Clinical Findings

Venetoclax—Obinutuzumab Demonstrates Efficacy Over Chlorambucil Combo in Untreated CLL

Venetoclax has previously demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL). Now, the results of a new study comparing the treatment plus obinutuzumab with the combination of chlorambucil and obinutuzumab have demonstrated that the venetoclax combination is associated with longer progression-free survival (PFS) among previously untreated patients with CLL and coexisting conditions.

At 24 months, PFS was 88.2% among patients receiving venetoclax—obinutuzumab compared with 64.1% among patients receiving chlorambucil–obinutuzumab. This survival benefit was observed regardless of TP53 deletion, mutation, or both, in patients with unmutated IGHV and in other subgroups.

Results of the CLL14 trial, which were presented at the 2019 Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois, and published in the New England Journal of Medicine, led to the approval of the venetoclax combination for these patients in May.

The phase 3 trial was spread across 21 countries at 196 sites and enrolled 432 patients with CD20+ CLL who were randomized 1:1 to receive either venetoclax—obinutuzumab or chlorambucil–obinutuzumab for 12 cycles of treatment that lasted 28 days each.

Obinutuzumab was administered intravenously for 6 cycles starting with 100 mg on day 1 and 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1, and subsequently 1000 mg on day 1 during cycles 2 through 6. Chlorambucil was administered orally at 0.5 mg/kg on days 1 and 15 of each cycle until completion of the 12 cycles. Venetoclax was initiated on day 22 of cycle 1, starting with a 5-week dose ramp-up (1 week each of 20, 50, 100, and 200 mg, then 400 mg daily for 1 week), and then was administered at 400 mg daily until completion of cycle 12.

At data cutoff, patients had discontinued therapy for a median of 17.1 months in the venetoclax—obinutuzumab group and 17.9 months in the chlorambucil–obinutuzumab group. In the 3 months following completion, there were higher rates of patients in the venetoclax group who were negative for minimal residual disease in peripheral blood (75.5% vs 35.2%) and in bone marrow (56.9% vs 17.1%).

“Minimal residual disease negativity was consistently more common across all subgroups and was more sustainable with venetoclax—obinutuzumab than with chlorambucil–obinutuzumab,” explained the researchers.

Patients treated with the venetoclax combination also had significantly higher rates of partial response (84.7% vs 71.3%) and complete response (49.5% vs 23.1%).

After a median follow-up of 28.1 months, there were 14 events of disease progression and 16 deaths among those receiving venetoclax—obinutuzumab and 69 events of disease progression and 8 deaths among those receiving chlorambucil–obinutuzumab.

Median overall survival (OS) was not reached in either treatment group, and during the complete observation period, OS did not differ significantly between the 2 groups. There was at least 1 adverse event (AE) of any grade among 94.3% of patients receiving venetoclax—obinutuzumab and in 99.5% of patients receiving chlorambucil–obinutuzumab. These AEs resulted in treatment discontinuation among 16% of patients receiving the venetoclax combination and among 15.4% of patients receiving the chlorambucil combination.

The most common grade 3 or 4 AE was febrile neutropenia, and grade 3 or 4 infections were reported in 5.2% and 17.5% of patients, respectively, receiving the venetoclax combination, and in 3.7% and 15% of patients receiving the chlorambucil combination. During treatment, 5 fatal AEs occurred in the venetoclax—obinutuzumab group and 4 occurred in the chlorambucil–obinutuzumab group. Following treatment, 11 fatal AEs occurred in the venetoclax–obinutuzumab group and 4 occurred in the chlorambucil–obinutuzumab group.

Reference

More From TAILORx: Adding Clinical Risk to Genomic Testing Can Guide Therapy Choices in Breast Cancer

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi: 10.1056/NEJMoa1815281.The 21-gene assay, Oncotype DX, which a year ago was found to help many women with a common type of breast cancer avoid chemotherapy, may be best used alongside an assessment of tumor size and stage, according to investigators of the TAILORx trial.

But these new results published in the New England Journal of Medicine,¹ appear with an editorial that explores why they come a year after the original results. Precision medicine, the commentators say, is sometimes “messier” than the name suggests.²

Last year’s practice-changing results were a headline of the 2018 meeting: chemotherapy with endocrine therapy after surgery offered no benefit for 70% of women with hormone receptor—positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer.

This time, Joseph A. Sparano, MD, of the Albert Einstein College of Medicine, and his coauthors used the same data to show that adding “clinical risk” to the equation—tumor size and histologic grade—offers extra prognostic value, “that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy.”

However, the recommendations from these new results are drawn from other studies, not from the data. The Oncotype DX assay provides a recurrence score of 0 to 100, with higher scores indicting worse prognosis. TAILORx enrolled 10,273 women with early breast cancer to learn more about the risks for patients with this type of cancer, specifically the risks for women with scores in the middle range, 11 to 25. Based on results from earlier trials, those with scores of 0 to 10

received endocrine therapy only; those with scores above 26 received endocrine therapy and chemotherapy. Those in the middle range were randomized

to receive either chemotherapy and endocrine therapy or endocrine therapy alone. Patients were followed for 9 years.³

Results reported in June 2018 showed that although most women in this range did not need chemotherapy, some women would still benefit from it: those age 50 or younger with a recurrence score of 16 to 25.

Adding Clinical Risk

The investigators used a binary classification system from the MINDACT trial that divided patients into high or low risk based on tumor size and histologic grade. They report that the “integration of genomic and clinical information may provide a more accurate estimate of prognosis for individual patients than could be provided by either the genomic or clinical information alone.”

Notably, the analysis found predictive information about recurrence, but not benefits of chemotherapy. Results showed:

• For women with recurrence scores of 11 to 25 who received endocrine therapy only, the hazard ratio comparing high clinical risk to low clinical risk was 2.73 (95% CI, 1.93-3.87).

• For women with recurrence scores of 11 to 25 who received chemotherapy and endocrine therapy, the hazard ratio for high versus low risk was 2.41 (95% CI, 1.66-3.48).

• For women with recurrence scores of 26 or higher, who all had both chemotherapy and endocrine therapy, the hazard ratio for high versus low risk was 3.17 (95% CI, 1.94-5.19).

Among women who were 50 years or younger who had endocrine therapy alone, the investigators wrote, “The estimated rate of distant recurrence at 9 years was less than 5%,” with a low recurrence score, regardless of clinical risk.

The risk rose above 10% among younger women who had an intermediate recurrence score and high clinical risk.

Aromatase Inhibitor May Be an Option

So, what to do for these patients? Sparano et al noted that some of chemotherapy’s ability to reduce death rates in younger women is attributed to its ability to induce menopause; while offering plenty of caution, they suggest that for some younger women, adding an aromatase inhibitor to tamoxifen may be in order.

They wrote, “Given the incremental benefits observed with ovarian suppression plus tamoxifen or an aromatase inhibitor, as compared with tamoxifen alone in premenopausal women, and the low percentage of premenopausal women who received ovarian suppression in TAILORx, it is possible that similar incremental benefits observed in younger women who received chemotherapy and had a recurrence score of 16 to 25 could be achieved with ovarian suppression and an aromatase inhibitor, as observed in other trials.”

Unlike the clarity of last year’s findings, the authors of the editorial said this time the TAILORx team must rely on interpretations. David J. Hunter, MBBS, and David L. Longo, MD, wrote that the investigators “speculate on the basis of previous studies that adding ovarian suppression and an aromatase inhibitor might give a reduction in risk equivalent to that observed using adjuvant chemotherapy.”

“The promise of ‘precision’ medicine has collided with the rather messier world of using all available evidence to try to make educated guesses to improve patient outcomes. How could this be?” Hunter and Longo asked.

The answer, they said, comes from the need to reuse data from large studies like TAILORx, because such studies are too expensive to repeat every time there is a question—and the one asked in this new study will apply to many women. The commentators commend the TAILORx investigators for taking on the questions they have asked, and note, “Distinguishing between results that warrant a change in practice and those that do not will not lead to a ‘precise’ process.”

References

1. Sparano JA, Gray RJ, Ravdin PM, et al. Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer [published online June 3, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1904819.

2. Hunter DJ, Longo DL. The precision of evidence needed to practice “precision medicine.” [published online June 3, 2019]. N Engl J Med. doi: 10.1056/NEJMe1906088.

Maintenance Olaparib Aids PFS in BRCA-Mutated Metastatic Pancreatic Cancer, but Not OS

3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710.Patients with advanced pancreatic cancer linked to germline genetic mutations did not see their disease worsen for an additional 3.6 months when treated with olaparib (Lynparza), but an early interim analysis did not show a statistically significant difference in overall survival (OS) either, according to recent study results.

The results of the subset of patients with germline mutations in the BRCA1 and BRCA2 genes were also published in the New England Journal of Medicine. Topline results were released in February.

Pancreatic cancer affects nearly 57,000 Americans annually; once it spreads, fewer than 10% of patients are alive 5 years after initial diagnosis. About 4% to 7% of patients with pancreatic cancer have a germline BRCA mutation. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is sold by Astra Zeneca and Merck. AstraZeneca and a grant from the National Institutes of Health funded the study.

The phase 3 study, called POLO (Pancreas Cancer Olaparib Ongoing), included 154 patients; 92 received olaparib at 300 mg twice a day and 62 received placebo. The 154 patients had confirmed BRCA1/2 mutations via use of the BRACAnalysis CDx companion diagnostic from Myriad Genetics. It is currently the only FDA-approved test to find germline BRCA1/2 mutations.

To be eligible for the randomized controlled trial, the patients had to have received at least 16 weeks of continuous first-line platinum-based chemotherapy, with no evidence of disease progression. The primary end point of the study, median progression-free survival, was significantly longer in the olaparib group than in the placebo group (7.4 vs 3.8 months; hazard ratio [HR] for disease progression or death, 0.53; 95% CI, 0.35-0.82; P = .004). At 24 months, 22% of the patients in the treatment group had not seen the disease progress compared with 9.6% of the placebo group.

Given the deadly nature of advanced pancreatic cancer, the fact that maintenance olaparib could stop progression for a few months for this group of patients “is really quite remarkable,” said Johnathan M. Lancaster, MD, PhD, the chief medical officer for Myriad Genetics, in an interview with The American Journal of Managed Care ®.

The interim analysis of OS, a secondary end point, showed no significant difference, with a median 18.9 months for the olaparib group and 18.1 months for the placebo group (HR for death 0.91; 95% CI, 0.56-1.46; P = .68). Patient-reported outcomes (health-related quality of life scores) were also not significantly different.

Lancaster said those results are not surprising given the crossover that can occur between different therapies; the study reported that 15% of the placebo group received a PARP inhibitor after disease progression.

“For the first time now, we have the opportunity to use precision medicine intervention to identify patients with pancreatic cancer [who] will likely benefit from PARP inhibition,” he said.

There are a few reasons why the results are important, Lancaster said. POLO has clinical implications for a select group of patients who have few options, and it highlights not only the role of genetic testing for cancer in general but also for pancreatic cancer specifically, where BRCA is more well known for its role for breast and ovarian cancers for some populations. He also noted that the National Comprehensive Cancer Network updated its guidelines earlier this year to recommend universal germline BRCA testing for all patients with pancreatic cancer. In addition, this study defines the potential and very nature of precision medicine, Lancaster said, despite the small numbers and percentages in the study.

“The whole paradigm of precision medicine, is, indeed, to identify the 1 in 20 patients who carry a biomarker and offer them a drug,” as opposed to offering the drug to everyone, where, he said, “the effect is washed out.”

Myriad announced earlier this year that it intends to seek FDA approval to use BRACAnalysis CDx as a companion diagnostic for olaparib in patients with pancreatic cancer; it is already used to identify patients with germline BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal

cancer. It is also being studied in prostate cancer.

A first-in-class PARP inhibitor, olaparib is approved to treat multiple indications of advanced ovarian, fallopian, and metastatic breast cancer, including those with both inherited and acquired BRCA mutations. The BRCA1 and BRCA2 genes help cells repair DNA damage, and inherited mutations can make both women and men more likely to develop certain cancers.

Olaparib works by blocking the DNA damage response in cells and tumors.

Reference

Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer [published online June 3, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1903387.

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