Conference Coverage: NCCN Clinical Updates

NCCN Ovarian Cancer Guidelines Add Options for PARP Inhibitors, Bevacizumab

The field of ovarian cancer has come a long way over the past decade, David O’Malley, MD, of The James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center, reminded attendees of the National Comprehensive Cancer Network (NCCN) 2019 Annual Conference.

He opened his talk with a slide of the first ovarian cancer guideline, issued in 2007. “It was all on 1 page,” he said. “There wasn’t much for us to do.”

By contrast, the newest guidelines, updated in March, cover 126 pages. “In the last 10 years we’ve seen an unprecedented time of drug development. We’ve had more agents and more indications in 5 years than in the previous 50 years,” O’Malley said.

The big news involves 2 areas: new uses for the antivascular therapy bevacizumab (Avastin) and approvals in ovarian cancer for poly (ADP-ribose) polymerase (PARP) inhibitors, targeted therapies that kill cancer cells by blocking enzymes that let the cells repair DNA. These therapies are effective in patients who have certain genetic mutations, including BRCA1/2. There are now 3 FDA-approved PARP inhibitors in ovarian cancer: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca).

Findings that include GOG 218,¹ SOLO-1,² and ARIEL3³ and subsequent FDA approvals have O’Malley questioning assumptions about the treatment of ovarian cancer, which

the CDC still ranks as the fifth leading cause of cancer death for women. However, median survival has increased from less than 3 years to 5 years, he said.

“Is maintenance treatment curing people? I used to say no, but we may have to look at that,” O’Malley said. “Can we cure people after recurrence? I used to tell people no, but I need to question my counseling.”

Major updates in maintenance therapy

The guidelines make several updates in maintenance therapy in stage II, III, and IV disease.

Olaparib is recommended as first-line maintenance therapy for patients with BRCA1/2 mutations in complete clinical remission or partial remission. The recommendation is category 1 for germline mutations and category 2B for somatic mutations; O’Malley said this occurred because there were so few patients with somatic mutations studied. The recommendation applies whether or not the patient was previously treated with bevacizumab.

The recommendation for olaparib is based on results from the SOLO-1 trial, which evaluated progression-free survival (PFS) based on RECIST criteria and found that median PFS was not reached in the olaparib arm compared with 13.8 months in the placebo arm (hazard ratio [HR] 0.30; 95% CI, 0.23- 0.41; P <.0001).2 Bevacizumab is also recommended for maintenance therapy postremission for patients with partial or complete responses who received it in primary treatment or for patients with stable disease.

Updates for bevacizumab were based on the GOG 218¹ and the ICON7⁴ trials, which O’Malley reviewed. GOG 218 was cited in the June 13, 2018, FDA approval for bevacizumab in combination with paclitaxel or carboplatin, followed by bevacizumab as a single agent, for stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer after initial resection.⁵

The GOG 218 trial randomized 1873 women into 3 groups: The control group took chemotherapy and had a median PFS of 10.3 months; a second group started bevacizumab with chemotherapy but stopped, and PFS was 11.2 months; the third group continued with bevacizumab throughout treatment. The HR for progression to death relative to the control group was 0.717 for those treated with bevacizumab throughout (95% CI, 0.625-0.824; P <0.001).¹

In reviewing the ICON7 results, O’Malley noted that although the overall results for did not reach statistical significance, bevacizumab was very effective for the highest-risk patients; published results show that the estimated median PFS was 10.5 months with standard therapy versus 15.9 months with bevacizumab (HR, 0.68; 95% CI, 0.55-0.85; P <.001).⁴

Persistent and resistant disease and recurrence

If patients have platinum-sensitive disease and relapse more than 6 months after completing chemotherapy, a new algorithm in the guidelines calls for 2 platinum therapies (a platinum doublet), possibly alongside bevacizumab or a PARP inhibitor. The algorithm allows these options if patients with advanced cancer are in complete or partial response to platinum-based chemotherapy. All 3 PARP inhibitors—olaparib, rucaparib, and niraparib&mdash;are listed. In support of these updates, O’Malley presented findings from the OCEANS

trial⁶ involving bevacizumab with carboplatin and gemcitabine, the GOG 213 trial,⁷ and separate trials involving each PARP inhibitor.

Rucaparib received FDA approval for this indication in April 2018 based on results of the ARIEL3 trial, which found that median PFS for the overall study population was 10.8 months versus 5.4 months for placebo.⁸ For patients in BRCA-mutated subgroups, the risk of progression to death fell 77%; median PFS was 16.6 versus 5.4 months (HR 0.23; 95% CI, 0.16-0.34; P <.0001). Niraparib received approval in this setting in 2017 based on the NOVA trial.⁹

Bevacizumab is also the centerpiece of regimens with nonplatinum combinations, O’Malley said, based on results from the 2014 AURELIA trial.¹⁰

Testing recommendations upgraded

As seen across the updated NCCN guidelines during the conference, the updated recommendations in ovarian cancer call for tumor molecular testing if not previously done. Validated molecular testing should include BRCA1/2 and microsatellite instability or DNA mismatch repair, if not previously done. Homologous recombination deficiency testing can be considered.

Because a PARP inhibitor may be used, “all patients should have germline testing,” O’Malley said. “But we should not delay therapy for testing.”

REFERENCES:

1. Burger RA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. doi: 10.1056/NEJMoa1104390.
2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi: 10.1056/NEJMoa1810858.
3. Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.
4. Perren TJ, Swart AM, Pfisterer J, et al; ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496. doi: 10.1056/NEJMoa1103799.
5. FDA approves bevacizumab in combination with chemotherapy for ovarian cancer. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm610664.htm Updated June 13, 2018. Accessed March 24, 2019.
6. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/JCO.2012.42.0505.
7. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-2045(17)30279-6.
8. FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm603997.htm. Updated April 6, 201 Accessed March 24, 2019.
9. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT=OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi: 10.1056/NEJMoa1611310.
10. Poveda AM, Selle F, Hilpert F, et al. Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA trial. J Clin Oncol. 2015;33(32):3836-3838. doi: 10.1200/JCO.2015.63.1408.

PD-L1 Testing "Name of the Game" in First-Line Treatment of NSCLC

The word "giddy" was circled in a 2014 New York Times article that Matthew A. Gubens, MD, MS, referenced to start his update on the use of checkpoint inhibitors in non—small cell lung cancer (NSCLC). The thoracic oncologist reminded attendees of the National Comprehensive Cancer Network (NCCN) 2019 Annual Conference that less than 5 years have passed since the approval of pembrolizumab (Keytruda), the first cancer drug based on a tumor’s characteristics rather than its location.

The giddy phase may be over. But Gubens, of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, said the excitement has given way to an immuno-oncology tsunami: 940 agents in clinical testing, 303 targets, 864 companies, and 3042 trials with enrollment of 577,076 patients.

Much of that progress has come in NSCLC, and Gubens presented new guidelines for first-line recommendations in immunotherapy and biomarker testing. Following Gubens,

Marianne Davies, DNP, MSN, RN, CNS, ACNP-BC, AOCNP, of Yale Cancer Center, presented updates on strategies for managing adverse events.

“PD-L1 testing is really the name of the game,” Gubens said, referring to assays that measure the level to which tumors overexpress the programmed death ligand 1 (PD-L1) protein. As Gubens explained, the KEYNOTE-024 trial showed that pembrolizumab in patients with NSCLC more than doubled median overall survival compared with chemotherapy if PD-L1 expression, making that level an important cut point in deciding on treatment. If PD-L1 expression is below 50%, decisions turn on whether the cancer is squamous or nonsquamous.

Several guidelines that took effect in January 2019¹ combine pembrolizumab with chemotherapy. Although this brings greater toxicity, Gubens said, clinicians and patients alike “will consider the higher disease burden with the idea that ‘I want a response now; I may not get to second line.’”

With greater shared decision making, he said, savvier patients understand that choosing more aggressive therapies brings the higher response.

New guideline based on KEYNOTE-024. Pembrolizumab is preferred as firstline therapy for NSCLC when PD-L1 expression is 50% or greater. This is a category 1 guideline, which means there is uniform consensus that the intervention is appropriate. This guideline applies to both adenocarcinoma and squamous cell carcinoma.

New guideline based on KEYNOTE-189. What about PD-L1 expression of less than 50%? Gubens reviewed the KEYNOTE-189 results, a phase 3 trial that involved patients with metastatic nonsquamous NSCLC who had no prior treatment. Patients were randomized 2:1 to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab or placebo. Patients could cross over if they progressed on the control arm. Although survival was more pronounced on those with 50% or greater PD-L1 expression, improved survival was seen across the board. Based on these results, the new guideline update adds the following as preferred category 1 initial systemic therapy options (ECOG performance status of 0-1) for advanced or metastatic adenocarcinoma in NSCLC (if no contraindications to adding pembrolizumab): pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed.

What if patients cannot take pemetrexed? Based on the guideline, Gubens said the best option for patients with adenocarcinoma in NSCLC is the next recommended category 1 combination, atezolizumab/carboplatin/paclitaxel/bevacizumab.

New guideline based on KEYNOTE-407. A study published in November 2018 in the New England Journal of Medicine, KEYNOTE-407, is reflected in the guideline update for combination therapies in squamous NSCLC. The preferred category 1 recommendations are pembrolizumab/carboplatin/paclitaxel or pembrolizumab/carboplatin/albumin-bound paclitaxel.

Biomarker testing. As important as PD-L1 testing is now, Gubens said, this is the just the beginning. He discussed the growing importance of understanding patients with high tumor mutation burden as a distinct population from those with high PD-L1 expression and said that forthcoming blood assays could be promising in predicting which immunotherapies will work. “In 5 years, PD-L1 might be archaic. Stay tuned for multidimensional and serial testing,” he said, referring to tests that occur throughout cancer treatment, not just at the start.

Guidelines for Immune-Related Adverse Events

The overall NCCN guideline², Management of Immunotherapy-Related Toxicities, received a substantial update in January 2019 from its February 2018 version, notably adding a section on managing the effects of chimeric antigen receptor T-cell therapy. Davies focused on updates relating to adverse events (AEs) from checkpoint inhibitors in lung cancer, noting that onset can occur between 5 and 12 weeks and may take place concurrently or sequentially. “Every organ system in the body can be involved, and we need to be cognizant of that,” she said.

Davies reviewed AEs from 8 recent trials (4413 patients with NSCLC) that contributed to the updates. She then discussed a meta-analysis that showed that 46.53% of patients had high-grade AEs from chemotherapy, including 13.92% who subsequently discontinued therapy; 14.26% of patients had high-grade AEs from PD-1/PD-L1 treatments, including 5.94% who stopped therapy because of AEs. Patient deaths attributable to AEs were seen in 1.12% of chemotherapy and 0.48% of PD-1/PD-L1 patients. By far, the most common

AE was fatigue.

The guideline contains specific algorithms for dermatological, gastrointestinal, endocrine, pulmonary, renal, ocular, cardiovascular, and hepatic AEs, including when to temporarily or permanently discontinue immunotherapy or switch therapies. Steroids, both topical and prednisone, are frequently indicated; with long-term use, vitamin D and calcium are indicated.

REFERENCES:

1. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer, version 3.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/nscl.pdf. Published January 18, 2019. Accessed March 22, 2019.
2. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related Toxicities, version1.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published November 14, 2018. Accessed March 22, 2019.

&#8203;&#8203;&#8203;&#8203;&#8203;NCCN Prostate Cancer Update Emphasizes Germline Testing

A March 6, 2019, update¹ of the National Comprehensive Cancer Center (NCCN) guidelines for the treatment of prostate cancer included an emphasis on gathering family history and “more careful interrogation of germline mutations,” according to James D. Mohler, MD, associate director and senior vice president of translational research at Roswell Park

Comprehensive Cancer Center.

Mohler gave an overview of the guideline updates at the National Comprehensive Cancer Network (NCCN) 2019 Annual Conference in Orlando, Florida. He was joined by Emmanuel S. Antonarakis, MBBCh, an associate professor of oncology and urology at the Sidney Kimmel Comprehensive Cancer Center at John Hopkins Medicine, who discussed ways to integrate genetic testing into clinical practice.

As Mohler discussed, knowledge of the importance of family history in prostate cancer has increased since the 1990s; recent research findings show the importance of germline DNA repair abnormalities, notably BRCA mutations and Lynch syndrome. The mutations can manifest in a host of cancers, including breast, ovarian, and pancreatic (NCCN guideline updates in this disease also reflect knowledge gained about germline testing).

More testing recommended. The guidelines update calls for taking a family history immediately at diagnosis; along with prior recommendations to explore BRCA mutations and Lynch syndrome, a new one advises testing for the presence of intraductal carcinoma (IDC). Mohler cited work by Antonarakis that shows this is associated with aggressive disease. If a patient has a family history of mutations or IDC, germline testing is recommended, preferably with genetic counseling. If family history is unknown, testing may still be considered, based on clinical features.

The guidelines contain a risk stratification and staging workup for germline testing of clinically localized disease. Mohler said that clinicians can weigh next-generation sequencing (NGS) or targeted testing; if NGS is used, the panel must include BRCA1, BRCA2, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2. NGS costs about $3500, and targeted testing is cheaper, he said.

“By using targeted testing, you could miss mutations that could affect the course of treatment later,” he said. Mohler addressed the controversy over more widespread testing, noting that earlier this year,² the American Society of Breast Surgeons called for testing every diagnosed breast cancer patient with a multigene panel. “This is an area where we will have to pay close attention,” he said.

Tumor testing. Antonarakis discussed updates that related to testing of the tumor itself; testing for microsatellite instability or deficient mismatch repair (MMR) could inform clinicians whether pembrolizumab is indicated as a second- or third-line therapy for adenocarcinoma in castration-resistant prostate cancer (CRPC), with or without visceral metastases. “The evidence is level 2B because there [are] no prospective data, yet we have an FDA approval,” Antonarakis said, referring pembrolizumab’s historic “site agnostic” approval. MMR mutations occur in 3% to 5% of metastatic CRPC (mCRPC) patients, he said. The guidelines also call for genetic counseling and germline testing for homologous recombination deficiency (HRD), which Antonarakis said occurs in 15% to 25% of mCRPC cases. Where HRD is found, investigational poly (ADP ribose) polymerase inhibitors can be considered, he said.

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Patients with intermediate risk. The large, diverse group of patients classified as intermediate risk presents a challenge for clinicians developing treatment approaches. These patients are divided into “favorable” and “unfavorable” groups. The new guidelines say that for the favorable group, after initial therapy, observation is now preferred; for the unfavorable group, the following apply: Initial therapy changes from external beam radiation therapy (EBRT) androgen deprivation therapy (ADT) for 4 to 6 months to EBRT ADT for 4 to 6 months, or initial therapy changes to EBRT + brachytherapy ADT for 4 to 6 months.

Mohler drilled down data comparing intermittent and continuous use of ADT intermittently and continuously; new language calls for considering intermittent ADT in M0 prostate-specific antigen cancer. He noted language now appearing in the guidelines: “Whether treatment of regional nodes in addition to the primary improves outcomes remains uncertain; nodal treatment should be performed in the context of a clinical trial.”

For metastatic castration-naive disease, “ADT is the gold standard,” the guideline reads, but a phase 3 trial comparing continuous with intermittent could not show noninferiority for survival. Quality of life was better in the intermittent arm.

Castration-Resistant Prostate Cancer. Updates also addressed secondary hormone therapy in nonmetastatic CRPC, or M0 CRPC. Mohler reviewed clinical trials that led to recommendations for apalutamide and enzalutamide, which appear in the guidelines, as well as a trial for darolutamide, which is not included because it is not yet approved.

A “rousing debate” centered on whether these therapies should become the new standard of care, said Mohler, who addressed the cost of the therapies. If a man is diagnosed with CRPC that becomes metastatic, the cost can easily run from $500,000 to $1 million.

“We need to start thinking about the cost of treatment or [financial] toxicity,” Mohler said, noting that this is becoming an especially big problem for families of patients with prostate cancer. “We need good data in this field, and there [are] not a whole lot,” he said.

REFERENCES:

1. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer, version 1.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/prostate.pdf. Published March 6, 2019. Accessed March 22, 2019.
2. Caffrey M. Breast surgeons seek genetic testing for all patients with breast cancer. The American Journal of Managed Care. website. ajmc.com/newsroom/breast-surgeons-seek-genetic-testing-for-all-patients-withbreast-cancer. Published February 18, 2019. Accessed March 22, 2019.

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