ASCO Clinical Findings

Nearly Half of Patients With Metastatic CSCC Respond to Fast-Tracked Cemiplimab

Mary Caffrey

After taking the programmed death-1 inhibitor cemiplimab for an average of close to 8 months, nearly half of patients with metastatic cutaneous squamous cell carcinoma (mCSCC) responded to treatment in a phase 2 study. A median duration of response had not been reached, however, according to results presented June 4, 2018, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

The results were simultaneously published in the New England Journal of Medicine.¹ The journal featured both reports of the expansion cohort from phase 1, which saw a response from 13 of 26 patients (50%; 95% CI, 30%-70%) as well as results from phase 2, which reported responses from 28 of 59 patients.

“The study of cemiplimab for the treatment of advanced cutaneous squamous cell carcimona was underpinned by the recognition that a high mutation burden may render these tumors sensitive to effector T cells in the context of immune checkpoint blockade,” the authors write.

The study of 54 men and 5 women, with an average age of 71 years (range, 38-93 years), involved a 3-mg/kg dose given intravenously every 2 weeks. Tumor measurements were performed every 8 weeks. Overall response rate (ORR) was the primary endpoint, and duration of response was the key secondary endpoint.

The FDA has already granted priority review status to cemiplimab, which is being developed by Regeneron and Sanofi. A decision on the biologics license application is expected by October 28, 2018.²

CSCC, or skin cancer, is very common in the United States, and most often it is treatable. But in 5% of the cases, it becomes metastatic, and there is no standard of care for this form of the disease. Thus, cemiplimab would fill a significant unmet need for patients with mCSCC. At ASCO 2017, Regeneron presented promising phase 1 results that resulted in the FDA’s earlier designation of cemiplimab as a breakthrough therapy in this indication.3 Results presented this year include data through October 27, 2017.⁴

At the time of data cutoff, patients had been followed for an average of 7.9 months (range, 1.1-15.6 months). ORR, as measured by an independent review team examining patient scans, was

47% (95% CI, 34%-61%). The rate of durable disease control was 61% (95% CI, 47%-74%), with 4 complete responses and 24 partial responses. The average time to initial response was 1.9 months.¹ Of the 28 patients who had a response, the duration of response exceeded 6 months for 57%, and 82% still had a response and were taking cemiplimab at the time of the data cutoff.

The most common adverse events (AEs) were diarrhea (27%), fatigue (24%), and nausea (17%). The paper reported 25 AEs of grade 3 or higher, including 17 that were serious and 3 that led to discontinuation of treatment; 3 were associated with an outcome of death. The study’s authors said the side effects observed were typical among patients treated with checkpoint inhibitors.^{3​​​​​​}

“The strong results seen with cemiplimab are noteworthy given that advanced CSCC is a very serious condition that currently has no approved treatments once surgery is no longer an option,” Michael R. Migden, MD, co-lead author and associate professor in the Departments of Dermatology and Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, said in a statement. “Advanced CSCC tumors were shown to be responsive to cemiplimab in both metastatic and locally advanced patients, with the results being clinically meaningful and consistent between the phase 1 and phase 2 trials.”⁵

References

1. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma [published online June 4, 2018]. N Engl J Med. doi:10.1056/NEJMoa1805131.
2. FDA to conduct priority review of cemiplimab as a potential treatment for advanced cutaneous squamous cell carcinoma [press release]. Paris, France, and Tarrytown, NY: Sanofi; April 30, 2018. news.sanofi.us/2018-04-30-FDA-to-Conduct-Priority-Review-of-Cemiplimab- as-a-Potential-Treatment-for-Advanced-Cutaneous-Squamous-Cell-Carcinoma. Accessed June 4, 2018.
3. Harris J. FDA grants cemiplimab breakthrough designation for CSCC. OncLive® website. onclive.com/web-exclusives/fda-grants-cemiplimab-breakthrough-designation-for-cscc. Published September 8, 2017. Accessed June 4, 2018.
4. Rischin D, Migden MR, Chang A, et al. Primary analysis of phase 2 results for cemiplimab, a human monoclonal anti-PD-1, in patients with metastatic cutaneous squamous cell carcinoma (mCSCC). J Clin Oncol. 2018;36(suppl; abstr 9519). meetinglibrary.asco.org/ record/159083/abstract.
5. New England Journal of Medicine publishes pivotal cemiplimab trials showing positive results in advanced cutaneous squamous cell carcinoma [press release]. Paris, France, and Tarrytown, NY: Sanofi; June 4, 2018. news.sanofi.us/2018-06-04-New-England-Journal-of- Medicine-publishes-pivotal-cemiplimab-trials-showing-positive-results-in-advanced-cutaneous-squamous-cell-carcinoma. Accessed June 4, 2018.

KEYNOTE-042 Confirms First-Line Pembrolizumab Superior to Chemotherapy in PD-L1— Low Advanced NSCLC

Surabhi Dangi-Garimella, PhD

A late-breaking abstract presented on June 3 at the 2018 American Society of Clinical Oncology Annual Meeting confirmed that pembrolizumab significantly improved the primary end point of overall survival (OS) over plati- num-based chemotherapy in treatment-naive advanced/metastatic non—small- cell lung cancer (NSCLC). The effect, the authors from the KEYNOTE-042 study found, was agnostic of PD-L1 expression, meaning the monoclonal antibody was effective for tumors expressing PD-L1 at ≥50%, ≥20%, and ≥1%.¹

However, the secondary outcome of progression-free survival (PFS) was not met at data cut-off on February 26, 2018.

Previously, pembrolizumab monotherapy has shown significant improvement in OS over docetaxel as second-line treatment in metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥1%. Additionally, patients whose NSCLC had a PD-L1 TPS of ≥50% saw significant improvements in both PFS and OS with first-line pembrolizumab, compared with platinum-based chemotherapy (KEYNOTE-024).²

Results from the KEYNOTE-189 study, published earlier this year, emphasized the advantage of combining chemotherapy with pembrolizumab: The researchers showed that the combination approach as first-line treatment in patients with metastatic NSCLC, who had no EGFR or ALK alterations, was significantly better than chemotherapy alone and was agnostic of PD-L1 expression.³

“Our trial, KEYNOTE-042, is evaluating pembrolizumab monotherapy against platinum-based chemotherapy for metastatic NSCLC with low expression of PD-L1,” said lead author Gilberto Lopes, MD, MBA, Sylvester Comprehensive Cancer Center, University of Miami Health System. The trial was designed to develop a more effective and tolerable first-line treatment for metastatic NSCLC, he said.

Eligibility criteria included locally advanced or metastatic tumors with PD-L1 TPS ≥1%, without EGFR or ALK alterations. The ECOG status had to be 0 or 1; patients had to be free of untreated or unstable CNS metastases.

Treatment-eligible patients were randomized 1:1 to ≤35 cycles of pembroli- zumab 200 mg every 3 weeks or investigator’s choice of ≤6 cycles of paclitaxel + carboplatin or pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary end points were OS in patients with TPS≥50%, ≥20%, and ≥1%. Secondary end points were PFS and objective response rate for all 3 TPS, and safety in patients with TPS ≥1%.

At 12.8 months median follow-up, 13.7% of patients were still on pembrolizumab and 4.9% were receiving pemetrexed maintenance treatment.

In the TPS ≥50% subset, median OS at 24 months was 20 months (range, 15.4-24.9) in the pembrolizumab-treated patients (event rate: 44.7%) and 12.2 months (range, 10.4-14.2) in those treated with chemotherapy (event rate: 30.1%). Similarly, in the TPS ≥20% subset, median OS at 24 months was 17.7 months (range, 15.3-22.1) in the pembrolizumab-treated patients (event rate: 40.5%) and 13.0 months (range, 11.6-15.3) in those treated with chemotherapy (event rate: 29.6%). Among patients whose tumors expressed a low level of PD-L1 (TPS ≥1%), median OS at 24 months was 16.7 months (range, 13.9-19.7) in the pembrolizumab-treated arm (event rate: 39.3%) and 12.1 months (range, 11.3-13.3) in those treated with chemotherapy (event rate: 28.0%).

Lopes shared the PFS data in the TPS ≥20% cohort. Median PFS at 12 months was 6.2 months (range, 5.1-7.8) in the pembrolizumab-treated arm (event rate: 32.4%) and 6.6 months (range, 6.2-7.3) in those treated with chemotherapy (event rate: 28.8%).

Grade 3-5 drug-related adverse events (AEs) were less frequent with pembroli- zumab, Lopes said (17.8% vs 41.0% for chemotherapy). However, the rates of discontinuation (about 9.0%) and treatment-related deaths (about 2.0%) were similar between the 2 groups. Immune-related AEs (irAEs) are significant concerns that accompany the use of immune checkpoint inhibitors such as pembrolizumab.⁴ Lopes shared that about 27.8% of patients treated with pembrolizumab experienced irAEs, and 1 patient died as a result. Only 7% of patients in the chemotherapy arm had irAEs.

“KEYNOTE-042 is the first study with a primary end point of overall survival to demonstrate superiority of pembrolizumab over platinum-based chemotherapy in patients with previously untreated advanced/metastatic NSCLC without sensitizing EGFR or ALK alterations and a PD-L1 TPS ≥1%,” the authors concluded.

“Our data confirm and potentially extend the role of pembrolizumab monotherapy as a standard first-line treatment for patients with PD-L1—expressing tumors,” said Lopes. He shared that based on the advice of their external drug monitoring committee, the trial continues to evaluate PFS in this trial population.

Leena Gandhi, MD, currently the director of thoracic medical oncology and an associate professor of medicine at the New York University School of Medicine, who will soon be joining Eli Lilly and Company,⁵ was the discussant for this abstract.

Comparing the performance of nivolumab, the other PD-1 inhibitor, with pembrolizumab, Gandhi questioned whether the crossover allowed in the CheckMate-026 study may have resulted in the failure of nivolumab as first-line treatment in advanced/metastatic NSCLC. “Overall, the studies are more similar than they are different,” she said. However, CheckMate-026 allowed 60.4% of patients in the chemotherapy arm to cross over to the nivolumab arm, whereas only 19.8% in KEYNOTE-042 who received chemotherapy were subsequently treated with pembrolizumab.

She identified several caveats with the KEYNOTE-042 results:

• The benefit is driven by high PD-L1 expressors
• PD-L1 expression has high clinical utility and should be used, but it could be complemented by following tumor mutation burden expression in the tumor samples
• She advised researchers to analyze the tumor microenvironment

References

1. Lopes G, Wu Y, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first- line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(suppl; abstract LBA4).
2. Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-24 Investigators. Pembrolizumab versus chemo- therapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi: 10.1056/ NEJMoa1606774.
3. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
4. Davio K. Oncologists must weigh risks, benefits of immune checkpoint inhibitors. The American Journal of Managed Care® website. ajmc.com/conferences/nccn-2018/oncologists-must-weigh-risks-benefits-of-immune-check- point-inhibitors. Published March 26, 2018. Accessed June 4, 2018.
5. Leena Gandhi, MD, PhD, to lead Lilly oncology immuno-oncology medical development [news release]. Indianap- olis, IN: Eli Lilly and Company; April 30, 2018. prnewswire.com/news-releases/leena-gandhi-md-phd-to-lead-lil- ly-oncology-immuno-oncology-medical-development-300638547.html. Accessed June 4, 2018.

Phase 3 TAILORx Results Confirm Chemotherapy Unnecessary in 70% of Women With Early-Stage Breast Cancer

Surabhi Dangi-Garimella, PhD

Trial Assigning Individualized Options for Treatment (Rx), or TAILORx, suc- cessfully confirmed the benefit of endocrine therapy (ET) alone in patients with early-stage breast cancer who have an Oncotype DX Breast Recurrence Score (RS) of 11 to 25.

The long-awaited results of the TAILORx study, the largest-ever breast cancer treatment trial, sponsored by the National Cancer Institute and led by the ECOG- ACRIN Cancer Research Group, were presented at the 2018 American Society of Clinical Oncology Annual Meeting by Joseph A. Sparano, MD, professor of medicine and obstetrics, gynecology, and women’s health at the Albert Einstein College of Medicine; associate chairman for clinical research in the Department of Oncology at Montefiore Medical Center; and associate director for clinical research at the Albert Einstein Cancer Center, all in New York City.

The Oncotype DX RS ranges from 0 to 100 and can predict chemotherapy benefit when the score is high, meaning higher than either 26. A score lower than 10 means the risk of distant recurrence is low, and the women will not benefit from chemotherapy. “The gray area has been the mid-range RS score of 11 to 25—this target population accounts for about 50% of women in the United States,” Sparano said.

The TAILORx trial was designed to help personalize treatment for women aged 18 to 75 years with hormone receptor—positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node (AN)-negative breast cancer whose tumors were 1.1 cm to 5.0 cm in size and who had a mid-range RS. The trial, which enrolled 10,273 women, aimed to clarify whether hormone therapy alone or together with chemotherapy is better for women with an RS of 11 to 25. The trial also was designed to confirm that a low RS of 0 to 10 is associated with a low rate of distant recurrence when patients receive endocrine therapy alone.

A majority (6711; 69%) of the 9719 eligible women had a midrange RS of 11 to 25 and were randomized to either the chemoendocrine treatment (CET) arm or the ET arm. Women with an RS of 10 or lower (1619; 17%) were in the ET arm and those with a RS of 26 or higher (1389; 14%) were in the CET arm. The primary endpoint was invasive disease-free survival (iDFS), and the trial was designed to show noninferiority for ET alone.

Key secondary end points included freedom from recurrence of breast cancer at a distant site, freedom from recurrence of breast cancer at a distant or local— regional site, and overall survival (OS).

At a median follow-up of 90 months (7.6 years), there were 836 iDFS events at final analysis. ET was noninferior to CET for iDFS (hazard ratio [HR], 1.08; 95% CI, 0.94-1.24; P = .26) in the intention-to-treat (ITT) population. ET was also noninferior for distant recurrence-free interval (DRFI; HR, 1.03; P = .80), recurrence-free interval (RFI; HR 1.12; P = .28), and OS (HR, 0.97; P = .80).

Nine-year rates were similar for iDFS (83.3% vs 84.3%), DRFI (94.5% vs 95.0%), RFI (92.2% vs 92.9%), and OS (93.9% vs 93.8%) for the RS 11-to-25 arm. The overall recurrence rate was 5%. The study found 3% distant recurrence with ET alone in the RS 0-to-10 arm and 13% distant recurrence with CET in the RS 26-to-100 arm.

The study observed a potential chemotherapy benefit in younger women (≤50 years) with an RS of 16 to 25, while RS of 0 to 15 had good prognosis with endocrine therapy. “Chemotherapy should be used with caution in this [RS 11-to-25] subgroup with a shared decision-making process for deciding the treatment path,” Sparano concluded.

Sparano concluded that in women with hormone receptor—positive, HER2- negative, AN-negative breast cancer who had a RS of 11 to 25, adjuvant ET was not inferior to CET in the ITT analysis. However, recurrence was high in the RS 26-to-100 arm despite adjuvant CET.

“The results of our trial suggest that the 21-gene assay may identify up to 85% of women with early breast cancer who can be spared adjuvant chemotherapy, especially those who are older than 50 years of age and have a recurrence score of 25 or lower, as well as women 50 years of age or younger with a recurrence score of 15 or lower,” Sparano and colleagues wrote in the accompanying paper, published in the New England Journal of Medicine.

Reference

Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer [published online June 3, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1804710.

Cetuximab With Chemoradiation Worse Than Chemoradiation Alone in Older Patients With HNSCC

Surabhi Dangi-Garimella, PhD

Treatment with cetuximab (CX), concurrent with chemoradiation (CRT), in older patients diagnosed with head and neck squamous cell carcinoma (HNSCC) has similar toxicity as CRT alone, but the overall survival (OS) is inferior. These are the results of a retrospective analysis that was presented at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.¹

Cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor, was approved in 20062 for the treatment of metastatic colorectal cancer; local or advanced HNSCC, in combination with CRT; and metastatic HNSCC.

The antibody has been increasingly used in older patients with HNSCC as a radiosensitizer for CRT. “However, overall survival after definitive CRT-CX, compared with definitive CRT, has not been adequately evaluated outside of younger more highly selected clinical-trial populations with locally advanced HNSCC,” said Dan Paul Zandberg, MD, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, who presented the results of the study.

For their study, the authors used the Surveillance Epidemiology and End Results (SEER) cancer registry programs data that were linked with the Medicare database to evaluate OS in patients with HNSCC diagnosed between 2005 and 2011.

Inclusion criteria included individuals who had continuous Medicare Part A and B coverage. Patients on a health maintenance organization plan during the 12 months prior to receiving their diagnosis were excluded. Additionally, inclusion in the study required access to complete claims for at least a year after diagnosis and primary treatment should have been radiation treatment (RT) alone or CRT.

Enforcement of the inclusion/exclusion criteria identified 2135 beneficiaries, a majority of whom were male (73.5%), with a median age of 73 years (range, 66-104 years). Primary subsites of disease in these patients were oropharynx (OP, 61%), hypopharynx (HP, 15%), nasopharynx (5%), and larynx (19%). Eighty-two percent of patients received platinum-based chemotherapy, of which 52% received cisplatin.

The authors found that OS in the CRT-CX—treated patients was worse than those who received CRT (P <.005) and similar to RT (P = .21): The 5-year OS was 46% for CRT, 35% for CRT-CX, and 32% for RT. The median survival was 4.5 years (range, 3.8-4.9 years), 2.5 years (range, 2.2-3.0 years), and 2.2 years (range, 2.0-3.0 years) in the CRT, CRT-CX, and RT populations, respec- tively. The risk of death was greater with CRT-CX compared with CRT (HR, 1.41 [range, 1.24-1.61]; P = .0001), after stratifying by stage and primary site and adjusting for gender, race, age, income, Charlson comorbidity index, marital status, hospital type, and year of diagnosis.

In the context of the primary site, a similar trend was observed. The 5-year OS in patients with OP disease was highest with CRT-treated patients (54%; median OS, 5.59 years) compared with CRT-CX (39%; median OS, 2.95 years) and RT (34%; median OS, 2.24 years). In patients with HP disease, the 5-year OS was 34%, 22%, and 26% in the CRT, CRT-CX, and RT groups, respectively.

However, CRT led to a significantly higher rate of hearing loss within the first 3 months of treatment compared with CRT-CX (9.3% vs 4.1%; P <.001); dysphagia, gastrostomy tube placement, pneumonia, and weight loss occurred at similar rates between the 2 treatment groups over the first 12 months after diagnosis.

“Analysis of real-world data and the large patient numbers are the strengths of our retrospective study,” Zandberg said. He acknowledged, however, that their research group was unable to obtain data on performance status, overall frailty, and severity of comorbidities in the patient population.

Zandberg concluded that definitive treatment with CRT-CX was associated with inferior OS compared with CRT even after adjust- ment for established prognostic factors, and with similar toxicity, in the SEER-Medicare patient population. “Our data suggest that noncetuximab-based CRT should be used for eligible older HNSCC patients,” he said.

Cisplatin remains the standard of care for concurrent therapy with RT, with CX as an option in patients who cannot tolerate cisplatin.

References

1. Zandberg DP, Cullen KJ, Varki V, et al. Definitive cetuximab-based (CRT-CX) vs. non-cetux- imab based chemoradiation (CRT) in older patients with squamous cell carcinoma of the head and neck (HNSCC): analysis of the SEER-Medicare linked database. J Clin Oncol. 2018;36(suppl; abstr 6001).
2. Cetuximab. National Cancer Institute website. cancer.gov/about-cancer/treatment/drugs/ cetuximab. Updated March 9, 2018. Accessed June 4, 2018.

Immune Checkpoint Inhibitors Improve Outcomes in Mismatch Repair Deficient CRC, but Can Induce Immune-Related Adverse Effects

Surabhi Dangi-Garimella, PhD

Treatment of colorectal cancer (CRC)—the third leading cause of cancer-related death in the United States&mdash;remains challenging. But according to leading oncologists in the field, who were speaking at a session at the 2018 American Society of Clinical Oncology Annual Meeting, screening patients diagnosed with CRC for deficient mismatch repair (dMMR) could help create a road- map for precision treatment.

Michael J. Overman, MD, of The University of Texas MD Anderson Cancer Center in Houston, chaired the session and was the first presenter. During his presentation, Optimal Approach to Colorectal Cancer With Deficient Mismatch Repair, he said that microsatellite instability (MSI) and dMMR testing should be universal for patients with CRC, especially individuals who have a family history of CRC.

In terms of new treatment options, he noted that immune checkpoint inhibitors, namely the programmed death-1 (PD-1) inhibitors, nivolumab and pembrolizumab, now have added indications in the treatment of CRC:

• Nivolumab: MSI high (MSI-H) or dMMR metastatic CRC (mCRC) that has progressed on fluoropyrimidine, oxaliplatin, and irinotecan
• Pembrolizumab: adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR CRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

The National Comprehensive Cancer Network, Overman said, recommends nivolumab or pembrolizumab as a treatment option for patients with metastatic dMMR CRC as second- or third-line therapy.

The rationale here is based on studies showing that high tumor mutational burden (TMB) can increase sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and programmed death ligand-1 (PD-L1) blockade immunotherapy.

Frameshift mutations in CRC can result in new neoantigen targets, including proteins involved in differentiation (eg, melanocyte differentiation antigens), overexpressed proteins (eg, human epidermal growth factor receptor 2), and viral proteins (eg, human papillomavirus). MSI-H tumors have a very high mutation rate; when that is combined with frameshift mutations, in which a single alteration leads to multiple amino acids, the results are mutations that have significant qualitative and quantitative mutation rates.

“In the clinic, we typically see patients present with a very high rate of mutation,” Overman said.

He noted, however, that there remain significant discrepancies between the testing methodologies used to detect dMMR. Mosaic testing, Overman said, is much more sensitive and more specific than polymerase chain reaction.

Overman’s group conducted studies comparing nivolumab and ipilimumab in patients diagnosed with dMMR/MSI-HCRC who had received at least 2 prior lines of treatment. They investigated whether addition of the cytotoxic T-lymphocyte- associated protein 4 inhibitor, ipilimumab, could further enhance outcomes compared with nivolumab alone. The study results, published in the Journal of Clinical Oncology,¹ found that the investigator-assessed objective response rate (ORR) was 55% (95% CI, 45.2%-63.8%) and the disease control rate for ≥12 weeks was 80% for patients treated with the combination. At data cut-off, the median duration of response was not reached and most responses were ongoing. Progression-free survival (PFS) rates were 76% (9 months) and 71% (12 months), and overall survival (OS) rates were 87% (9 months) and 85% (12 months).

Overman also drew attention to the results from KEYNOTE-164, which evaluated pembrolizumab in patients with MSI-H CRC who had received at least 2 prior lines of treatment. When data were acquired in October 2017, after a median of 12.6 months of follow-up, the ORR was 32% (95% CI, 21%-45%), with 2 complete responses and 18 partial responses. Median PFS was 4.1 months, and the 12-month PFS rate was 41%. The 12-month OS rate was 76%.²

“Questions remain, however, around the durability of nivolumab’s effect in dMMR CRC,” Overman said.

Several phase 3 trials are ongoing, he said, to test these immune checkpoint inhibitors in patients with MSI-H/dMMR CRC.

• NRG-G1004/SWOG-1610 is evaluating how well the combination of chemotherapy, bevacizumab, and/or atezolizumab will work in advanced MSI-H/dMMR CRC3
• KEYNOTE-177 is evaluating the combination of pembrolizumab with mFOLFOX/bevacizumab in advanced MSI-H/CRC4
• Alliance 021502 is evaluating combination chemotherapy and atezolizumab in patients with stage II dMMR CRC.⁵

“Pembrolizumab is now standard of care for dMMR non-CRC patients” Overman said, and he sees a way forward for success with immune checkpoint inhibitors in combination with chemotherapy, in CRC as well.

Immune-Related Adverse Events

Another speaker during the session, Marc S. Ernstoff, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, gave an overview of the management of immune-related adverse events (irAEs) in mCRC.

When Ernstoff surveyed oncologists asking if they were comfortable with managing irAEs, the results indicated that discomfort is common, he shared. A total of 32% of providers are very uncomfortable with managing irAEs, he said, while 5% are somewhat uncomfortable, 19% somewhat comfortable, and 33% very comfortable.

Ernstoff noted that immune toxicities in CRC may not necessarily be related to the specific antibody being administered. It’s important to understand, he said, that the effects are not immediate; rather, one might be dealing with latent toxicity, and such toxicities can affect any organ.

The most common of these toxicities are pruritis, rash, and diarrhea, and they were more often observed when nivolumab was combined with ipilimumab, compared with when nivolumab was administered alone. The incidence of irAEs was also high when ipilimumab was administered alone.⁶

The recognition of irAEs is vital, Ernstoff emphasized. Some of the more unusual symptoms can include the development of diabetes, nephritis, myositis, myocarditis, and uveitis.

“A high percentage of low-grade (<3) irAEs are common, even with single agents,” he said, with 10%-25% remaining unresolved for at least 12 months. Ernstoff explained that a majority of patients may require steroid treatment for symptom resolution, especially if they are on combination immune checkpoint inhibitors.

Dealing with long-term irAEs is the biggest challenge of cancer survivorship in patients receiving these checkpoint inhibitors, he said.

It is vital to recognize the grade of the AEs: For low-grade AEs, symptom management can usually suffice, whereas for high-grade AEs, immunosup- pression using glucocorticoids or infliximab/mycophenalate is recommended. Chronic immune suppression would require steroid treatment, anti-integrins, or anti—tumor necrosis factor agents.

Is mitigation an option? This remains unknown for the time being, Ernstoffsaid, adding that an individual’s genetic predisposition could be investigated. Another strategy could be boosting the microbiome, using, for instance, probiotic agents. A further tactic would be identifying members of high-risk popula- tions, including those patients with existing autoimmune disease or those who have had an organ transplant.

“Overall, immune checkpoint inhibition of the PD1/PD-L1 axis has been well tolerated and is safer than conventional chemotherapy,” Ernstoff said. He emphasized the importance of oncologists educating themselves and profile of these agents, especially because “irAEs can masquerade as other common symptoms.”

References

1. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mis- match repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773- 779. doi: 10.1200/JCO.2017.76.9901.
2. Le DT, Kavan P, Kim TW, et al. KEYNOTE-164: pembrolizumab for patients with advanced microsatellite instability high (MSI-H) colorectal cancer. J Clin Oncol. 2018;36(suppl; abstr 3514).
3. Combination chemotherapy, bevacizumab, and/or atezolizumab in treating patients with deficient DNA mismatch repair metastatic colorectal cancer. clinicaltrials.gov/ct2/show/NCT02997228. Updated and accessed June 4, 2018.
4. Study of pembrolizumab (MK-3475) vs standard therapy in participants with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) stage IV colorectal carcinoma (MK-3475-177/KEYNOTE-177). clinicaltrials.gov/ct2/show/NCT02563002?term=Keynote-177&rank=1. Updated May 18, 2018. Accessed June 4, 2018.
5. Combination chemotherapy with or without atezolizumab in treating patients with stage III colon cancer and deficient DNA mismatch repair. clinicaltrials.gov/ct2/show/NCT02912559?term=Alliance+021502&rank=1. Updated and accessed June 4, 2018.
6. Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-pro- grammed death-1 agents. Oncologist. 2016;21(10):1230-1240.

Cemiplimab, in GOG 2016, Looks to Break New Ground for Immunotherapy in Cervical Cancer

Mary Caffrey

Several studies involving immunotherapy to treat cervical cancer have reached phase 2. But a phase 3 trial is under way with cemiplimab, after researchers at Regeneron saw a positive signal in a phase 1 study and opted to move immediately to a randomized clinical trial. GOG 3016, which is now recruiting participants at 53 locations in the United States and internationally, activated in late 2017 to study patients with recurrent and metastatic cervical carcinoma.¹

While patients with cervical cancer may experience modest survival benefits with initial treatment (with or without bevacizumab), those who have a recurrence after being treated with platinum-based chemotherapy have a median survival of just 7 months, according to the research update offered June 4, 2018, at the annual meeting of the American Society of Clinical Oncology, held in Chicago, Illinois.²

But the nature of cervical cancer meant that immunotherapy could be a treatment choice.

“For women with metastatic cervical cancer who have progressed on first-line therapy, there really has been nothing out there for them,” Matthew Fury, MD, senior director of clinical sciences in oncology for Regeneron, said in an email to The American Journal of Managed Care^®. “Because almost all cervical cancers are HPV [human papilloma virus]-associated, the presence of a viral antigen in these tumors creates the potential for robust anti-tumor immune responses and prolonged survival.”

GOG 3016, a randomized (1:1), open-label trial, seeks to enroll 436 patients who have previously been treated with platinum-based chemotherapy. They will receive either cemiplimab, a human monoclonal anti—programmed death cell-1 therapy, or the investigator’s choice of several forms of chemotherapy:

• antifolate: pemetrexed
• topoisomerase 1 inhibitor: topotecan or irinotecan
• nucleoside analogue: gemcitabine
• vinca alkaloid: vinorelbine¹

Fury said GOG 3016 results from the phase 1 study of cemiplimab showed durable responses in 2 of the 3 cervical cancer patients who were enrolled in the dose-escalation portion of the study. “We thought that this was a potentially important efficacy signal in a patient population with unmet need,” Fury said, and the results dovetailed with those being seen with immune checkpoint inhibitors in other virally associated cancers, like oropharynx cancer and Merkel cell carcinoma.

“These observations suggested to us that cemiplimab has the potential to improve survival in women with advanced cervical cancer who have exhausted the potential for clinical benefit with currently available treatments, and that a phase 3 trial was the way to go,” Fury said.

Similarly, Regeneron moved quickly on an early impressive signal in a patient with advanced cutaneous squamous cell carcinoma, he said.

References

1. Study of REGN2810 in adults with cervical cancer. clinicaltrials.gov/ct2/show/ NCT03257267?term=03257267&rank=1. Updated May 17, 2018. Accessed June 5, 2018.
2. Tewari KS, Vergote I, Oaknin A, et al. GOG 3016/ENGOT-cx9: an open-label, multi-national, randomized, phase 3 trial of cemiplimab, an anti-PD-1, versus investigator’s choice (IC) chemotherapy in ≥2 line recurrent or metastatic cervical cancer. J Clin Oncol. 2018;36 (suppl; abstr TPS5600).

Identifying Rational Immunotherapy Combinations for Gliobastoma: A Progress Report

Surabhi Dangi-Garimella, PhD

For immunotherapy to work in glioblastoma multiforme (GBM), which has an estimated 5-year survival rate of 33% in the United States, combination treatments are the way forward, according to global experts who appeared at a session of the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

Chairing the session was Amy B. Heimberger, MD, professor, Department of Neurosurgery, The University of Texas MD Anderson Cancer Center. During her presentation, Heimberger offered a flavor of the potential strategies that clinicians can pursue for antitumor immune induction in glioblastoma.

“What are key steps necessary for an optimal antitumor immune therapeutic response in brain tumors?” she asked, considering that glioblastomas are highly immunosuppressive.

How do we overcome lack of T-cell infiltration in the tumor? She shared the results of a successful single-patient strategy in a patient with recurrent multifocal glioblastoma who received chimeric antigen receptor (CAR) T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple intracranial infusions of the IL13Rα2 CAR T cells in the resected tumor cavity, as well as in the ventricular system, resulted in a regression of intracranial and spinal tumors in that patient—a response that was sustained for 7.5 months.¹

The CAR domain has several limitations, Heimberger pointed out: the lack of tumor-specific antigens, antigen escape, and in vivo persistence and generation of a product in a timely fashion.

“All these limitations need to be addressed to view the efficacy of CAR T cells in GBM,” she said.

Her laboratory has developed a small molecule inhibitor against STAT3, which is another key driver of GBMs. The researchers developed a small-molecule inhibitor called WP1066, which, they found, can block M2 macrophages. The drug has minimal toxicity, but it is lipophilic, meaning it is difficult for the drug to dissolve in the blood stream. The team had to be innovative in its approach, so the researchers spray-dried the drug with methylcellulose. A phase 1 trial of WP1066 is ongoing in patients with GBM refractory to treatment.

Another approach to treating GBM is via viral vaccines, and Michael Platten, MD, Mannheim University Hospital, German Cancer Research Center, provided the audience with an overview of where the field stands. His team has developed a novel method to detect the immunological presentation of the mutated antigen in tumor tissue of patients with brain tumors.

“We don’t know what the relevance of whole tumor vaccines is,” Platten said, and explained that several unknowns remain, including:

• How do you select appropriate target antigens?
• What are the appropriate biomarkers?
• How do you bring the vaccine in context with immunotherapeutics and checkpoint blockade agents?

There are 3 categories of antigens in GBMs, he noted:

• Tumor-associated antigens are shared antigens that have both low immunogenicity and potential for side effects
• Viral antigens are usually not endogenous; they are heterogenous if exogenously expressed
• Tumor antigen are specific but do not elicit a strong immune response

A recent paper published by Liau et al evaluated the impact of adding an autologous tumor lysate-pulsed dendritic cell vaccine to standard therapy in new GBM. The randomized phase 3 trial results demonstrated a median overall survival of 34.7 months from surgery, with a 3-year survival rate of 46.4%.²

Platten said that there is growing understanding in the field for neoepitope vaccines; these are unique to tumor cells and most arise from single nucleotide variables. Most neoepitopes are private, meaning they are found within a single family or small population, with the majority being class II epitopes. Gliomas have about 30 to 100 nonsynonymous mutations per megabase. Shared neoepitopes include EGFRvIII and IDH1R132H receptors.

“Clonality remains a question with shared epitope vaccines,” he said, adding that the natural clonal evolution of GBM results in the acquisition and loss of subclonal neoepitopes.

Platten believes the following treatments can complement vaccines in GBM treatment:

• Immunosuppressive agents for the tumor microenvironment
• Radiation therapy and oncolytic viruses
• Immune checkpoint blockade agents
• Small molecule targets

Immune response monitoring remains a significant issue in GBM treatment. “We need better tools to capture patient response to treatment,” said Platten.

Gavin P. Dunn, MD, PhD, Washington University School of Medicine in St. Louis, was up next. He provided an update on checkpoint inhibitors and combination strategy with targeted immunotherapies in GBM. Current checkpoint inhibitors do not have any indication for GBM.

Although there are some responders to immunotherapies, presenting with long-term control and partial remission after pseudoprogression, the question is, how do you identify these responders? “While there are anatomic site-specific considerations, the checkpoint pathway does remain the canonical pathway for targeting T-cell immune responses,” Dunn said.

Study findings have shown a trend of increased sensitivity to checkpoint blockade with increasing mutational burden for different cancer types, he said. “Therefore, mutation burden is the engine for generating candidate neoantigens.”

Whereas some studies’ results have shown that the incidence of hypermutated genotype in primary GBMs is low, research from Dunn’s lab shows that hypermutated patients with GBM do respond to PD-1 inhibitors—in this case, pembrolizumab (Keytruda).³

However, researchers need to be aware of the failure nodes of immune function, which can lead to lack of response to checkpoint blockade in GBM:

• Lack of efficient antigen presentation
• Impaired homing mechanisms
• STAT reactivation at the tumor site
• Checkpoint inhibition blockade inhibition or T-cell exhaustion

Dunn noted that there are 4 ongoing trials that are evaluating rational combination treatments for recurrent GBM, including the CAPTIVE trial,⁴ and another evaluating a LAG3 inhibitor or urelumab⁵ in combination with nivolumab.

Dunn agreed with previous speakers that combination therapy may be the way forward for the successful treatment of GBMs.

References

1. Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561-2569. doi: 10.1056/NEJMoa1610497.
2. Liau LM, Ashkan K, Tran DD, et al. First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16(1):142. doi: 10.1186/s12967- 018-1507-6.
3. Johanns TM, Miller CA, Dorward IG, et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 2016;6(11):1230-1236.
4. Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE). clinicaltrials.gov/ct2/ show/NCT02798406. Updated March 16, 2018. Accessed June 5, 2018.
5. Anti-LAG-3 or Urelumab Alone and in Combination With Nivolumab in Treating Patients With Recurrent Glioblastoma. clinicaltrials.gov/ct2/show/NCT02658981?term=LAG3+nivolumab&cond=glioblastoma&rank=1. Updated May 28, 2018. Accessed June 5, 2018.

Persephone Trial: Cutting Trastuzumab Duration by Half Safer, Efficacious in HER2-Positive Breast Cancer

Surabhi Dangi-Garimella, PhD

More than 4000 women with HER2-positive early-stage breast cancer who were treated with trastuzumab (Herceptin) for 6 months had a similar rate of disease-free survival (DFS) as women who received the drug for twice the length of time. Meanwhile, nearly double the number of women who were treated with trastuzumab for a year dropped out of the trial due to cardiac problems compared with the shorter duration. These results from the Persephone trial were presented during the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, Illinois.¹

The 12-month adjuvant treatment with trastuzumab, added to chemotherapy, is adopted from the drug’s registration trials and is the current standard of care. However, the addition of trastuzumab led to significantly high rates of cardio-toxic effects, resulting in several follow-up studies evaluating the high risk of cardiac problems that the drug induces.^2,3

The Persephone trial worked on the hypothesis that a shorter treatment duration could reduce toxicities and cost while providing similar efficacy. Hailed as the largest reduced-duration noninferiority international trial, Persephone recruited HER2-positive patients diagnosed with early-stage breast cancer who were then stratified based on their estrogen receptor (ER) status, chemotherapy type, and timing of chemotherapy and trastuzumab. The trial’s primary endpoint was DFS from the time of diagnosis. The noninferiority query of the 6-month treatment was defined as “no worse than 3%” below the 80% 4-year DFS assumed for the 12-month arm.

Of the 4089 patients randomized to receive the treatment in 152 sites in the United Kingdom between 2007 and 2015:

• 69% were ER positive
• 41% received anthracycline-based chemotherapy
• 49% received anthracycline- and taxane-based chemotherapy
• 10% received taxane-based chemotherapy
• 85% received adjuvant chemotherapy
• Sequential trastuzumab was administered in 54% of patients

At a median follow-up period of 5 years, the researchers found near-identical results between the 2 treatment arms: DFS was 89.4% among women in the 6-month arm and 89.8% in the 12-month arm (HR, 1.29).

Significant reductions in cardiac events was observed in the 6-month treated group compared with the 12-month treated group: Only 4% of women treated with trastuzumab for 6 months experienced heart-related issues and stopped treatment. On the other hand, 8% of women in the 12-month group had to stop their cancer care because of cardiotoxicity (P <.0001).

Speaking during a press cast hosted by ASCO prior to the meeting, the study’s lead author, Helena Earl, MD, professor of clinical cancer medicine, University of Cambridge, United Kingdom, said that the results from the Persephone trial confirmed the noninferiority of 6-month adjuvant treatment with trastuzumab compared with the 12-month treatment. “The 6-month treatment also reduced cardiac toxicity and costs the patient and the health system less,” she added.

Ongoing research in this patient population is evaluating quality-of-life and patient-reported outcomes in this study population. The study authors are also conducting health economic assessments of the reduced treatment duration with the drug.

References

1. Earl HM, Hiller L, Vallier AL; PERSEPHONE Trial Investigators. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2018;36(suppl; abstr 506). abstracts.asco.org/214/AbstView_214_217191.html.
2. Onitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors. Ther Adv Drug Saf. 2014;5(4):154-166. doi: 10.1177/2042098614529603.
3. Patt D. Influence of cardiotoxic risk on treatment choice in adult cancers. Am J Manag Care. 2015;21(SP8):SP271-SP272.

Opdivo Plus Chemo Boosts Progression-Free Survival 26% Over Chemo Alone in Late-Stage NSCLC

Mary Caffrey

Combination treatments involving checkpoint inhibitors continue to gain attention, including those involving more than 1 immunotherapy and that comprise immunotherapy and chemotherapy. Researchers continue to seek biomarkers that will allow them to match treatment combinations with patients who will most benefit.

Bristol-Myers Squibb results presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, followed up on results ASCO released earlier in 2018 from the phase 3 Checkmate 227 trial in non—small cell lung cancer (NSCLC). The earlier results, involving the nivolumab (Opdivo) and ipilimumab (Yervoy) combination, showed that this combination reduced progression risk by 42% for patients with a high tumor mutation burden.¹

The Checkmate 227 results presented June 4, 2018, involved patients in the trial arm who were treated with nivolumab and chemotherapy. The abstract included 550 chemotherapy-naive patients with stage IV or recurrent NSCLC; they had no known EGFR/ALK mutations and had <1% PD-L1 expression. The results compared 177 patients in the nivolumab-plus-chemotherapy arm compared with 186 who were treated with chemotherapy only.²

Those in the nivolumab/chemotherapy arm had improved progression-free survival (PFS) over the chemotherapy arm (HR, 0.74; CI 95%, 0.58-0.94). The minimum follow-up was 11.2 months, and patients were treated for up to

2 years. Most subgroups saw PFS with the nivolumab/chemotherapy combina- tion, but the benefit was more pronounced among nonsquamous (HR = 0.68) than among squamous (HR = 0.92) histologies.

The rates of adverse events that caused patients to stop taking therapy were about the same in both the nivolumab/chemotherapy arm (13%) and the chemotherapy arm (14%).

References:

1. Harris J. Frontline nivolumab/ipilimumab reduces progression risk by 42% in TMB-high NSCLC. OncLive^®website. onclive.com/conference-coverage/aacr-2018/frontline-nivolumabipilimumab-reduces-progression-risk-by-42-in-tmbhigh-nsclc. Published April 16, 2018. Accessed June 4, 2018.
2. Borghaei H, Hellman MD, Paz-Ares LG, et al. Nivolumab (Nivo) + platinum doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression. J Clin Oncol. 2018;36(suppl; abstr 9001). abstracts.asco.org/214/AbstView_214_229709.html.

Nelarabine With Chemotherapy Boostd Outcomes in Pediatric and YA Patients With T-Cell Cancers

Surabhi Dangi-Garimella, PhD

A phase 3 study, started in 2007 by the Children’s Oncology Group (COG), among children and young adults diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic leukemia (T-LL), has found a 90% survival rate at 4 years after the start of treatment. Among these patients, 84% were declared cancer free at the 4-year mark in their treatment trajectory. Results were presented at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

The COG AALL0434 study enrolled 1895 patients aged 1 to 30 years between January 2007 and July 2014 to test nelarabine (Arranon), an antineoplastic agent directed against T cells, in combination

with chemotherapy. The trial had 4 arms, and all patients received COG-augmented Berlin-Frankfurt-Munster (BFM) or augmented BFM chemotherapy. Additionally, they were randomized to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (Oncaspar) (CMTX) or high-dose MTX (HDMTX) plus leucovorin rescue. Patients with moderate or high risk (based on genetics or prior radiation exposure) were randomized to receive, or not receive, six 5-day courses of nelarabine 650 mg/m2/day complemented with chemotherapy and cranial radiation.

“T-cell ALL is a disease that requires the use of a very intense and complex chemotherapy regimen. Historically, about 80% of people live at least 4 years after being treated for their disease, but we felt we could and must do better,” lead author Kimberly Dunsmore, MD, professor, Virginia Tech Carilion School of Medicine, said in a press release. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”

For all patients, the overall disease-free survival (DFS) rate was 84.3% +/- 1.1% at 4 years and the overall survival rate was 90.2% +/- 0.9%. The 4-year DFS rate for patients with T-ALL randomized to nelarabine (n = 323) versus no nelarabine (n = 336) was 88.9% +/- 2.2% versus 83.3% +/- 2.5%, (P = .0332).

Among patients with T-ALL randomized to CMTX, the 4-year DFS for nelarabine (n = 147) versus no nelarabine (n = 151) was 92.2% +/- 2.8% versus 89.8% +/- 3.0% (P = .3825). For patients randomized to HDMTX, the 4-year DFS was 86.2% +/- 3.2% with nelarabine (n = 176) versus 78.0% +/- 3.7% without nelarabine (n = 185; P = .024).

There was no advantage of nelarabine treatment for high-risk patients with T-LL. The 4-year DFS rates were 85.0% +/- 5.6% for nelarabine (n = 60) and 89.0% +/- 4.7% for patients who did not receive nelarabine (n = 58; P = .2788).

Overall toxicity and neurotoxicity were acceptable and not significantly different between all 4 arms, the authors concluded.

Future studies are directed to evaluate using nelarabine along with chemotherapy without cranial radiation to avoid the late adverse effects associated with radiating the brain, including cognitive changes, learning disabilities, neuroendocrine changes, and the development of secondary cancers.

Reference:

Dunsmore KP, Winter S, Devidas M, et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy. J Clin Oncol. 2018;36(suppl; abstr 10500). abstracts.asco.org/214/AbstView_214_218959.html.

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