October 2019 Edition Vol.11, Issue 10

Pivotal Trials at ESMO 2019 Expand Treatment Options and Change Standards

By Ted Bosworth

Even in cases where the standard of care was not definitively changed, pivotal trials presented at the European Society of Medical Oncology (ESMO) Congress 2019 have expanded treatment options for common malignancies. In some cases, experts labeled the new trial data practice changing even in the absence of an overall survival (OS) benefit.

KEYNOTE-522: CPI Boosts Pathological Complete Response in Triple Negative Breast Cancer

When a checkpoint inhibitor (CPI) was added to chemotherapy in first-line treatment of triple negative breast cancer (TNBC), pathological complete response (pCR) rates reached 65%, according to interim results of the KEYNOTE-522 trial. Compared with the 51% pCR rate for chemotherapy alone (P=0.00055), this result is potentially practice changing because pCR is known to correlate with overall survival (OS).

“These are preliminary data, but they provide a strong sign that the addition of immune therapy to neoadjuvant chemotherapy prevents breast cancer recurrence,” reported Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London, UK.

In the trial, 602 patients with previously untreated, non-metastatic TNBC were randomized 2:1 to receive the CPI pembrolizumab or placebo on top of standard chemotherapy. After definitive surgery, patients continued on pembrolizumab or placebo for nine cycles.

The hazard ratio (HR) for event-free survival (EFS) for the pembrolizumab arm was 0.63 (95% CI 0.43 – 0.93).  Dr. Schmid was only willing to characterize this risk reduction as a “favorable trend” after a median followup of 15.5 months.

Pembrolizumab did not contribute substantially to the risk of adverse events (AEs). The majority of patients had grade 3 or higher AEs whether or not they were taking a CPI (78% vs. 73%, respectively). During maintenance pembrolizumab after surgery, AE rates were low, supporting Dr. Schmid’s contention that most toxicity was related to chemotherapy.

Given the importance of pCR as a surrogate marker of OS, the addition of CPI to chemotherapy “could become a standard of care in TNBC if approved,” according to Fabrice André, MD, PhD, Research Director, Instiut Gustave Roussy, Villejuif, France. However, it will be important to confirm the OS benefit in further followup.

CheckMate 027: Chemotherapy-Free Dual CPI Regimen Improves Survival in Advanced NSCLC

In chemotherapy-naïve patients with advanced non-small cell lung cancer (NSCLC), a chemotherapy-free combination of the CPIs nivolumab plus ipilimumab has been found to be more effective than chemotherapy alone, according to CheckMate 027 results. For the primary endpoint of OS, the dual CPI regimen relative to chemotherapy was superior for all randomized patients (HR 0.73); for those with PD-L1 expression <1% (HR 0.62); and for those with PD-L1 expression ≥1% (HR 0.79; P=0.007).

With the CPI combination “we now have a chemotherapy-sparing option” in the treatment of advanced NSCLC,” reported Solange Peters, MD, PhD, Centre Hospitalier Universitaire, Lausanne, Switzerland. There are numerous other options in advanced NSCLC that have not yet been directly compared, so the results of CheckMate 027 do not define a new standard, but “in my opinion these data are practice changing,” she said.

In CheckMate 027, 1189 chemotherapy-naïve patients with stage IV or recurrent NSCLC without known targetable EGFR mutations or ALK alterations were randomized to nivolumab plus ipilimumab, nivolumab alone, or histology-based chemotherapy. About half of patients had <1% PD-L1 expression. Outcomes were stratified by both PD-L1 expression and histology, which was not an important discriminator for response.

Grade 3 or higher AEs were less common in the nivolumab monotherapy arm (19%) when compared with the dual CPI arm (33%) and the chemotherapy arm (36%). For specific toxicities, chemotherapy was more closely associated with gastrointestinal and hematological AEs, while dual CPI therapy was more likely to cause diarrhea, rash, and fatigue.

Marian Chiara Garassino, MD, PhD, Istituto Nazionale dei Tumori, Milan, Italy, agreed that these data establish a new treatment option in NSCLC, but she does not believe they establish a new standard. One problem is that she does not consider the comparator arm of chemotherapy alone as a currently relevant standard of care for comparison. In addition, she believes that more data are needed to understand the importance of PD-L1 expression and the value of other clinical factors in selecting among the multiple treatment strategies now available for advanced NSCLC.

IMvigor130: Atezolizumab Plus Chemotherapy Improves PFS in Metastatic Urothelial Carcinoma

A combination of the CPI atezolizumab plus chemotherapy is more effective than either treatment alone for metastatic urothelial carcinoma (mUC), according to interim results from the multicenter phase 3 IMvigor130 trial. At the interim analysis, the progression-free survival (PFS) advantage for the combination relative to either alone has reached significance. There was an encouraging trend for an improved survival for atezolizumab monotherapy over chemotherapy in those with an elevated PD-L1 expression.

In those overexpressing PD-L1, the hazard ratio for OS in the monotherapy atezolizumab arm relative to chemotherapy was 0.68, “suggesting that we should be testing for PD-L1 in these patient to guide treatment selection,” said lead author, Enrique Grande, MD, head of the Medical Oncology Service, MD Anderson Cancer Center, University of Texas, Houston.

In IMVigor130, which was called the largest randomized mUC trial ever conducted, 1213 previously untreated mUC patients were randomized to atezolizumab alone, atezolizumab plus a platinum-based chemotherapy consisting of gemcitabine plus either cisplatin or carboplatin, or to a platinum-based chemotherapy alone. PFS and OS were co-primary endpoints.

When atezolizumab plus chemotherapy was compared with chemotherapy alone, the median PFS (8.2 vs. 6.3 months) favored the arm with CPI (HR 0.82; P=0.007). The median OS (16.0 vs. 13.4 months) also favored the combination (HR 0.83; P=0.027), although this difference did not reach the prespecified threshold at the interim analysis for significance. The objective response rate was only slightly higher for the combination (47% vs. 44%), but the complete response (13% vs. 7%) was almost twice as great.

The discontinuation rate for adverse events was 34% in both arms with chemotherapy.

Thomas Powles, MBBS, professor of genitourinary oncology, Barts Cancer Institute, London, UK, said that mature OS data are needed before advocating a change in practice, but he considers these results of significant interest. He emphasized the need for new options for this indication.

CheckMate 459: Nivolumab Near OS Advantage over Sorafenib in Hepatocellular Carcinoma

Based on a strong trend for improved survival, nivolumab appears to be a reasonable alternative to sorafenib for previously untreated advanced hepatocellular carcinoma (HCC), according to CheckMate 459 results. There was no difference in PFS after a minimum followup of 22.8 months (about 3.8 months in both groups), but the nearly two-months OS advantage of nivolumab (16.4 vs. 14.7 months) approached statistical significance (P=0.0752). Nivolumab was also better tolerated with a far lower rate of grade 3 or higher AEs (22% vs. 49%).

Referring to patient reports, Thomas Chung Cheung Yau, MBBS, clinical associate professor, University of Hong Kong, China, said, “Those randomized to nivolumab experienced a better quality of life.”

In this study, 743 treatment-naïve patients with advanced HCC were randomized to 240 mg nivolumab delivered intravenously every two weeks or 400 mg of oral sorafenib twice daily.

The objective response rate was twice as great in those treated with the CPI relative to those who received the tyrosine kinase inhibitor (15% vs. 7%). The objective response was higher for those treated with nivolumab in those with PD-L1 expression <1% (12% vs. 7%) but was even more pronounced in those with ≥1% PD-L1 expression (28% vs. 9%). Nivolumab was more active across all predefined subgroups, such as those with or without hepatitis, those with or without extrahepatic spread, and non-Asians versus Asians.

At 24 months, 38.6% of those randomized to nivolumab versus 33.1% of those randomized to sorafenib were still alive, and the survival curves appeared to be still separating at followup out to 36 months.

However, failing to meet the primary endpoint of OS, CheckMate 459 is technically a negative trial, according to Arndt Vogel, MD, PhD, professor of gastrointestinal oncology, Hannover Medical School, Hannover, Germany. He did agree that the results support nivolumab as an alternative to sorafenib in advanced HCC.

“The package of efficacy, safety, and quality of life is in favor of nivolumab,” Dr. Vogel said.

FLAURA: Positive OS Data for Osimertinib in EGFR mutation-positive NSCLC

The third generation tyrosine kinase inhibitor (TKIs) osimertinib provides an OS benefit over second-generation agents when used as first-line therapy for patients with EGFR mutation-positive NSCLC, according to newly reported results from FLAURA. Although the previously reported PFS advantage of osimertinib, which is better tolerated, had already led many experts to consider osimertinib the superior therapy, the OS data prove that sequencing of TKIs leads to inferior outcomes.

“The survival advantage of starting with osimertinib was statistically and clinically meaningful,” said Suresh S. Ramalingam, MD, Winship Cancer Institute, Emory University, Atlanta, Georgia.

In FLAURA, 556 treatment-naïve patients with advanced EGFR mutation-positive NSCLC patients were randomized to 80 mg osimertinib once daily or to a once daily second-line TKI: gefitinib (250 mg) or erlotinib (150 mg). Crossover at progression to the opposite therapy was permitted, which is an important point for recommending osimertinib first-line.

The FLAURA OS results show a nearly seven-month (38.6 vs. 31.8 months) advantage for using the third-generation osimertinib first (HR 00.799; P=0.0462).

Pasi A. Jänne, MD, PhD, Dana-Farber Cancer institute, Boston, said these OS data prove “you should use the best drug first” in EGFR positive-mutation NSCLC. In explaining why sequencing of TKIs is not appropriate, he pointed out that 30% of patients in both arms never had the opportunity to receive a subsequent TKI mostly because of progression or death.

MONARCH 2 and MONALEESA-3: CDK 4/6 inhibitors Plus Endocrine Therapy Yield OS Advantage

In women with HR+/HER2- advanced breast cancer, a CDK 4/6 inhibitor plus an estrogen-receptor antagonist should be considered a standard of care, according to the OS data from both the MONARCH 2 and MONALEESA-3 trials. Results of the two trials were similar and complementary.

Relative to fulvestrant alone, which was the only active therapy in the control arms of both studies, MONARCH 2 had previously shown a substantial PFS advantage for the CDK 4/6 inhibitor abemaciclib plus fulvestrant while MONALEESA-3 had shown a similar PFS advantage for ribociclib plus fulvestrant. At many centers, practice had already changed in advance of the new OS data.

In MONARCH 2, which randomized 669 patients with HR+/HER2- breast cancer, the median OS was increased 9.4 months (46.7 vs. 37.3 months) after a median followup of 47.7 months, translating into a 22% relative advantage for abemaciclib over placebo (HR 0.78; P<0.0001), according to George W. Sledge, MD, Stanford University, Stanford, California.

In MONALEESA-3, 726 patients were randomized. About half were being treated for the first time. After a median followup of 39.4 months, the median OS has not been reached in the experimental arm versus 40.3 months in control arm, producing a roughly 28% relative advantage for ribociclib over placebo (HR 0.724; P=0.0046), according to Dennis J. Slamon, MD, University of California, Los Angeles.

MONAEESA-3 was restricted to postmenopausal women but previously published data from MONALEESA-7, which only enrolled premenopausal women, produced similar results.

With the now substantial clinical evidence demonstrating an OS benefit with a CDK 4/6 inhibitor in advanced HR+/HER2- breast cancer, a combination of a CDK 4/6 inhibitor and estrogen receptor antagonist “should now be considered the standard of care, ” according to Nadia Harbeck, MD, PhD, Head of the Division of Breast Cancer, University of Munich, Germany. She added, “I think these therapies will make a huge impact.”

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