#ASCO18: Genetic Test Can Rule Out Chemo Use in Early Breast Cancer

About 70% of women with the most common form of early breast cancer don’t need chemotherapy after surgery, a researcher said.

The finding from a randomized clinical trial suggests a change in clinical practice for majority of women with disease that is hormone receptor-positive, HER2-negative, and axillary node-negative, according to Joseph Sparano, MD, of Albert Einstein Cancer Center and Montefiore Health System in New York City.

After surgery, most of those women are usually treated with hormone therapy and chemotherapy, Sparano told reporters here at the American Society of Clinical Oncology (ASCO) annual meeting. The results were also published in the New England Journal of Medicine.

But if they have a low or mid-range score on a genetic test for the risk of recurrence — as did about 70% of women in the study — chemotherapy appears to have no detectable effect on the danger of the cancer returning, Sparano said.

In clinical practice, he said, “application of this test would be expected to spare chemotherapy in about 70% of women and select chemotherapy in about 30%.”

The presentation and publication of the data marks an “extraordinary day” for doctors and patients, commented ASCO expert Harold Burstein, MD, PhD, of Dana-Farber Cancer Center in Boston.

“It allows us to individualize treatment based on extraordinary science that now has tremendous prospective validation,” he said. “The most challenging decisions we make with these patients is whether or not to recommend chemotherapy with all its side effects and its potential benefits.”

Now, the “vast majority of women who have this test performed on their tumor can be told they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance,” Burstein stated.

He noted that the gene test (Oncotype DX Breast Recurrence Score) has been in use for more than a decade, based on data that suggested it was prognostic at the high and low ends. But that data was based on older chemotherapy and hormone therapies, and it was not clear how well it applied to modern treatments.

The study validates the gene test in the modern era and also clears up a “gray zone” — how to treat women with scores that were not clearly prognostic, Burstein said.

TAILORx (Trial Assigning IndividuaLized Options for Treatment) enrolled 10,273 women for what Sparano called the “largest adjuvant breast cancer trial ever performed.”

It was aimed at “threading the needle,” he said: Defining which women were being over- or undertreated.

On the gene test, whose possible scores range from 0 to 100, 1,629 women had tumors with a low score of ≤10 were given endocrine therapy alone, he reported. Another 1,389 had scores of ≥26 and were treated with chemotherapy in addition to endocrine therapy. Standard regimens were used, he said.

The investigators randomized the remaining 6,711 women, with scores from 11 through 25, to get endocrine therapy alone or combined treatment. The primary endpoint of the study was invasive disease-free survival — defined as invasive disease recurrence, second primary cancer, or death — measured on a non-inferiority basis.

The 9-year rates were almost identical — 83.3% for those on endocrine therapy alone and 84.3% for those on combined treatment. The rates yielded a non-significant hazard ratio of 1.08, and the study met the non-inferiority criterion.

Other endpoints, such as distant recurrences and overall survival, were also similar, Sparano said.

However, an exploratory analysis suggested, however, that some women with midrange scores might still benefit from the addition of chemotherapy, Sparano said. Specifically, those ages ≤50 with a recurrence score from 16 through 25 appeared to have fewer distant recurrences if they had combined treatment.

But overall, three groups of women appear to be able to dispense with chemotherapy:

• Those of any age with a recurrence score of ≤10
• Those age >50 with a score from 11 through 25
• Those ≤50 with a score from 11 through 15

The TAILORx results by comes just a few months after a study showing that another test — the PAM50 gene signature — could be used to help decide which patients with early breast cancer should get adjuvant chemotherapy.

The study was supported by the National Cancer Institute, the American College of Surgeons, Cancer and Leukemia Group B, NSABP Foundation, NCIC Clinical Trials Group, North Central Cancer Treatment Group, and Southwest Oncology Group.

Sparano disclosed relevant relationships with Metastat, AstraZeneca, Celgene, Celldex, Genentech/Roche, Juno Therapeutics, Eli Lilly, Merrimack, Novartis, Pfizer, and Prescient Therapeutics. Co-authors disclosed multiple relevant relationships with industry.

• Primary Source

  American Society of Clinical Oncology

  Source Reference: Sparano JA, et al “TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score” ASCO 2018; Abstract LBA1.

• Secondary Source

  New England Journal of Medicine

  Source Reference: Sparano JA, et al “Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer” N Engl J Med 2018; DOI: 10.1056/NEJMoa1804710.

https://bit.ly/2kMTlu2

#ASCO18: Novartis makes a case for earlier Kisqali use in breast cancer

Novartis’ breast cancer drug Kisqali so far hasn’t lived up to expectations, and the drugmaker’s hoping some strong new data in metastatic patients will help. Can the numbers actually boost the drug’s sales? Depends on how doctors decide to use them.

Novartis unveiled the results Sunday at the American Society of Clinical Oncology annual meeting, showing that among patients with HR-positive, HER2-negative breast cancer, adding Kisqali to fulvestrant kept the disease at bay for nearly eight months longer than fulvestrant alone.

That’s “among the biggest improvements since the induction of hormonal therapy some 45 years ago,” study investigator Dennis Slamon, M.D., Ph.D., said.

The results covered women who hadn’t been treated before and those whose disease had progressed after one line of treatment.

In previously untreated patients, the Kisqali-fulvestrant combo staved off disease for a median 20.5 months, compared with just 12.8 months for solo fulvestrant. And investigators estimated that nearly 70% of women in that first-line subgroup still hadn’t seen their disease progress at a median follow-up of 16.5 months.

Up to this point, “the dogma has been that these patients should receive hormonal therapy first, and then if they progress on that, then you give the combination,” Slamon said. Now, though, these data set “a new potential standard for patients that have not seen prior hormonal therapy,” he said.

Whether Kisqali’s performance in this trial translates to earlier use in the real world, though, remains to be seen.

“I’d like to tell you I think it’s going to be used a lot more given these data, but just given what I’ve seen in the past, it’s going to be interesting” to see how prescribing patterns play out, Slamon said. He pointed to Roche blockbuster Herceptin, which physicians—“who tend to be quite conservative in their approach”—continued to hold back until after further lines of chemo, even after data rolled out supporting its first-line use.

Novartis, for one, is hoping to see doctors run with the new data—and bolster Kisqali’s sales in the process. While its rival drug Ibrance, a Pfizer blockbuster, had a big head start on its in-class rivals, analysts still predicted that Kisqali and Eli Lilly player Verzenio could crack the $1 billion mark at their respective sales peaks. So far, though, Kisqali has failed to gain major traction—so much so that CEO Vas Narasimhan, before stepping into the company’s top spot, included jump-starting the product on his list of the top three challenges he’d face as helmsman.

Meanwhile, positive new breast cancer data on Ibrance and Verzenio have continued to boost the profile of the CDK 4/6 class as a whole—and, in turn, expand sales prospects for all three players. “I think it’s been remarkable, since we initially did the first studies, how consistent the data have been across all members of the class,” Slamon said, adding that the results the class has put up so far show that “this is an important new therapeutic approach.”

https://bit.ly/2JahCVg

#ASCO18: Celldex, Bristol update on immunooncology Phase 1/2 studies

Celldex Therapeutics (CLDX) presented two programs at the 2018 American Society of Clinical Oncology Annual Meeting. Data from the Phase 1/2 study of Celldex’s varlilumab, a CD27 targeting investigational immune-activating antibody, and Bristol-Myers Squibb’s (BMY) Opdivo, or nivolumab, an anti-PD1 immunotherapy, for patients with ovarian cancer and colorectal cancer, were presented. In addition, an overview of the Phase 2 study of the anti-ErbB3 antibody CDX-3379 in combination with Erbitux in advanced head and neck squamous cell cancer was presented in a “clinical trials in progress” poster session. Varlilumab was featured in an oral presentation that highlighted the ongoing Phase 2 study of varlilumab in combination with Opdivo. The Phase 1/2 study includes cohorts in ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, renal cell carcinoma and glioblastoma, with data from ovarian cancer and colorectal cancer patients included in the presentation. The majority of patients enrolled in the study had baseline tumors that were mostly “cold” with low expectation of responding to checkpoint inhibition therapy. The combination was well tolerated at all varlilumab dose levels tested. One patient with PD-L1 negative, MSI-high disease experienced a confirmed partial response in the Phase 2 study portion and continues on treatment. Of note, a patient with PD-L1 negative disease, initially considered MMR proficient as determined by standard screening laboratory analysis, achieved a near complete response in the Phase 1 portion of the study, which now continues at 35 months. As part of this study, an additional molecular analysis was conducted on this patient’s tumor. The tumor had a high mutational burden and mutations in genes regulating DNA repair, which together likely contributed to the response. DCR was 20%. CDX-3379 was featured in a “clinical trials in progress” poster presentation that highlighted the ongoing Phase 2 study of CDX-3379, a human monoclonal antibody designed to block the activity of ErbB3, in combination with Erbitux in patients with human papillomavirus negative, Erbitux-resistant, advanced head and neck squamous cell carcinoma. The proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. The multicenter, open-label, Simon two-stage design study is expected to enroll approximately 27 patients. The primary objective of the study is objective response rate. Secondary objectives include assessments of clinical benefit response, duration of response, progression-free survival and overall survival, and safety and pharmacokinetics associated with the combination. Four clinical trial sites are currently open to enrollment, and Celldex is targeting to complete enrollment to the first stage of the study by the end of the third quarter of 2018. The company continues to explore potential other opportunities in additional indications where ErbB3 is believed to play a role.

https://bit.ly/2LUJjDa

AstraZeneca, MedImmune meet primary endpoints in Phase 3 leukemia trial

AstraZeneca and MedImmune, its global biologics research and development arm, presented results from the Phase III ‘1053’ clinical trial that evaluated moxetumomab pasudotox in 80 patients with relapsed or refractory hairy cell leukemia who had received at least two prior lines of therapy. Moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin, showed a 75% objective response rate, a 41% complete response rate, and a 30% durable CR rate. The majority of patients with a complete response had a durable response and achieved a negative minimal residual disease status. The primary endpoint of the trial was durable CR, which is defined as CR with HR for greater than180 days. The median time to HR was 1 month. The most frequent treatment-related adverse events were nausea, peripheral edema, headache, and pyrexia; 8% had infections and 3% had neutropenia deemed treatment-related. Three patient deaths occurred, none of which were determined to be treatment-related. Treatment-related AEs leading to discontinuation were hemolytic uremic syndrome, capillary leak syndrome, and increased blood creatinine. Seven patients had CLS and seven had HUS; this includes four patients who had both CLS and HUS. CLS and HUS were manageable and reversible. In April 2018, AstraZeneca announced that the Food and Drug Administration accepted the Biologics License Application for moxetumomab pasudotox for the treatment of adult patients with HCL who have received at least two prior lines of therapy. The BLA is based on results from the Phase III ‘1053’ clinical trial. The FDA has granted Priority Review status with a Prescription Drug User Fee Act action date set for the third quarter of 2018.

https://bit.ly/2LXTyH8

AbbVie announced positive data from Phase 2 leukemia combo study

AbbVie announced positive data from the Phase 2 CAPTIVATE study evaluating IMBRUVICA, or ibrutinib, in combination with VENCLEXTA in previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma patients. Early results of the combination oral regimen suggest promising activity in treatment-naive CLL/SLL with 77% of the first 30 patients achieving responses with no detectable minimal residual disease after six cycles of the combination therapy. MRD is determined by measuring the number of cancer cells remaining and helps confirm depth of remission. The first 14 CLL/SLL patients to complete the clinical trial combination therapy of 12 cycles achieved responses with no detectable MRD in approximately nine out of 10 patients, with 93% achieving MRD negativity when measuring in peripheral blood and 86 percent with MRD negativity when measuring in the bone marrow. The most common AEs were diarrhea, fatigue, nausea, headache, upper respiratory tract infection and arthralgia. Grade 3 or higher AEs – occurring in greater than or equal to 3% patients – were neutropenia, hypertension, diarrhea and thrombocytopenia. No clinical tumor lysis syndrome occurred and lab TLS was seen in 1 of 164 patients. In treated patients with baseline LDi 5 cm or greater, LDi decreased to less than 5 cm in 43 of 53 patients after ibrutinib lead-in. TLS risk shifted from high to medium/low in 36 of 40 patients, and overall, the proportion of high-risk TLS decreased from 24% at baseline to 3% after ibrutinib lead-in.

https://bit.ly/2J8ykIL

FDA wants to shorten new drug monopolies to cut costs

In an effort to increase competition and bring down prescription drug prices, FDA Commissioner Scott Gottlieb speaking at the American Society of Clinical Oncology Annual Meeting said he wants to speed approval times for rivals to promising new first-to-market medicines, according to Reuters. The U.S. Food and Drug Administration chief has made a commitment to speeding up approvals of cheap generic medicines, the report added.

https://bit.ly/2suiePd

Merck, Eisai detail expanded use of combo med for several cancers

Eisai and Merck announced results from presentations of new data and analyses of LENVIMA, an orally available kinase inhibitor discovered by Eisai, in combination with Merck’s anti-PD-1 therapy, KEYTRUDA, in four different tumor types: unresectable hepatocellular carcinoma, squamous cell carcinoma of the head and neck, advanced renal cell carcinoma, and advanced endometrial carcinoma. LENVIMA and KEYTRUDA are not approved for use in combination in any cancer types today. Early phase results from Study 116/KEYNOTE-524 support further investigation in unresectable HCC. Study 116/KEYNOTE-524 is a Phase 1b open-label, single-arm multicenter study evaluating the tolerability and safety of the combination of LENVIMA and KEYTRUDA in patients with unresectable HCC, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, and ECOG performance status of 0 or 1. The primary endpoint was safety; secondary and exploratory endpoints included overall survival, objective response rate, progression-free survival and time to progression using modified Response Evaluation Criteria in Solid Tumors criteria. Tumor assessments of complete or partial response were confirmed greater than or equal to four weeks after initial response. Part 1 evaluated tolerability by assessing dose-limiting toxicities during the first cycle of treatment in patients for whom no other appropriate therapy was available. After tolerability was confirmed, additional patients with no prior systemic therapy for unresectable HCC were enrolled. The expansion part of the study will evaluate ORR and duration of response as measured by mRECIST.

https://bit.ly/2HhxHa3