Skip to main content
Premium Trial:

Request an Annual Quote

Precision Oncology Highlights From ESMO 2018

NEW YORK (GenomeWeb) – The European Society of Medical Oncology's annual meeting in Munich, Germany featured data from studies involving cancer drugs that target molecular aberrations driving patients' tumors.

During the meeting held from Oct. 19 to 23, researchers presented studies that involved combination immunotherapies that looked at the efficacy of giving molecularly-informed treatments earlier in the disease continuum and investigated how tumor markers may impact drug efficacy in settings, such as triple-negative breast cancer, lacking in targetable receptors.  

Below is a roundup of a few of the presentations featuring new precision oncology approaches.


Immunotherapy

In the Phase II CheckMate-142 study, Bristol-Myers Squibb is studying Opdivo (nivolumab)or Opdivo combinations in patients with recurrent or metastatic colorectal cancer and whether their microsatellite instability status impacts response. Based on earlier data from this study, the US Food and Drug Administration this year approved Opdivo and low-dose Yervoy (ipilimumab) in this subpopulation of patients for metastatic colorectal cancer patients who were resistant to chemotherapy.

The researchers wanted to further explore in CheckMate-142 whether metastatic patients, earlier in their care continuum and before receiving any prior treatment, would derive benefit from this combination. Data presented at the ESMO annual meeting on a cohort of 45 patients in CheckMate-142 showed patients with MSI-High status had durable clinical benefit after receiving Opdivo and low-dose Yervoy.

At the time of data cut off, the median duration of response, progression-free survival, and overall survival had not been reached. Tumors shrank in 84 percent of patients, and 74 percent responded to the combination treatment for more than six months. The 12-month progression-free survival and overall survival were 77 percent and 83 percent, respectively.

The use of low-dose Yervoy resulted in less toxicity than seen in studies using higher doses of the drug, the researchers said. Treatment-related grade 3/4 toxicities were seen in 16 percent of patients and 7 percent discontinued treatment due to adverse events.

The data demonstrate Opdivo plus low-dose Yervoy to be effective in most patients with MSI-H status, Thierry André from Hospital Saint-Antoine in Paris said in a statement about the study. He noted that some patients have improved so dramatically on this combination that they are able to return to work. "This is in contrast to other metastatic cancers (melanoma, lung or kidney), where it is more difficult to select patients who benefit from immunotherapy."

BMS could use these Phase II results to seek FDA approval for the combination as a first-line treatment for metastatic colorectal cancer with MSI-H status, André added, though the European Medicines Agency will likely require a randomized Phase III study.

In another exploratory analysis, researchers investigated the Opdivo/Yervoy combination in the neoadjuvant setting for 14 early-stage colorectal cancer patients with and without mismatch repair deficiencies. They reported that all of the seven patients with mismatch repair-deficient tumors achieved a major pathologic complete response. No pathological complete responses were seen in patients without mismatch repair deficiency, though they had significant increases in T-cell infiltration.

Lead author Myriam Chalabi from the Netherlands Cancer Institute said in a statement that the extent of benefit seen in this study was unexpected. She added that mismatch repair deficient colorectal cancer patients who received the Opdivo/Yervoy combination as neoadjuvant treatment responded far more dramatically than metastatic patients, warranting further exploration.

In the Phase III IMPassion-130 study, researchers enrolled around 900 patients with previously untreated, metastatic triple-negative breast cancer, and randomized them to receive standard chemotherapy nap-paclitaxel plus Roche/Genentech's Tecentriq (atezolizumab) or chemotherapy plus placebo. At a median follow up of nearly 13 months, all patients in the Tecentriq-combination arm had a 20 percent lower risk of disease worsening or death, while those expressing PD-L1 had a 38 percent lower risk of disease progression or death.

In all comers, median progression-free survival was 7.2 months for those receiving the combination and 5.5 months for those on chemo only. Approximately 40 percent of patients had PD-L1 positive tumors, and in this subgroup, the median progression-free survival was 7.5 months versus 5.0 months, respectively. An interim analysis showed median overall survival was 21.3 months on the combo arm versus 17.6 months on chemo in the entire cohort. In the PD-L1 positive group, median overall survival was 25 months versus 15.5 months, respectively.

Triple-negative breast cancer is the most aggressive type of breast cancer and is largely treated with chemotherapy due to the lack of targetable receptors. Patients tend to develop resistance to chemo in a few months and live on average a year to 15 months once the cancer metastasizes. As such, experts at ESMO were optimistic about the suggested survival benefit in IMPassion-130.

Marleen Kok from The Netherlands Cancer Institute said in a statement reflecting on this study that although the progression-free survival benefit was small in this study, the gain in overall survival in the PD-L1-positive subset of patients was "impressive." "We also need more studies to determine a biomarker for selecting patients most likely to benefit from this treatment," she added.

In the KEYNOTE-048 study, researchers compared 600 metastatic head and neck cancer patients who received either Merck's Keytruda (pembrolizumab) or standard treatment with Erbitux (cetuximab) plus platinum-based chemo. The study authors reported at the meeting that those with a combined PD-L1-positive score (CPS) of greater than 20 — a measurement of PD-L1 expression in tumor and the surrounding cells — lived longer on the immunotherapy.

Overall survival was 14.9 months compared to 10.7 months on Keytruda versus standard treatment, while the response rate was 23 percent and 36 percent, respectively. Median duration of response was longer on Keytruda but there was no difference in progression-free survival between the arms. The outcomes were similar in patients with a lower cutoff point of PD-L1 expression (CPS >1).

"[Keytruda] appears to prolong life even when the cancer continues to grow, suggesting that it should be a first-line therapy in recurrent and metastatic head and neck cancer," Barbara Burtness, from Yale School of Medicine and the first author of this study, said in a statement. "Whether pembrolizumab is given alone or with chemotherapy may depend on PD-L1 expression, and we are conducting analyses to answer this question."

Commenting on the findings for ESMO, Tanguy Seiwert from University of Chicago Medicine, stated that KEYNOTE-048 "establishes PD-L1 CPS as a valid marker for head and neck cancer that should be routinely measured in these patients," though he noted the need to more firmly establish the cut off for this biomarker. He also said there was a need to study other biomarkers for predicting benefit, such as tumor mutational burden, and additional analyses needed in patients with low or no PD-L1 expression who could derive less benefit.

Meanwhile, in the Phase III JAVELIN Renal-101 study, investigating the efficacy and safety of combining EMD Sorono/Pfizer's Bavencio (avelumab) and Pfizer's tyrosine kinase inhibitor Inlyta (axitinib) in first-line, advanced renal cell cancer, PD-L1 expression wasn't predictive of therapy benefit.

In the study, where 442 patients received the Bavencio/Inlyta combination and 444 patients received another tyrosine kinase inhibitor, Sutent (sunitinib), median progression-free survival was 13.8 months versus 7.2 months, respectively, for patients with PD-L1 positive tumors. However, median progression-free survival irrespective of PD-L1 expression was 13.8 months versus 8.4 months, respectively.

"The findings support the potential of avelumab plus axitinib as a new treatment approach for patients with advanced renal cell carcinoma," Robert Motzer, the study lead from Memorial Sloan Kettering Cancer Center, said in a statement. "The combination benefit was shown in all subgroups of patients, by independent review as well as by investigators, and whether tumor cells stained positive for PD-L1 or not."

Tumor mutations

Novartis' PI3K inhibitor alpelisib showed efficacy in hormone receptor-positive breast cancer patients who have PIK3CA mutations. In the SOLAR-1 trial, 572 patients with hormone-receptor-positive, HER2-negative, advanced breast cancer were randomized to receive either alpelisib or placebo plus intramuscular fulvestrant.

Approximately 340 patients had PIK3CA mutations in the study. Median progression-free survival in this molecularly-defined subset of patients was nearly twice as long among those receiving alpelisib compared to placebo, 11 months versus 5.7 months, respectively. More than a third of patients with PI3KCA-mutated breast cancer responded to the alpelisib/fulvestrant regimen, while the overall response rate in the study was 16 percent. The cohort of patients without PI3KCA mutations did not meet the predefined PFS endpoint.

Lead author Fabrice André from the Institut Gustave Roussy in France said in a statement that although the study suggests that hormone receptor-positive, HER2-negative advanced breast cancer patients with PI3KCA mutations may live longer with alpelisib treatment compared to placebo, researchers are unable to conclude there is a long-term survival benefit with the drug due to the relatively short follow up of 20 months in the trial.

Approximately 40 percent of hormone receptor-positive breast cancer patients harbor PIK3CA mutations. In André's view, the study opens the door for clinical genomics for breast cancer "as the first study to show that treatment based on a patient's tumor genomic profile — specifically PI3KCA mutation — can improve the outcome."

Another study looking at neoadjuvant treatment for stage IIIA-N2, EGFR-mutated non-small cell lung cancer patients with Genentech's Tarceva (erlotinib) suggested the targeted treatment might benefit patients in this earlier disease setting.

The study screened 386 patients across 17 centers in China and randomized 72 patients to receive Tarceva or gemcitabine/cisplatin chemotherapy. The objective response rate was 54 percent in the Tarceva arm and 34.3 percent in the chemotherapy arm. Following neoadjuvant therapy, 84 percent of patients receiving Tarceva and 69 percent on chemo underwent surgery. Median progression-free survival was 21.5 months and 11.9 months in the Tarceva versus chemo arms, respectively, and overall survival data hadn't yet matured.  

"While the difference between EGFR TKI and chemotherapy is significant, the impact of neoadjuvant EGFR TKI is relatively disappointing," Tony Mok, from the Chinese University in Hong Kong, said in a statement about the study. "Response rate of 54 percent is lower than what is expected of TKI in stage IV disease (about 70 percent), and only 13 percent of patients had attained major pathologic response."

While the reason for this is unclear, Mok suggested that perhaps a a treatment duration of 42 days with the EGFR inhibitor is insufficient. "Overall, this important study offers us the rationale to consider neo-adjuvant EGFR TKI," he said in a statement.

In newly diagnosed, advanced ovarian cancer patients who have a BRCA1 or BRCA2 mutation, two-year maintenance therapy with AstraZeneca's PARP inhibitor Lynparza (olaparib) significantly improved progression-free survival, researchers reported at the ESMO annual meeting.

In the Phase III, randomized SOLO-1 trial, 391 patients with high-grade serous or endometrioid ovarian cancer who had complete or partial responses to chemotherapy upon entering the study, were randomized to Lynparza or placebo for two years.

Median PFS for patients on placebo was 13.8 months, and while those receiving Lynparza in the first-line setting hadn't reached the median of this endpoint, researchers estimated that Lynparza-treated patients could have median progression-free survival that's three years longer than the placebo group. Median progression-free survival 2 — an endpoint defined as the time from randomization to the second progression-free event a patient experiences — was 41.9 months for the placebo group, but not yet reached for the Lynparza arm.  

"The results of SOLO-1 herald a new era in treatment for women diagnosed with advanced ovarian cancer who carry a BRCA mutation," Kathleen Moore, from the University of Oklahoma's Stephenson Cancer Center, said in a statement.

Moore, who presented the results at the meeting, noted it's too early to say if front-line Lynparza treatment could be curative for the subset of women in this study. "The fact that it is estimated that over 50 percent of women on the olaparib arm were still progression free at four years as compared to only 11 percent for placebo speaks to this hope," she said.  

Myriad Genetics' BRACAnalysis CDx was used to identify patients with BRCA1/2 mutations in SOLO-1, and last week the company said it intended to file a supplementary premarket approval application for the test with the FDA. The test is already approved as a companion and complementary diagnostic for Lynparza in other indications.