grade ovarian carcinoma (HGOC) and a 

 mutation (BRCAmut); analysis of pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2). 

Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. 

 2017;18(1):75-87. doi:10.1016/S1470-2045(16)30559-9.

Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. 

Articles

A panel of gynecologic oncology specialists discusses novel agents for the second, third, fourth, and even fifth lines of therapy and the growing importance of molecular signature, histology, and time to recurrence in treatment decisions.

PARP Inhibitors Are Changing Paradigm in Recurrent Ovarian Cancer

Gastroesophageal cancer (GEC) is a complex disease, encompassing cancers with different histological and molecular subtypes. Growing insight into the molecular biology of GEC is poised to change the treatment landscape for this disease, although many questions remain unanswered.

 recently assembled a distinguished panel of experts to discuss the evolving treatment paradigm for advanced GEC. In addition to discussing the complex epidemiology of GEC, the Peer Exchange panel reviewed findings from studies of emerging therapeutic regimens.

Classes of targeted agents that have shown promise for GEC include monoclonal antibodies, antiangiogenic agents, and immunotherapy drugs. Some targeted therapies, such as trastuzumab (Herceptin) and ramucirumab (Cyramza), have already been approved for certain types of GEC.

To add context to recent developments in managing GEC, it helps to understand the different cancer subtypes and their geographic distribution. Although GEC is rare in the United States, it is relatively common in Asian countries.

Ian Chau, MD, FRCP, noted that gastric cancer is the third most common cause of cancer death in Asia and the second most common cause if esophageal cancer is included.

Esophageal cancer is divided into 2 histological subtypes: squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Whereas ESCC is the predominant subtype in Asia and developing countries, EAC accounts for most US cases of esophageal cancer.

During the past several years, the incidence of EAC, which primarily affects the lower esophagus (the gastric junction), has been increasing in Western countries, including in the United States.

 “A lot of it is because of gastroesophageal reflux disease, and that might be related to obesity, which is becoming more and more common in the Western world,” Chau said.

In 2014, the Cancer Genome Atlas (TCGA) completed a molecular evaluation of 295 gastric adenocarcinomas and proposed 4 major subtypes of gastric cancer

Epstein-Barr virus—associated tumors, most of which contain 

 mutations, have excessive DNA hypermethylation, and overexpress JAK2, PD-L1, and PD-L2

Microsatellite unstable tumors, which can also have 

 mutations and commonly overexpress HER2 or EGFR

Genomically stable gastric cancers, characterized by 

Tumors with chromosomal instability, including 

 mutations and RTK-RAS, VEGFR, and p110 amplifications

​The TCGA analysis and subsequent studies carried out by other research groups have identified several potential therapeutic targets in GEC. Approved therapies already exist for some of these targets, but must still be validated in patients with GEC. Researchers are also investigating whether novel targeted agents alone or in combination can prolong survival and reduce the unwanted toxicities of systemic chemotherapy.

Immune checkpoint inhibitors prevent cancer cells from initiating a signaling cascade that ultimately blunts the response of activated T cells to the cancer. “The whole concept of immunotherapy is where you get your own immune system to attack the tumor,” said Johanna C. Bendell, MD, who served as moderator for the Peer Exchange discussion.

The first checkpoint inhibitors were approved to treat advanced melanoma, and subsequently for lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, and bladder cancer.

 Checkpoint inhibitors are currently being studied in a host of other cancer types, including GEC. Most target PD-1, a protein that binds to PD-L1 and PD-L2.

“If you look at the mutational burden of the tumors that have been historically studied and targeted with checkpoint inhibitors, such as melanoma and subtypes of lung cancer, gastric cancer is actually very close to the mutational burden on that spectrum,” said Yelena Y. Janjigian, MD. She said this is because the gastrointestinal mucosa is often subjected to repeated DNA damage (and repair) due to chronic inflammation or 

Nivolumab is a PD-1 inhibitor approved in the United States for melanoma and several other cancers. The CheckMate-032 study evaluated the safety and efficacy of nivolumab in 59 heavily treated patients with advanced or metastatic gastric or gastroesophageal junction cancer.

 These patients have few options and a poor prognosis.

According to data presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, the overall response rate (ORR) was 12% and median overall survival (OS) was 7 months. In the subset of patients with PD-L1—positive tumors, the ORR was 18%.

More recently, Bristol-Myers Squibb, which manufactures nivolumab, publicized preliminary data from the ONO-4538-12 study, which was a phase III trial evaluating nivolumab in Asian patients with unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer. The ORR was 14%, which increased to 27% in a subset analysis of patients with PD- L1—positive disease,

“I think what impresses everybody the most [about checkpoint inhibitors] is these durable responses that can even go on for years,” Bendell said. Despite this, Chau noted that it can take weeks for checkpoint inhibitors to take effect and advised caution when selecting patients for immunotherapy. Janjigian agreed that checkpoint inhibitors are probably not the best option for patients who are presenting with obstructive symptoms or peritoneal carcinomatosis.

Combining checkpoint inhibitors may increase the risk of toxicities. Janjigian said in her experience, combining a PD-1 inhibitor with a checkpoint inhibitor that targeted CTLA-4 was associated with a higher response rate, but also an increase in grade 3/4 toxicities. “Instead of febrile neutropenia and neuropathy, these patients get potentially life-threatening immune processes,” she said.

After disappointing results from the AVAGAST first-line trial of the VEGF inhibitor bevacizumab, it was unclear whether antiangiogenic agents had a role in GEC.

 The panel discussed how AVAGAST’s multinational population may have contributed to the trial’s failure to meet its primary endpoint. “Asians really don’t seem to derive any benefit from bevacizumab, either in progression-free survival [PFS] or OS, whereas the Pan-Americans seem to have some benefits,” Chau said.

In contrast to AVAGAST, both the phase III RAINBOW and REGARD trials observed significant benefits with the VEGF/HER2 inhibitor ramucirumab in patients with GEC.8 The study findings prompted the FDA to approve ramucirumab for GEC.

Manish Shah, MD, highlighted differences between the protocols for AVAGAST and the ramucirumab trials. “RAINBOW and REGARD were second-line studies...Also, the proportion of patients from Asia were limited in those studies.” Subgroup analyses of RAINBOW data associated ramucirumab with superior PFS relative to placebo in Japanese and Western cohorts. But only the Western population experienced improvement in OS. Shah said modeling suggests that using a higher dose of ramucirumab might improve survival outcomes.

Chau praised REGARD as “the first randomized controlled trial that shows an antibody against VEGF has a survival advantage.” He also praised the drug’s safety profile, which was highly favorable in both studies. Although ramucirumab is typically given with paclitaxel, Chau said that because data established ramucirumab as effective monotherapy, he feels comfortable discontinuing paclitaxel if a patient develops neuropathy. Bendell said that based on the favorable findings, she would like to see a trial of ramucirumab plus chemotherapy in the first-line setting.

Apatinib is a novel VEGF-HER2 inhibitor and was evaluated in a phase III trial of Chinese patients with chemotherapy-refractory GEC.

 The apatinib arm had significantly longer median OS than the placebo group and longer PFS. Shah said the findings of the Chinese study, combined with the results of RAINBOW and REGARD, support a role for VEGF inhibition in GEC.

Janjigian predicted that combination regimens are the future paradigm for GEC due to its molecular complexity. “Because of the nature of the epithelium and where the tumor is located, it will be important to find combinations of targeted agents that will help us control the tumor if we ever want to move away from cytotoxic chemotherapy,” she said.

Several experts on the panel are currently conducting clinical trials that combine targeted agents. Janjigian is involved in a trial that is evaluating the HER2 inhibitor trastuzumab with a PD-1 inhibitor in patients with GEC.

Bendell, Chau, and their colleagues are conducting a phase I trial that pairs the PD-1 inhibitor pembrolizumab with ramucirumab in patients with solid tumors, including GEC.

 Chau explained the rationale behind the combination: “Preclinical evidence says that if you give a tumor low-dose antiangiogenic therapy, you change it from an immunosuppressive environment to a much more immunosupportive environment.”

Safety data they presented at the 2016 ASCO Annual Meeting shows “the 2 drugs [together] are very safe—hardly any grade 3/4 toxicity or even grade 2 toxicities,” said Chau. The study is being expanded to include patients naïve to cytotoxic chemotherapy, and they hope to present efficacy data next year.

As the session ended, Shah expressed appreciation for how much progress researchers have made. “In the last 10 years, we have 5 new drugs that have been approved [for GEC],” he said. The panelists acknowledged that despite the tremendous progress, GEC remains a difficult disease to treat and much more needs to be done.

Shah said improving outcomes and patients’ quality of life will depend on “learning to sequence the drugs and combine them in a smarter way to understand the molecular profiles and to be proactive in terms of managing the patient’s side effects.”

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Cancer Research Institute. Timeline of progress. http://www.cancerresearch.org/our-strategy-impact/timeline-of-progress/ timeline-detail. Accessed November 28, 2016.

Le DT, Bendell JC, Calvo E, et al. Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): results from the CheckMate-032 study. 

Opdivo (nivolumab) Demonstrates overall survival benefit in patients with unresectable advanced or recurrent gastric cancer in phase III study [press release]. Princeton, NJ: Bristol-Myers Squibb; November 10, 2016. http://news.bms.com/press-release/bmy/opdivo-nivolumab-demonstrates-overall-survival-benefit-patients-unresectable-advan. Accessed November 28, 2016.

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Herbst RS, Bendell JC, Isambert N, Calvo E, Santana-Davilla R, Cassier P, Perez-Garcia J, Yang J, Rege J, Ferry D, Mi G, Chau I. A phase I study of ramucirumab (R) plus pembrolizumab (P) in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC): phase Ia results [ASCO abstract 3056]. 

Gastroesophageal cancer (GEC) is a complex disease, encompassing cancers with different histological and molecular subtypes. Growing insight into the molecular biology of GEC is poised to change the treatment landscape for this disease, although many questions remain unanswered.


Targeted Therapy Makes Inroads in Gastroesophageal Cancer

Approximately 75% of invasive breast cancers are estrogen receptor (ER)—positive

. Although ER-positive breast cancer typically responds well to initial endocrine therapy, most patients eventually become resistant to treatment and experience disease progression.

 The discovery that ER gene mutations contribute to endocrine therapy resistance has led to the development of novel targeted therapies for progressive ER-positive breast cancer.

 Mutations and Endocrine Therapy Resistance

 Peer Exchange panel titled “Expert Perspectives on the Latest Advancements in Breast Cancer,” a group of breast cancer specialists led by Adam M. Brufsky, MD, PhD, discussed recent progress in the understanding and management of ER-positive tumors. They reviewed emerging data presented at the 2016 ASCO Annual Meeting in June and expressed optimism about what those data suggest for the future of patients with heavily pretreated, metastatic, ER-positive disease.

Efforts to determine how ER-positive breast cancer escapes endocrine deprivation led to the identification of 

 mutations in hotspot regions of the ligand-binding domain (LBD) of ER, which Carlos L. Arteaga, MD, hailed as a “major discovery.”

 mutations facilitate ligand-independent, constitutive ER activity in women receiving an aromatase inhibitor (AI).

 mutations affect <1% of newly diagnosed breast cancers, their clinical significance was not fully appreciated until recently, when a series of studies detected a greater prevalence of 

 mutations in metastatic ER-positive breast cancer that became resistant to AI therapy.

“Up to 30% of patients who progress on AI therapy in the metastatic setting have these alterations,” Arteaga said.

 The panel discussed abstracts presented at the 2016 ASCO Annual Meeting that addressed 

The PALOMA3 study was a randomized phase III trial that compared palbociclib (Ibrance) plus fulvestrant (Faslodex) versus fulvestrant plus placebo in 360 patients with metastatic breast cancer who had progressed during endocrine therapy.

 In PALOMA3, researchers analyzed circulating tumor DNA (ctDNA) in 395 plasma samples for 

. All 106 patients whose tumors tested positive for an 

 mutations] in patients who had prior tamoxifen, so it’s a very treatment-dependent effect,” explained Sunil Verma, MD.

 mutation independently predicted shorter progression-free survival (PFS). Median PFS was 5.7 months for patients with an 

 mutation versus 9.2 months for patients without one.

In updated data from PALOMA3 published in the 

 in September, the authors reported median PFS for patients with an 

 mutation of 9.4 months for those treated with palbociclib/fulvestrant compared with 3.6 months for those taking fulvestrant/placebo (

 wild-type patients in the palbociclib/fulvestrant arm, median PFS was 9.5 months compared with 5.4 months for those in the fulvestrant/placebo arm (

“Despite these mutations, there was a benefit favoring palbociclib,” Verma said. Palbociclib is a CDK 4/6 inhibitor, and he said the findings are important because they suggest CDK 4/6 inhibitors are effective in patients with an 

Arteaga said he found it interesting that “the patients who had prior response to endocrine therapy—who showed some evidence of being luminal and hormone-dependent&mdash;were the ones who developed acquired ER mutations.”

He said the fact that patients who did not respond to endocrine therapy did not acquire mutations suggests their tumors had found other ways to circumvent ER inhibition.

He predicted that selective estrogen down-regulators (SERDs) could eventually become the standard of care for patients with an 

 mutation and suggested the ease of detecting the mutations (in plasma with no biopsy required) means “we may need to start thinking of incorporating measuring these mutations into our standard of care for patients who progress on an AI.”

Joyce A. O’Shaughnessy, MD, agreed that the findings from PALOMA3 are important and might have interesting implications for the adjuvant setting but said she was not ready to order ER assays for her patients based on the data. “I don’t think it’s really specifically actionable right now... we’re not going to change our practice patterns because we are going to use the CDK 4/6 inhibitors,” O’Shaughnessy explained.

She compared the findings with those of the BOLERO-2 trial. Although 

 mutations predicted shorter overall survival (OS), patients who received everolimus plus exemestane had similar median PFS regardless of whether they had an 

“The everolimus is going to work no matter whether patients have the mutation or not [and] we’re going to continue to treat patients as we do anyway, so I don’t think we need to check it out,” she said.

Both Kimberly L. Blackwell, MD, and Arteaga proposed that testing for an 

 mutation could help determine whether a patient should receive fulvestrant—the only SERD approved for metastatic ER-positive breast cancer&mdash;or enroll in a clinical trial for a novel SERD.

“There are trials now that enroll based on these mutations...it’s probably important that [those patients] know there are options for them,” said Arteaga.

 mutation predicts worse OS with subsequent treatments,

 having the mutation essentially means the patient “is no longer eligible for endocrine therapy.”

Palbociclib and abemaciclib are both CDK 4/6 inhibitors.

In February 2016, the FDA approved palbociclib in combination with fulvestrant for women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy. It was already approved in combination with letrozole as first- line therapy for women with this cancer who are postmenopausal.

Approvals were based on findings from the PALOMA series of trials. PALOMA-2 and PALOMA-1 compared palbociclib plus letrozole versus letrozole monotherapy in women with ER-positive/HER2-negative advanced breast cancer.

“We now have 3 trials that basically look at the addition of palbociclib to antiestrogen therapy,” Blackwell said. “What we see across the board is almost a near doubling—give or take a month or two&mdash;in PFS with the addition of palbociclib to the endocrine therapy backbone,” she said, calling the results exciting.

The trials have yet to show an OS benefit with palbociclib, which Blackwell said is difficult to achieve in this population. She predicted palbociclib will become the standard of care for patients with metastatic breast cancer who require endocrine therapy. Brufsky agreed the PFS findings for palbociclib—based regimens in the PALOMA trials were impressive.

Abemaciclib is not FDA approved but was designated a breakthrough therapy for patients with advanced breast cancer in 2015 based on data from the MONARCH trial series.

O’Shaughnessy said abemaciclib inhibits CDK4 more than CDK6 and therefore causes less myelosuppression than palbociclib. “It can be given daily, so you don’t have to have the 3 weeks on, 1 week off—which may end up being a therapeutic advantage at the end of the day,” she said.

At the ASCO meeting, investigators presented data from the phase II MONARCH1 trial of abemaciclib in HR-positive/HER2-negative metastatic breast cancer refractory to endocrine therapy or chemotherapy.

 The response rate was 17%, which Brufsky said failed to meet the study’s primary endpoint.

O’Shaughnessy said early chemotherapy trials showed that clinical benefit rate (CBR) is a more important measure of efficacy in the endocrine therapy setting and that the CBR in MONARCH1 was an impressive 42%.

She said abemaciclib also showed exciting potential for patients with brain metastases because it penetrates the central nervous system (CNS).

“I have a patient with multiple brain metastases who has been on it for over 3 years now and another patient who went to the University of Colorado to participate in their ongoing CNS-directed therapy. Right now, she’s responding,” O’Shaughnessy said.

“What was really appealing to me when we looked at the data is the duration of response,” Verma said. He described the approximately 10-month duration of response as a “good result” for such a heavily pretreated population.

Despite the underwhelming response rate in MONARCH1, PFS was 5.7 months, which Blackwell said was nearly double the PFS observed in trials of first-line endocrine therapy. “The PFS and the duration of response are the really exciting things to come out of that study,” she said.

Brufsky highlighted the nearly 18-month OS, noting that OS in trials of eribulin (Halaven) in heavily pretreated patients was only about 13 months. He predicted the CDK 4/6 inhibitors would bring a “sea change” in practice. Everyone agreed the findings with these drugs in HR-positive breast cancer were exciting.

Arteaga said CDK 4/6 inhibitors may improve quality of life for women with ER-positive disease by allowing them to forgo antiestrogen therapy. Ongoing trials are studying abemaciclib plus letrozole or fulvestrant in metastatic breast cancer. “It’s an unmet need, and I really want [abemaciclib], so I’m hoping that it will get approved,” O’Shaughnessy said.

Another CDK 4/6 inhibitor being investigated for this patient population is ribociclib. In May 2016, the Data Monitoring Committee for the phase III MONALEESA-2 trial of ribociclib plus letrozole recommended halting the trial early because it had already met its primary endpoint of improved PFS.

According to Verma, the data cumulatively point to a class effect for CDK 4/6 inhibitors in HR-positive breast cancer but that “it really remains to be seen how we can take this and how we identify those patients early on to potentially potentiate this effect.”

The panel debated whether the promising findings mean CDK 4/6 inhibitors should be given first. “The fact that the control arm [in MONALEESA-2] had such prolonged PFS...probably suggests that we should consider this in all patients as first-line [therapy] in the metastatic setting and not wait,” Arteaga said.

O’Shaughnessy said she would first like longer follow-up and more biomarker data. Brufsky said he wants data on sequencing strategies for women whose cancer progresses after palbociclib therapy, including where exemestane and everolimus fit into the plan.

Despite the many outstanding questions, Verma said it was an exciting time in HR-positive breast cancer, with paradigms starting to shift dramatically. “We’ve got a lot of great stuff going on,” Brufsky agreed.

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Turner NC, Jiang Y, O’Leary B, et al. Efficacy of palbociclib plus fulvestrant (P+F) in patients(pts) with metastatic breast cancer (MBC) and 

 mutations (mus) in circulating tumor DNA (ctDNA). 

Chandarlapaty S, Chen D, He W, et al. Prevalence of 

 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial [published online August 11, 2106]. 

Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2—advanced breast cancer (ABC). 

Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: results from a phase II study of abemaciclinb, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2—breast cancer, after chemotherapy for advanced disease. 

Approximately 75% of invasive breast cancers are estrogen receptor (ER)–positive. Although ER-positive breast cancer typically responds well to initial endocrine therapy, most patients eventually become resistant to treatment and experience disease progression.

Experts Focus on New Ways of Attacking Resistance in ER+ Breast Cancer

The armamentarium for advanced melanoma was sparse in March 2011, when ipilimumab (Yervoy) became the first drug in 13 years to earn approval FDA approval for the disease. Since then, the armamentarium has rapidly expanded.

“In the last 5 years, there have been FDA approvals for 12 new agents and combination therapies for patients with advanced melanoma,” said Keith T. Flaherty, MD, who moderated an 

 Peer Exchange panel titled “Treatment of Advanced Melanoma and Basal Cell Carcinoma.”

Novel melanoma treatments fall broadly into 2 categories: agents that target MAPK pathway signaling or agents that target immune system proteins. Several more melanoma treatments are poised to emerge from the pipeline. Data on the optimal way to incorporate these novel drugs into practice lag far behind the breakneck pace of approvals.

What sets melanoma apart from other malignancies is its high mutational burden and immunogenicity. Jeffrey S. Weber, MD, PhD, explained how the interplay between these 2 factors makes melanoma highly susceptible to targeted therapies. “If you look at average mutational load, melanoma is No. 1 of all tumors, with a median of about 600 to 700 individual non-synonymous mutations,” he said.

Non-synonymous means the mutation is found only in tumor cell DNA, where it encodes peptides and protein fragments not expressed by normal cells. This is important because melanoma derives from transformed melanocytes, and one function of melanocytes is to present antigens to immune cells. When the melanoma melanocytes present the “alien” mutation-encoded antigens to T cells, it triggers an immune response.

“A lot of mutations means the cells grow out of control and make cancers, [but the cell] contains within it the potential seed of its own destruction… by the immune system,” Weber said.

Georgina Long, PhD, MBBS, identified the 3 most common genetic drivers of melanoma as 

 alterations. Approximately 40% of patients with cutaneous melanoma have a BRAF mutation, up to 25% have an NRAS mutation, and about 12% have an 

With several more melanoma treatments poised to emerge from the pipeline, data on the optimal way to incorporate these novel drugs into practice lag far behind the breakneck pace of approvals.

Christin Melton, ELS

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