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For decades, physicians treating patients with melanoma had 1 option with demonstrated efficacy in the adjuvant setting: interferon alfa-2B.

That changed in 2015 with the approval of ipilimumab (Yervoy), an anti—CTLA-4 checkpoint blockade immunotherapy, as adjuvant therapy for patients with high-risk stage III melanoma. Now researchers are seeking to determine whether the plethora of new therapies that have been introduced in recent years in the advanced and metastatic settings can benefit patients at risk of recurrence earlier in the treatment timeline.

The potential for the expansion of therapeutic options was evident at the 2017 European Society for Medical Oncology (ESMO) Annual Congress, held in September in Madrid, Spain. Findings reported at the conference and simultaneously published in the 

 demonstrate a role for 2 modalities: nivolumab (Opdivo) monotherapy, a checkpoint blockade immunotherapy, for patients of any mutation status and combination therapy with dabrafenib (Tafinlar) and trametinib (Mekinist), small molecules that target kinases in the MAPK cell-signaling network, for patients with

In the CheckMate 238 trial, nivolumab resulted in a 35% improvement in relapse-free survival (RFS) compared with high-dose ipilimumab after a minimum 18-month follow-up, with a lower rate of adverse events (AEs).

 Nivolumab, an anti—PD-1 monoclonal antibody, was also superior on 1-year RFS in patients with 

-mutant disease. In the COMBI-AD trial, adjuvant treatment with dabrafenib and trametinib reduced the risk of relapse or death by 53% compared with placebo for patients with 

-mutant stage III melanoma after a median follow-up of 2.8 years.

 Dabrafenib inhibits BRAF while trametinib is aimed at MEK. The findings sparked a lively debate among key researchers at the ESMO conference about how best to administer adjuvant treatment.

Jeffrey S. Weber, MD, PhD, who presented the CheckMate 238 data, said nivolumab “looks like a superior adjuvant melanoma regimen compared with ipilimumab from every angle” and may also be a better choice than targeted therapy in this setting for patients with 

“It comes down to whether you believe there will be a tail on the curve for immunotherapy with RFS in the adjuvant mode as you see in metastatic patients, compared with a lesser tail on the curve for BRAF-MEK modes and metastatic modes,” said Weber, who is deputy director of the Perlmutter Cancer Center at New York University Langone Health in New York City. “It’s going to be a tough decision. I would speculate that a lot of doctors will like immunotherapy and use nivolumab even in mutated patients, and some considerable number of patients will get BRAF/MEK in the adjuvant setting.”

Axel Hauschild, MD, lead investigator on the COMBI-AD study, noted that patients might have a different perspective. Immunotherapy must be infused twice weekly while dabrafenib/trametinib are taken orally. He also noted that the treatments have distinct toxicity profiles.

“There will be patients who are not good candidates for targeted therapy,” said Hauschild, who is a professor of dermatology at the University of Kiel in Germany. “There will be patients who are not good candidates for immunotherapy. That is just a practical consideration.”

The phase III CheckMate 238 trial included 906 patients with stages IIIB, IIIC, and IV completely resected melanoma who had ≥50% risk of relapse over 5 years. Patients were randomly assigned 1:1 to 3 mg/kg intravenous (IV) nivolumab given every 2 weeks or 10 mg/kg IV ipilimumab every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks. The primary endpoint was RFS.

The FDA approved ipilimumab for adjuvant therapy of resected stage III melanoma based on an improvement in RFS versus placebo in a randomized phase III trial, but more than 50% of patients treated with ipilimumab experienced a grade 3/4 AE.

“There is a clear need to improve the risk-benefit ratio of adjuvant treatment given the toxicity observed with the approved ipilimumab adjuvant regimen of 10 mg/kg, particularly for patients with high-risk resected stage IIIB/C and IV melanoma,” said Weber.

Most patients (85%) in the trial had cutaneous melanoma. Four of 5 patients in each arm had stage IIIB or IIIC disease, about 42% had a 

 mutation, and nearly 34% had PD-L1 expression ≥5% (Figure). The median number of doses administered was 24 in the nivolumab group and 4 in the ipilimumab group. None of the participants remained on treatment at the time results were reported.

Figure. Patient Populations in Adjuvant Melanoma Trials

The Data Safety Monitoring Committee halted the study early due to clear evidence of benefit for nivolumab. In the planned interim analysis at a minimum follow-up of 18 months, the rate of RFS was significantly improved with nivolumab compared with ipilimumab (66.4% vs 52.7%), corresponding to a 35% reduction in risk (HR, 0.65; 

Weber noted key milestones demonstrating superiority of nivolumab, “a 10% difference at 12 months, slightly widening to a 13% difference at 18 months, with 66% relapse-free at 18 months.” When the primary endpoint was analyzed by PD-L1 status, 1-year RFS was superior with nivolumab versus ipilimumab in the subset with PD-L1 expression <5% (64% vs 54%; HR, 0.71) and in those with PD-L1 expression ≥5% (82% vs 74%; HR, 0.50). The median progression-free survival was not reached in the nivolumab arm and was 15.9 months in the ipilimumab arm in the former subset; it was not reached in either arm in the latter subset.

Nivolumab was also superior for 1-year RFS in patients with

-mutant disease (68% vs 63%; HR, 0.72) and

 wild-type disease (72% vs 57%; HR, 0.58).

Results were similar across prespecified patient subgroups. Distant metastases-free survival among stage III patients, an exploratory endpoint, was 80% at 1 year in the nivolumab arm and 73% in the ipilimumab arm (HR, 0.73; 

 = .0204). Postprotocol treatment with immunotherapy was twice as frequent in the ipilimumab arm versus the nivolumab arm (23% vs 11%). Weber noted that roughly 15% of patients in each arm had surgery as postprotocol treatment.

“I was struck by the fact that a fair number of patients could have surgery, suggesting that some of these patients were rendered free of disease yet again,” he said. He added that ipilimumab might retain a role for patients when nivolumab fails and another resection is possible.

There were significantly fewer treatmentrelated, clinically relevant AEs (grade 3/4) in the nivolumab arm compared with the ipilimumab arm (14% vs 46%). Ten percent of patients in the nivolumab group discontinued treatment due to AEs compared with 43% in the ipilimumab group.

There were no treatment-related deaths in the nivolumab group. One patient in the ipilimumab group died of marrow aplasia and another died of colitis. The percentage of patients with low-grade thyroid disorders, primarily hypothyroidism, was greater with nivolumab compared with ipilimumab (20.4% vs 12.6%).

“The results of CheckMate 238 are very exciting,” said John Haanen, MD, head of the Division of Medical Oncology at the Netherlands Cancer Institute in Amsterdam. “They show for the first time that an anti—PD-1 drug is superior in the adjuvant setting and, because of its lower toxicity, nivolumab is much easier to give than ipilimumab. The same occurs in the metastatic setting where anti-PD-1 treatment is more efficacious and has a much better safety profile and has replaced ipilimumab as first-line treatment.”

The FDA initially approved nivolumab for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if 

—mutation positive, a BRAF inhibitor. Nivolumab is now approved for patients with unresectable or metastatic disease as a single agent regardless of 

 mutation status and in combination with ipilimumab.

Results from COMBI-AD adjuvant treatment show that dabrafenib plus trametinib reduced the risk of relapse or death by 53% compared with placebo for patients with 

-mutant stage III melanoma, suggesting that the combination is likely to play an important role for these patients going forward.

After a median follow-up of 2.8 years, the 3-year RFS rate with dabrafenib and trametinib was 58% compared with 39% for placebo (HR, 0.47; 95% CI, 0.39-0.58; 

 <.001). “This is a very remarkable hazard ratio and if you look at the P value for the primary endpoint of RFS there are 13 zeroes, and therefore it is very impressive,” Hauschild said. Early data for overall survival (OS) showed that 86% of patients in the combination arm were alive at 3 years versus 77% with placebo (HR, 0.57; 95% CI, 0.42-0.79; 

 = .0006). At the interim analysis, the OS advantage was not yet deemed statistically significant, according to predefined criteria requiring a

“For overall survival, there was a 43% reduction in the risk of dying from metastatic melanoma, noted Hauschild. “A very impressive result that is maintained over time.”

Patients with BRAF V600E/K stage III melanoma were randomly assigned to dabrafenib plus trametinib (n = 438) or placebo (n = 432). All patients were within 12 weeks of complete surgical resection and had stage IIIA (18%), IIIB (41%), or IIIC (40%) disease (Figure). Dabrafenib was administered at 150 mg twice daily with 2 mg trametinib once daily for 12 months. The salvage therapies received following the study were similar in each arm, and, in some cases, included a rechallenge with BRAF/MEK inhibition, Hauschild noted.

“Both the placebo and the combination group received the same amounts of salvage therapy. Seventy-four percent of the patients received systemic treatment for progressive disease,” he said. “It is unlikely that overall survival was impacted by the salvage therapies, since it was so balanced between the 2 groups.”

The baseline characteristics were similar between groups. In the combination arm, the median age of patients was 50 years and 91% of tumors had the 

 mutation with the remainder having the V600K alteration. Most patients (92%) had an ECOG performance status of 0. Twelve percent of patients in the combination group had in-transit metastases versus 8% with the placebo. Seventeen percent of patients had ≥4 positive lymph nodes, with the remainder having <4.

The median RFS was not reached with the combination versus 16.6 months for placebo. RFS was improved with dabrafenib/trametinib across all subgroups, Hauschild noted. “There was not a single outlier,” he noted. “All 3 stages benefited from the combination in the same way.” HRs across all subgroups ranged from 0.33 to 0.55 in favor of dabrafenib and trametinib versus placebo.

The 1-year OS rates were 97% versus 94% and the 2-year OS rates were 91% and 83% for the combination and placebo groups, respectively. The 1-year RFS rates were 67% versus 56% and the 2-year rates were 67% versus 44% for dabrafenib and trametinib versus placebo, respectively. The most common locations of recurrence, for the combination and placebo, respectively, were loco-regional (12% vs 25%), distant (22% vs 29%), and both local and distant (2% vs 2%).

The risk of distant metastases or death was reduced by 49% with the combination versus placebo (HR, 0.51; 95% CI, 0.40-0.65). Additionally, there was a 53% improvement in freedom from recurrence with the combination (HR, 0.47; 95% CI, 0.39-0.57).

Almost all patients (97%) assigned to dabrafenib and trametinib experienced AEs compared with 88% for placebo. The rates of grade 3/4 AEs were 41% for the combination and 14% for placebo. Overall, AEs led to discontinuation for 26% of those in the combination arm versus 3% with placebo. The most common all-grade AEs in the combination arm, which were mostly grade 1/2, were pyrexia (63%), fatigue (47%), and nausea (40%).

“There were fortunately no fatal adverse events with the combination of dabrafenib and trametinib. There were no new toxicities that were not described for stage IV melanoma,” said Hauschild. “There were AEs leading to discontinuation in 26% of the patients, which is a bit more than we expected in advance but this is the adjuvant setting so the pressure on the patient to continue getting therapy is lower than in the stage IV setting.”

The FDA initially granted an accelerated approval for the combination of dabrafenib and trametinib for patients with

-mutant metastatic melanoma in January 2014. The combination received a full approval in November 2015, and is now also indicated for the treatment of patients with 

Additional research presented at ESMO showed how elusive effective treatment for patients with completely resected, high-risk melanoma can be. In the BRIM8 trial, vemurafenib (Zelboraf), a BRAF inhibitor, induced mixed results for patients with high-risk disease.

 Vemurafenib is approved as single-agent therapy and in combination with cobimetinib (Cotellic), a MEK inhibitor, for 

-mutant unresectable or metastatic melanoma.

Patients with stage IIIC disease experienced a median disease-free survival (DFS) of 23.1 months in the experimental arm versus 15.4 months in the placebo arm. However, the difference did not achieve statistical significance. Patients with stage IIC-IIIB disease had a nonstatistically significant 46% reduction in the HR for DFS, but the trial design defined a positive outcome on the basis of results in later-stage disease.

In all, 498 patients were enrolled: cohort 1 was composed of 314 patients with stage IIC-IIIB disease and cohort 2 was composed of 184 patients with stage IIIC disease. Patients in each cohort were randomly assigned to vemurafenib or placebo (surgery only), and treatment continued for a year. The trial design prespecified DFS testing in the later-stage cohort and required a P value of ≤.05.

This DFS analysis yielded a 20% reduction in the HR in favor of vemurafenib, but the difference did not meet the prespecified definition of statistical significance (95% CI, 0.54-1.18; 

The later-stage vemurafenib cohort had a 12-month DFS of 78.9% versus 58.0% with placebo. However, the 24-month DFS showed no difference between treatment groups; it was 46.3% with vemurafenib and 47.5% with placebo.

In patients with resected stage IIC-IIIB melanoma, median DFS had yet to be reached in the vemurafenib arm, whereas the placebo group had a median DFS of 36.9 months. The difference was associated with an HR of 0.54 (95% CI, 0.37- 0.78; 

The 12-month DFS was 84.3% with vemurafenib and 66.2% with placebo. At 24 months, 72.3% of vemurafenib-treated patients remained alive without disease recurrence versus 56.5% in the placebo group.

“The magnitude of the DFS benefit [in earlier-stage disease] is of a proportion not previously demonstrated in this clinical setting,” said lead author Karl Lewis, MD, a medical oncologist at the University of Colorado Comprehensive Cancer Center in Aurora. “However, due to the prespecified statistical design of the study, these data cannot be described as statistically significant.”

Lewis said it is possible there may be different disease biology in later-stage disease as compared with stage IIC-IIIB. Furthermore, the 12-month duration of adjuvant therapy might not have been sufficient for the stage IIIC-IV cohort.

While the work to pair the ideal patient with the ideal treatment continues, physicians treating melanoma now have more tools in their armamentarium than ever before.

“As I tell patients, ‘Cancer is a bad disease. The good news is you have options,’” Weber said. “Now our patients have clearly beneficial options and that’s great news.”

Weber J, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238). Paper presented at ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA8_PR. doi: 10.1093/annonc/mdx440.048.

Weber J, Mandala M, Del Vecchio M, et al; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma [published online September 10, 2017].

Hauschild A, Santinami M, Long GV, et al. COMBI-AD: adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K—mutant melanoma. Paper presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA6_PR. doi: 10.1093/annonc/mdx440.046.

Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma [published online September 10, 2017]. 

Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial [published correction appears in Lancet Oncol. 2015;16(6):e262]. 

2015;16(5):522-530. doi: 10.1016/S1470- 2045(15)70122-1.

Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. 

 2016;375(19):1845-1855. doi: 10.1056/NEJMoa1611299.

Lewis K, Maio M, Demidov L, et al. BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. Paper presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA7_PR. doi: 10.1093/annonc/mdx440.047.

Articles

Researchers are seeking to determine whether the plethora of new therapies that have been introduced in recent years in the advanced and metastatic settings can benefit patients at risk of recurrence earlier in the treatment timeline for melanoma.

New Adjuvant Therapy Era Builds in Melanoma

Although the roles of cyclin-dependent kinases (CDKs) were established more than 20 years ago, early anticancer inhibitors in the class resulted in high toxicity levels. Now, a new generation of more selective inhibitors of CDK4 and CDK6 has entered the clinic in combination therapies for patients with breast cancer.

These agents also are being investigated in patients with 

-mutant malignancies. Early-stage results have been promising, but hopes for an advance in 

-mutant non—small cell lung cancer (NSCLC) were dampened recently when the phase III JUNIPER study evaluating abemaciclib (Verzenio) in this population failed to meet its primary endpoint.

There is a pressing need for new therapeutic strategies that target 

, the Kirsten rat sarcoma viral oncogene homolog, one of the most frequently mutated genes in human cancers. “Despite some recent advances, mutant 

 remains a very challenging target,” said Pier Paolo Scaglioni, MD, an associate professor at UT Southwestern Medical Center and a member of the Harold C. Simmons Comprehensive Cancer Center, both in Dallas, Texas. “There is a dearth of treatment options for tumors initiated by this gene.”

 signaling are both players in oncogenic events (

 CDK4/6 phosphorylates the retinoblastoma tumor suppressor protein through interaction with D-type cyclins, leading to G

 to S phase cell-cycle progression. CDK4 and CDK6 activity is regulated by the INK4 family, and the INK4- CDK4/CDK6-cyclin D axis is frequently genetically or epigenetically disrupted in cancer, leading to increased kinase activity. Furthermore, increased CDK4 or CDK6 activity has led to suppressed senescence, contributing to the initiation and maintenance of transformed cells.

Figure. Relationship of KRAS Signaling to CDKs

 are among the earliest and most important drivers of disease progression. When 

 is mutated, several downstream pathways, such as the MEK/ ERK and PI3K/AKT signaling pathways, become constitutively activated.

 mutations contribute to approximately 20% of human tumors. Most 

 mutations are point substitutions in codons 12 and 13 and have been shown to be negative predictors of response to antiEGFR antibodies. 

 mutations are detected through quantitative polymerase chain reaction (PCR)-based methods. Frequently used methods include allele-specific PCR, real-time PCR with melt-curve analysis, and nucleic acid sequencing (pyrosequencing and dideoxy sequencing). Recent studies have also investigated the detection of circulating tumor cells in peripheral blood, concluding that 

 mutations were identified in a similar percentage of blood samples compared with tumor tissue. Samples with at least 5% presence of the non—wild-type band have been considered 

 mutations are found in about 30% of lung adenocarcinomas, corresponding with a worse prognosis compared with patients having 

 wild-type tumors. Persistent activation of RAS signaling results from these mutations, contributing to uncontrolled growth and eventually, malignant transformation.

In KRAS-induced lung adenocarcinoma models, CDK4 activity is needed for tumor progression. CDK4 and RAS co-expression induces phosphorylation of the retinoblastoma protein, which leads to invasive neoplasms. Importantly, ablation of CDK4 leads to selective senescence of cells expressing KRAS, suggesting that CDK4 may be a worthy drug candidate for patients with 

-mutated non—small cell lung cancer (NSCLC).

 mutations have been reported in approximately 50% of colorectal cancers (CRCs), which lead to constitutive activation of the RAF/ MEK/ERK signaling pathway. These mutations are proven predictive biomarkers of resistance to antiEGFR therapy. Patients with KRAS mutations have fewer options for effective therapies, and currently, no therapies successfully exploit 

Table. Selected Studies of CDK4/6 Inhibitors in KRAS-Mutant Cancers

Since February 2015, the FDA has approved 3 CDK4/6 inhibitors for the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib. The estrogen receptor signaling pathway is closely linked with cyclin D1-CDK4, which may contribute to the sensitivity of breast cancer cells to antiproliferative drugs, particularly when they are combined with endocrine therapy. These agents are also being explored in 

Abemaciclib is the CDK4/6 furthest along in clinical development for 

-mutant cancers; it is being evaluated in NSCLC. The agent is a small-molecule inhibitor of CDK4/6, with greater selectivity for CDK4. Abemaciclib functions to inhibit cell cycle progression via phosphorylation prevention and functional inactivation of the retinoblastoma tumor suppressor protein.

Abemaciclib treatment results in fewer reports of neutropenia, which may be a result of enhanced selection of CDK4 versus CDK6 (CDK6 inhibition is correlated more strongly with neutropenia); therefore, abemaciclib can be given continuously. This administration schedule may more effectively drive cells into permanent G1 arrest and senescence, which may regress over time. Although abemaciclib has been classified as a selective CDK4/6 inhibitor, it has also been shown to inhibit other targets such as CDK9. This promiscuity may contribute to its clinical activity as a single agent.

“Abemaciclib, an oral CDK4/6 inhibitor, is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity,” noted Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute. “Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors.”

Preclinical evidence has suggested that there is a lethal interaction between KRAS oncogenes and CDK4 inhibition in lung cells. In vitro study results demonstrate effective growth inhibition of cancer cells, and xenograft studies demonstrate efficacy for human cancers such as NSCLC. The rationale for evaluating abemaciclib in patients with 

-mutant NSCLC was established through a multicenter study that investigated the safety, pharmacodynamics, pharmacokinetics, and clinical activity of the drug in 225 patients with breast cancer, NSCLC, glioblastoma, CRC, and melanoma.

There were 68 patients with NSCLC participating in the trial, including 29 who had tumors harboring 

 mutations. The disease control rate was 55% among patients with mutations (16 of 29) compared with 39% among patients with wild-type tumors (13 of 33). Furthermore, stable disease lasting at least 24 weeks was achieved in 31% of patients with mutated 

 wild-type disease. These findings demonstrated that compared with 

 mutation are more sensitive to abemaciclib.

An attempt to translate those early findings into later-stage success resulted in the JUNIPER trial, which was launched in 2014. The phase III study tested abemaciclib plus best supportive care versus erlotinib plus best supportive care in patients with previously treated stage IV 

-mutant NSCLC. Erlotinib was chosen as a control therapy because it is indicated for second- and third-line treatment of advanced NSCLC.

Patients were randomized to receive 200 mg of abemaciclib orally twice a day on a continuous dosing schedule, every 12 hours or 150 mg of erlotinib administered at its approved dose and schedule until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).

However, the study failed to meet its primary endpoint of OS, according to Eli Lilly and Company, which is developing abemaciclib.

 The company, which did not provide details of the findings, noted that the OS rate among patients in the control arm was higher than expected based on historical data.

At the same time, an analysis of PFS and ORR demonstrated that abemaciclib was active as monotherapy, the company said, adding that full results would be presented at a medical meeting in 2018.

“While the outcome is unfortunate for patients with 

-mutated, advanced lung cancer, we remain encouraged by the antitumor activity observed with abemaciclib in this form of lung cancer where few clinical advances have been achieved,” Levi Garraway, MD, PhD, senior vice president for global development and medical affairs at Lilly Oncology, said in a statement.

He noted that other studies with abemaciclib in NSCLC and other malignancies are ongoing. These include a 3-arm phase I trial evaluating the combination of abemaciclib with pembrolizumab in patients with stage IV NSCLC or HR-positive/ HER2-negative breast cancer; 1 arm is restricted to patients with 

On March 31, the FDA granted palbociclib regular approval as a treatment for HR-positive, HER2- negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women. The decision cemented and expanded accelerated approvals the drug received in 2015 and 2016 in breast cancer settings.

In the realm of KRAS-mutant cancers, palbociclib has shown activity in CRC and NSCLC. In preclinical models of 

-mutant CRC, results of in vitro studies demonstrated inhibition of cell growth and patient-derived xenograft models revealed tumor regression when treated with the combination of palbociclib and the MEK inhibitor, trametinib.

The results of a recent trial presented at the 2017 American Association for Cancer Research Annual Meeting demonstrate the tolerability of palbociclib combined with PD-0325901, a MEK inhibitor, with additional data revealing improved PFS in patients with NSCLC and 

-mutant tumors.6 Of 32 patients, 1 had a partial response and 7 exhibited stable disease for more than 6 months.

Separate ongoing phase I/II trials are investigating the combination of palbociclib with PD-00325901 or binimetinib, both MEK inhibitors, in patients with 

-mutant NSCLC or other solid tumors. The use of CDK4/6 inhibitors provides antitumor activity with an acceptable safety profile that may be developed further as a monotherapy and in combinations with other agents.

“Like all kinase inhibitors, CDK4/6 inhibitors will not be curative and cells will engineer a way around them,” stated Shapiro. “Defining the mechanisms of resistance will be critical for designing future strategies.”

Scientists discover new therapeutic target for lung cancer driven by KRAS [news release]. Dallas, TX: UT Southwestern Medical Center; July 28, 2016. utsouthwestern.edu/newsroom/articles/year-2016/kras-lung-cancer.html. Accessed October 4, 2017.

Matikas A. Mistriotis D, Georgoulias V, Kotsakis A. Targeting KRAS mutated non-small cell lung cancer: A history of failures and a future of hope for a diverse entity. Crit Rev Oncol Hematol. 2017;110:1-12. doi: 10.1016/j.critrevonc.2016.12.005.

Investigational drug abemaciclib shows promising activity against several cancer types [news release]. Boston, MA: Dana-Farber Cancer Institute; May 23, 2106. www.dana-farber.org/newsroom/news-releases/2016/investigational-drug-abemaciclib-shows-promising-activity-against-several-cancer-types/. Accessed October 4, 2017.

Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. 

2016;6(7):740-753. doi: 10.1158/2159-8290.CD-16-0095.

Lilly reports topline results from phase 3 JUNIPER trial evaluating Verzenio (abemaciclib) in KRAS-mutated, advanced non-small cell lung cancer [news release]. Indianapolis, IN: Eli Lilly and Company; October 10, 2017. www.prnewswire.com/news-releases/lilly-reports-topline-results-from-phase-3-juniper-trial-evaluating-verzenio-abemaciclib-in-kras-mutated-advanced-non-small-cell-lung-cancer-300533543.html. Accessed October 12, 2017.

Lee MS, Helms TL, Feng N, et al. Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in

mutant colorectal cancer models. Oncotarget. 2016;7(26):39595-39608. doi: 10.18632/oncotarget.9153.

CDK4/6 inhibitors: where they are now and where they are headed in the future. The ASCO Post website. www.ascopost.com/issues/may-10-2017-ce-supplement-cdk46-inhibitors/cdk46-inhibitors-where-they-are-now-and-where-they-are-headed-in-the-future. Published May 10, 2017. Accessed October 4, 2017.

A new generation of more selective inhibitors of CDK4 and CDK6 has entered the clinic in combination therapies for patients with breast cancer. These agents also are being investigated in patients with KRAS-mutant malignancies.

CDK4/6 Inhibitors Explored in KRAS-Mutant Cancers

Pseudoprogression, which has been observed in less than 10% of patients with lung cancer, occurs when an early scan shows tumor growth that may be due to a delayed benefit of the immunotherapy treatment or inflammation of the tumor as T cells become active. When a patient does respond to immunotherapy, the benefits can be long lasting.

 during the 18th Annual International Lung Cancer Congress hosted by Physicians’ Education Resource

) in July, Paul A. Bunn Jr, MD, said that it is important for physicians to be able to identify the difference between true progression and pseudoprogression. But until investigators learn more about this condition, it will take a bit of trial-and-error analysis, said Bunn.

Hyperprogression, which also occurs in a small subset of patients with lung cancer, is also a concern. It occurs when a patient experiences a significantly increased rate of tumor growth following immunotherapy treatment. A recent study published in Clinical Cancer Research defined this phenomenon as time-to-treatment failure (TTF) of less than 2 months, a greater than 50% increase in tumor burden compared with preimmunotherapy imaging, and a more than 2-fold increase in progression pace. Investigators found that MDM2/MDM4 and EGFR alterations correlated with TFF <2 months in a population of 155 patients with stage IV cancers who had been treated with anti—PD-1/PD-L1 immunotherapies.

“When it works, immunotherapy works for a long time, but when it doesn’t work, it doesn’t work,” Bunn said, adding that the ultimate goal is to identify biomarkers to help determine which patients will respond to immunotherapy, and which will not.

During the interview, Bunn discussed strategies for analyzing and responding to signs of progression for patients receiving immunotherapy. Bunn is a professor and the James Dudley Chair in Cancer Research in the Division of Medical Oncology at the University of Colorado Denver School of Medicine. In 2014, he was named is a Giants of Cancer Care 

 award winner in the Lung Cancer category.

Pseudoprogression is when it appears that the tumor is getting larger, but the patient is responding. If you have a tumor and the lymphocytes come in and kill the cancer, because of all the lymphocytes, the tumor might seem bigger in the scan, whereas the tumor may actually be smaller. That seems to happen more often in melanoma, but it clearly can happen in lung cancer.

Why is pseudoprogression a concern when you’re treating patients with immunotherapy?

How often does pseudoprogression occur in lung cancer?

What should community oncologists know about the difference between pseudoprogression and real progression?

An advantage of neoadjuvant care is you have the scan, but you also have the surgical specimen. If there are a bunch of lymphocytes in the surgical specimen and the tumor is gone or much smaller, you can actually see that. From preliminary data on less than 50 patients and 2 trials, there is no question that you can have major pathologic responses in the absence of a CT response because of all the infiltration of lymphocytes. 

For those people who benefit from immunotherapy, the responses frequently last a very long time. They occur in a minority of patients, so if they do occur, you don’t want to deprive the patient of the ability to have a long response.

True pseudoprogression in lung cancer is not that common. It is true that patients with Response Evaluation Criteria in Solid Tumors [RECIST] stable disease may have a true pathologic response. We’ve seen that in the early neoadjuvant trials, but with stable disease and immunotherapy, if the patient is doing well, you could continue the treatment. The big issue is if the tumor is 20% larger or more, which is RECIST progression, if that patient is having pseudoprogression because of the lymphocytes, you don’t want to stop the treatment. Having it get 20% bigger and have a response is not that common, but it can occur. So, what do you do? When that happens, it occurs early. So if the patient is doing well, their symptoms go away, and they seem to be benefiting, you could continue for 1 or 2 more [cycles of] treatment and repeat the CT scan. If the patient is deteriorating and the scan is getting worse, you obviously stop the treatment.

They should know that if the patient’s tumor got bigger and the patient has not gotten better, they should stop the treatment. But if early on the tumor got 25% bigger and the patient’s symptoms went away, they can consider continuing.

Why is hyperprogression a concern when treating patients with immunotherapy?

As we better understand immunotherapy, is there more that investigators are still learning about pseudoprogression and hyperprogression?

Another thing that isn’t standard of care yet, but that some of these studies have documented, is that if you have a molecular abnormality, that can be determined with circulating tumor DNA [ctDNA] in a liquid biopsy. In pseudoprogression, that has gone down. If the ctDNA is going down, but on scan the tumor got a little bigger and the patient is doing well, obviously you are going to continue. If the ctDNA goes up and the CT scan gets worse, time to stop the treatment. ctDNA may be helpful in the future as we get more data about this.

In these patients, you don’t want to deprive them of the opportunity to get something else that might be effective. Again, you have the CT scan, and if that is getting worse and the patient is getting worse and/ or the ctDNA is getting worse, it’s time to stop. If the ctDNA is getting better and the patient is getting better, but the scan isn’t, it’s OK to continue for 2 more cycles and repeat. 

Yes. If you have high levels to begin with, ctDNA can be very helpful. It’s possible there will be other markers. For example, in the peripheral blood, we can look at subsets of T cells or we can look at cytokines in the blood and we might be able to tell from other biomarkers in the future which is true progression and which is pseudoprogression, and hopefully be more accurate than that.

Kato S, Goodman A M, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyper-progressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. 

 2017;23(15):4242-4250. doi:10.1158/1078-0432.CCR-16-3133.

Paul A. Bunn Jr, MD, discusses strategies for analyzing and responding to signs of progression for patients receiving immunotherapy for non-small cell lung cancer.

Progression Issues Surface With NSCLC Immunotherapy

Tazemetostat, a small molecule that targets epigenetic activity of the 

 gene, is being investigated as a treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). The drug is being administered as monotherapy or in combination with prednisone in a 6-cohort, biomarker-driven phase II trial (NCT01897571).

The goal of the research, according to key trial investigators, is to develop another alternative for patients with the non-Hodgkin lymphoma subtypes. The study, which includes patients with FL, has more cohorts for adults 18 years and older with DLBCL, the paradigm for whom is frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

“In the last 10 years, there have been no new drugs approved for frontline treatment of patients living with DLBCL. Forty perfecnt of those patients will go on to relapse or become refractory to R-CHOP,” said Franck Morschhauser, MD, PhD, professor of hematology at the Centre Hospitalier Régional Universitaire de Lille, Hôpital Claude Huriez, Service des Maladies du Sang, France.

“Unfortunately, only a small percentage of patients with DLBCL are eligible for stem cell transplantation, and patients often aren’t ideal candidates for high-dose, complex chemotherapy due to their age or other comorbidities associated with their disease,” added Morschhauser, who is the lead investigator of the phase II portion of the study.

EZH2, a histone methyltransferase, is an important target as an epigenetic regulator of cellular differentiation programs. Mutations in 

, the enhancer of zeste homolog 2 gene, lead to abnormal histone methylation profiles, which can result in oncogenic transformation. Tazemetostat inhibits EZH2, and therefore promotes a tumor-suppressive environment. Somatic mutations in 

 have been observed in 21.7% of germinal center B-cell like (GCB) DLBCLs, a subset of the malignancy, and in 7.2% of FL samples.

 will alter the expression of an array of different genes, but for some reason the resultant expression pattern favors tumor formation. By blocking it with an EZH2 inhibitor, we tend to favor the more tumorsuppressive environment,” said John F. Gerecitano, MD, PhD, the lead trial investigator at Memorial Sloan Kettering Cancer Center in New York City, where he is a medical oncologist and clinical director of lymphoma outpatient services. “It is still not known which of those genes is most important in tumorigenesis, but there are many cases where affecting a wide variety of gene expressions can lead to either a more or less oncogenic milieu.”

The tazemetostat trial is being conducted in 2 parts: a phase I portion for patients with B-cell lymphomas and advanced solid tumors to establish the appropriate dose and a phase II portion that is intended to demonstrate the efficacy of the drug as monotherapy or in combination with prednisone. The phase I portion is closed to new participants. The phase II portion is currently recruiting in several cohorts, with more than 60% of the projected total of 340 patients already enrolled.

The trial includes 3 cohorts for patients with DLBCL subtypes who will receive tazemetostat monotherapy: 

 “The reason for that is that these mutations occur in 

 almost exclusively in GCB. The study wanted to look at mutated versus nonmutated [

], and the non-GCB subtype almost never has this mutation, so that was its own category,” said Gerecitano.

Another cohort was added this year for patients with DLBCL who will receive the drug in combination with prednisone. Additionally, there are 2 cohorts for patients with FL who will receive tazemetostat monotherapy, stratified by whether the patients have 

Tazemetostat has demonstrated favorable antitumor activity in early clinical trial results, according to interim phase II findings. Among participants evaluable for efficacy on June 1, the objective response rate (ORR) was 29% among patients with 

-mutated DLBCL (5 of 17 patients) and 15% among those with wild-type disease (18 of 119). For patients with FL, the ORR was 92% for those with the mutation (12 of 13) and 26% for those with wildtype disease (14 of 54).

The overall safety profile of tazemetostat has been favorable, according to Morschhauser, with low rates of dose reductions and study discontinuations. The common adverse events (AEs) include fatigue, anemia, neutropenia, thrombocytopenia, anorexia, constipation, and diarrhea, and are typically grade 1 or 2. Ten percent of patients experienced serious treatment-related AEs.2 “This gives us a nontoxic targeted therapy for patients who would be best served by avoiding chemotherapy, and patients tend to tolerate it very well with a promising response rate,” Gerecitano said.

In April 2017, the FDA granted a fast track designation to tazemetostat for both relapsed/refractory FL with or without an 

 activating mutations, according to Epizyme, the company developing the drug.

Morin RD, Johnson NA, Severson TA, et al. Somatic mutation of 

 (Y641) in follicular and diffuse large B-cell lymphomas of germinal center origin. Nat Genet. 2010;42(2):181-185. doi: 10.1038/ng.518

Morschhauser F, Salles G, McKay P, et al. Interim report from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas. Paper presented at: 14th International Conference on Malignant Lymphoma; Lugano, Switzerland; June 14-17, 2017. Abstract 4. doi: 10.1002/hon.2437_3.

Epizyme announces tasemetostat fast track designation for follicular lymphoma and plenary session on phase 2 NHL data at ICML [press release]. Cambridge, MA: Epizyme, Inc; April 25, 2017. amda-1rbic2.client. shareholder.com/releasedetail.cfm?ReleaseID=1022650. Accessed September 29, 2017.

Tazemetostat, a small molecule that targets epigenetic activity of the EZH2 gene, is being investigated as a treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma or follicular lymphoma.

EZH2 Inhibitor Tested as Epigenetic Option in NHL Types

Gastroesophageal Cancer Outcomes: East Asia Versus Western Countries

The landscape for treating patients with gastroesophageal cancers is undergoing rapid change, and international cooperation among specialists is crucial to the advancement of care, according to a panel of experts who participated in a recent 

 program. The panel, which included experts from the United States, the United Kingdom, and Japan, provided a global perspective on how the management of gastroesophageal cancers is developing. Gastroesophageal cancer encompasses malignancies of the stomach, esophagus, and gastroesophageal junction. Historically, gastroesophageal cancers have posed a tremendous challenge and are associated with low rates of long-term survival.

 New and emerging treatments have the potential to improve outcomes for patients, but limited information is available to guide clinicians on how to incorporate them into care models. “This is a quickly evolving field, and we will have new drugs [or] new treatment options for our patients, and we’ll need to be smart about how to sequence them,” said panel member Manish A. Shah, MD.

Johanna C. Bendell, MD, who served as moderator for the panel, pointed out that the main subtypes—gastric, esophageal, and gastroesophageal junctional carcinoma (GEJC)&mdash;are distinctly different diseases. Shah said most cases of gastroesophageal cancer are caused by helicobacter pylori (H pylori), a bacterium found in the stomach lining that affects half the world’s population. Cigarette smoking is another major risk factor.

 Identification and treatment of H pylori and declines in smoking rates have led to reductions in the incidence of gastric cancer in developed countries, but it remains a significant problem worldwide. Conversely, the incidence of GEJC continues to climb in developed and underdeveloped countries.

“Depending on what part of the world you’re in, your gastroesophageal cancer may have a different prognosis, behavior, and response to therapy,” Bendell said. It is widely recognized that the prevalence of gastric cancer is much higher in East Asian countries such as Japan and China than in Western countries, yet survival outcomes are typically better in the East.

Kohei Shitara, MD, said that despite the decrease in prevalence, “[Japan] still has 50,000 new gastric cancers, at best, annually.” As a result, Japan has implemented nationwide screening programs, which Shitara said means approximately 70% of gastric cancers are diagnosed at an early stage.

Ian Chau, MD, FRCP, said nationwide screening programs would not be cost effective in Europe or the United States, where gastric cancer is relatively uncommon. As a result, most patients in Western countries present with locally advanced disease, Shah said. Chau added that they are typically also older than Japanese patients at diagnosis and thus less able to tolerate intensive therapies.

“Historically, D2 gastrectomy is a standard surgical procedure for Japanese gastric cancer, and it achieves almost a 50% disease-free survival without any type of chemotherapy,” Shitara said. Shah said the survival rate with surgery alone is 30% or less in the United States and Europe, underscoring the differences in the disease between East Asian and Western countries.

“It’s a completely different ball game,” said Yelena Y. Janjigian, MD. Because of the differences, drug trials in Asian patients are routinely considered inapplicable to Western populations. That perspective may be evolving, however, after reports from clinical trials of checkpoint inhibitors showed similar response rates and survival outcomes in East Asian and Western patients.

In the phase III ONO-4538-12 (ATTRACTION-2) trial, patients from Japan, Korea, and Taiwan with advanced gastric cancer or GEJC were randomly assigned to salvage therapy (third or later line) with nivolumab (Opdivo) monotherapy (n = 330) or to placebo (n = 163) until unacceptable toxicity or disease progression.4 According to an interim analysis, the nivolumab arm had a significantly higher objective response rate (ORR) than the placebo arm (11.2% vs 0%, respectively; 

 <.0001) and a significantly longer median progression-free survival (PFS; 1.61 vs 1.45 months, respectively; 

The landscape for treating patients with gastroesophageal cancers is undergoing rapid change, and international cooperation among specialists is crucial to the advancement of care.

Vol. 18/ No. 20 | Oncology Live®

New Adjuvant Therapy Era Builds in Melanoma

CDK4/6 Inhibitors Explored in KRAS-Mutant Cancers

Progression Issues Surface With NSCLC Immunotherapy

EZH2 Inhibitor Tested as Epigenetic Option in NHL Types

Global Collaboration Is Key to Progress in Gastroesophageal Cancers

Photodynamic Therapy: Looking at Treatment of Early-Stage Oral Cancer in a New Light

Clinical Observations Can Change Research Failures Into Successes

New Era in Melanoma