Gina Columbus

led to complete remission in more than 50% of patients with previously untreated high- risk chronic lymphocytic leukemia (CLL), a blood cancer that lacks effective treatments. The findings from the phase 2 CLL2-GIVe trial were presented during the 2020 European Hematology Association Congress in June.

The triplet of Imbruvica (ibrutinib), Venclexta (venetoclax) and Gazyva (obinutuzumab), all targeted drugs, led to a complete remission rate of 58.5%. Furthermore, at cycle 15, 80.4% of patients had achieved minimal residual disease in their circulating blood, meaning that they had no detectable cancer. The combination also demonstrated an acceptable side effect profile.

Each component of the triplet therapy is a targeted drug that focuses on a different cancer-driving protein. Imbruvica interferes with Bruton’s tyrosine kinase, which drives growth. Venclexta inhibits the effects of B-cell lymphoma-2, facilitating cell death. Gazyva is an antibody against CD20, which is found on B cells.

All three drugs are already used in CLL treatment, either alone or with other drugs.

CLL starts in the bone marrow, where cancer cells multiply quickly and crowd out normal cells and can also involve lymph nodes. In high-risk CLL, genetic abnormalities are associated with poorer-than-average responses to therapy and health outcomes.

In May 2019, the FDA OK’d Venclexta plus Gazyva for the initial treatment of patients with CLL or small lymphocytic lymphoma. The approval was based on findings from the phase 3 CLL14 trial, in which the combination led to a 65% lower risk of disease progression or death compared with Gazyva plus chlorambucil, a chemotherapy, in this patient population.

Moreover, in January 2019, the FDA approved the combi- nation of Imbruvica and Gazyva as an initial treatment for patients with CLL or small lymphocytic lymphoma, based on data from the phase 3 iLLUMINATE (PCYC-1130-CA) trial. Among the participants, Imbruvica plus Gazyva led to a 77% reduction in the risk of disease progression or death versus chlorambucil plus Gazyva.

Previously, the triplet regimen of Imbruvica, Venclexta and Gazyva was explored in another phase 2 trial of patients with untreated, recurrent or treatment resistant CLL. At a median follow-up of 18 months, 23 of the 25 patients with recur- rent or treatment-resistant disease remained in the study and achieved some type of response: three complete, three complete with incomplete bone marrow recovery, and 17 partials, for an overall response rate of 92%.

In the CLL2-GIVe trial, investigators with the German CLL Study Group evaluated the triplet of Imbruvica, Venclexta and Gazyva as a first treatment in patients with high-risk CLL who lacked part of chromosome 17, known as 17p deletion, or had mutations to the 

All three agents were administered as part of a six-month regimen, followed by a combination of Venclexta and Imbruvica for an additional six months. If complete response with minimal residual disease was not achieved, Imbruvica was then administered as maintenance therapy, to help sustain response, for a total of 36 cycles.

Of the 41 patients enrolled, 24 were men. The participants ranged in age from 35 to 85 years, for a median age of 62. Twenty-six patients had a 17p deletion and 39 had TP53 mutations. In addition, 32 patients had an unmutated IGHV gene, which encodes a part of the antibody protein; this unmutated status predicts poorer prognosis.

The trial’s primary goal was to measure the complete response rate at cycle 15. Secondary goals involved measuring safety, minimal residual disease levels, time until disease progression and length of survival.

At cycle 15, or a median follow-up of 18.6 months, all patients were included in the efficacy and safety analyses, and 38 reached a final restaging of their disease. The investigators noted that 22 patients discontinued treatment at cycle 15 because of undetectable disease and a complete response with or without complete hematologic recovery. Treatment was discontinued in 13 patients for other reasons, including side effects and personal choice.

Results showed that the partial response rate was 34.2%, with 7.3% of responses not available. Three patients’ results could not be assessed: Two had died, one because of compli- cations of ovarian cancer and another because of cardiac failure, and the third withdrew consent at cycle 10. However, all three did experience a partial response.

Regarding safety, the regimen was well-tolerated. Serious or severe side effects included infections (19.5%), low neutrophil counts (43.9%), infusion-related reaction (7.3%), headache (2.4%), low platelet counts (14.6%), joint pain (2.4%) and irregular heartbeat (2.4%).

Articles

A three-drug treatment sparked complete responses in more than half of patients with high-risk chronic lymphocytic leukemia, who also tolerated the regimen well.
 

3 Drug Treatment Puts Some Patients With CLL On the Road to Remission

The Food and Drug Administration (FDA)’s Oncologic Drugs Advisory Committee (ODAC) unanimously voted 12 to 0 in favor of the agency approving belantamab mafodotin for the treatment of patients with relapsed or refractory multiple myeloma who have previously received at least four therapies.

The purpose of the Oncologic Drugs Advisory Committee (ODAC) is to review and evaluate data concerning the safety and effectiveness of marketed and investigational human drug products for their use in the treatment of cancer. In turn, the committee makes appropriate recommendations to the FDA’s commissioner.

For this meeting, the committee was tasked to assess whether the risk of ocular toxicity had been adequately identified in the DREAMM-2 trial and if the risk of ocular toxicity associated with belantamab mafodotin — an investigational anti-B-cell maturation antigen monoclonal antibody-drug conjugate – outweighed its benefit.

Keratopathy, or damage to the cornea, symptoms of blurred vision and dry eyes were the most notable side effects associated with the therapy, according to a briefing the FDA released before the meeting.

"It seems clear that this is an active agent," ODAC chairperson Dr. Philip C. Hoffman, a professor of medicine at University of Chicago Medicine, said during the hearing. "The toxicity is certainly not life threatening; in many instances, it isn't even comfort threatening, though evident on examinations. I do think patients are probably willing to take this risk, and the mitigation strategy that the company has outlined for thorough exams before each dosing, a grading system, and so on, addresses the concerns."

granted a priority review to belantamab mafodotin

 for the treatment of patients with relapsed or refractory multiple myeloma.

“I think the efficacy and toxicity remains favorable in the highly pretreated patient population that was studied,” Dr. Heidi D. Klepin, a professor of hematology and oncology at Wake Forest School of Medicine, said. "I think the informed consent process will allow patients to choose whether this tradeoff is worth it to them. I would encourage the sponsor to really put some additional effort into enrolling and reporting on a representative number of patients aged 75 or older, since that particular subgroup was poorly represented and is a large and growing group of patients who may have this choice. At present, we don't have enough evidence on the benefit to risk ratio in that patient population."

The FDA’s ODAC is an independent panel of experts that evaluates data concerning the efficacy and safety of marketed and investigational products for use in the treatment of cancer and makes appropriate recommendations to the FDA. While the agency considers these panel recommendations, of note, the FDA solely makes the final decision regarding the approval of agents and the recommendations by the panel are non-binding.

A version of this story originally appeared on OncLive® as “

FDA Panel Supports Belantamab Mafodotin for Relapsed/Refractory Myeloma

The Food and Drug Administration’s Oncologic Drugs Advisory Committee voted in favor of the agency approving belantamab mafodotin to treat patients with relapsed or refractory multiple myeloma who have previously received at least four therapies.
 

FDA Panel Unanimously Supports Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma

Myeloproliferative neoplasms, or MPNs, are a type of blood cancer that is often not heard about, which is why it is important for patients to speak with their doctors to learn more.

MPNS — essential thrombocythemia, myelofibrosis and polycythemia vera – begin with an abnormal change, or mutation, in a stem cell in the bone marrow, which leads to an overproduction of any combination of white cells, red cells and platelets.

 Talks Cancer” podcast, we teamed up with our sister publication “

” to speak with a patient-doctor duo on the disease.

Learn more from Dr. Ruben A. Mesa, director of the Mays Cancer Center at UT Health San Antonio MD Anderson, and Antje Hjerpe, a patient diagnosed with essential thrombocythemia in 1992. The pair discuss myeloproliferative neoplasms — what they are, how they’re treated and how patients can talk to their doctors to be their own best advocates.

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In this special edition of the “CURE Talks Cancer” podcast, we teamed up with our sister publication “OncLive on Air” to speak with a patient-doctor duo on myeloproliferative neoplasms.
 

Patient-Doctor Duo: The Basics of Myeloproliferative Neoplasms

When it comes to treating advanced kidney cancer, more may be better.

Since the April 2018 approval of two immunotherapies given together for patients with advanced disease, additional combination strategies have emerged, further transforming treatment options.

Primarily, these involve combining immunotherapies known as checkpoint inhibitors with targeted drugs — agents that affect cell functions such as growth, invasion and cell death that are relevant to their malignant behavior.

In April of this year, the Food and Drug Administration (FDA) approved the combination of the immunotherapy Keytruda (pembrolizumab) and the targeted drug Inlyta (axitinib) for initial treatment of patients with advanced kidney cancer, also known as renal cell carcinoma (RCC). Earlier, in February, the agency granted an expedited review to the experimental combination of Inlyta and a different immunotherapy, Bavencio (avelumab), in these patients.

Checkpoint inhibitors disable proteins that normally keep the immune system in check; this allows the immune system to rev up so it can better recognize and kill cancer. Targeted drugs inhibit the activity of proteins, genes or their microenvironment that help a cancer grow and survive.

With these novel regimens come unique side effects, dosage schedules and administration methods, so it’s important to carefully match treatments to the patients most likely to benefit from them, according to Dr. Bradley McGregor, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston and senior physician and instructor in medicine at Harvard Medical School.

“The field of RCC is changing at a rapid rate, and there are lots of options for our patients,” McGregor said in an interview during the 2019 OncLive ® State of the Science SummitTM on Genitourinary Cancers. (OncLive® is a sister publication of CURE ®.) “Determining which option for which patients is going to involve a balanced discussion with the patient about side effects, convenience, (oral) versus intravenous (administration) and how they want to manage their care going forward.”

The spate of regimens approved in the past couple of years amounts to no less than “a revolution in the first-line (initial treatment) setting,” McGregor said.

The evolution started when the combination of the immu- notherapies Opdivo (nivolumab) and Yervoy (ipilimumab) generated an improvement in overall survival in patients with advanced-, poor- and intermediate-risk kidney cancer that had not been treated before. Rates of complete response — all the cancer disappeared &mdash; reached 10%, a previously unheard-of level in this population, and the responses were relatively long-lasting. McGregor cautioned that the regimen does not work for everyone; the overall response rate, which includes all complete and partial responses, is 40%.

Then came the pairing of targeted drugs such as tyrosine kinase inhibitors with immunotherapies. Using Keytruda plus Inlyta as initial treatment for advanced kidney cancer generated an overall response rate of close to 60% and more of a survival benefit than with Sutent (sunitinib), a targeted drug that is a standard treat- ment for these patients. Those results led to the FDA’s recent approval of the combination.

Another advantage of Keytruda/ Inlyta: Patients can benefit regard- less of the risk classification of their disease. That makes the combination a better standard of care than Sutent for patients with good-risk disease, McGregor said.

Meanwhile, a similar combination of Bavencio plus Inlyta looks promising in clinical trials. “What stands out is the tolerability,” McGregor said. “Only 11% of patients required

high-dose steroids (to ease side effects caused by the immune system attacking healthy organs). It seems to be a well-tolerated regimen, and so it certainly offers another potential option for our patients; it’s exciting to see the data mature.”

Doctors are still sorting out which patients should get which regimen, but McGregor follows some guidelines in his own practice.

If a patient experiences a crisis such as symptomatic liver or lung metastases and needs immediate help from an anticancer medication, McGregor favors tyrosine kinase inhibitor/immunotherapy combinations because of their 50% to 60% response rate.

On the other hand: “I might have a younger patient who has minimal, small-burden disease, but I want to do whatever has the best chance to get (them) off therapy in the future,” he said. “Based on what we know right now ... some of these patients (are) able to stop therapy with Opdivo/Yervoy and maintain their complete response."

With numerous regimens being investigated, there is no sign that the breakthroughs will slow down anytime soon.

An immunotherapy/targeted drug duo that generated promising results in clinical trials combines the checkpoint inhibitor Tecentriq (atezolizumab) with Avastin (bevacizumab), which kills the blood vessels that tumors rely on to survive.

“We have seen (Tecentriq/Avastin) data in the IMmotion150 and IMmotion151 studies compared with (Sutent),” McGregor said. “Again, responses were similar to what we see with (Opdivo/Yervoy) — right around 40%.

“The combination is certainly a well-tolerated regimen, and from my experience in non-clear cell RCC (a minority of kidney cancers that respond less to treatment), there seems to be activity. However, we are waiting for more data to see where the role is going to apply in kidney cancer going forward. It is being studied in combination with (the targeted drug) Cabometyx (cabozan- tinib) right now in the front-line setting, both in non-clear cell and clear cell RCC, so it continues to evolve.”

Cabometyx, which simultaneously disables several cancer-driving proteins, is a standard RCC treatment for advanced renal cell carcinoma. It may soon also be used as an initial treatment for that condition, McGregor said.

The drug is being investigated as a first treatment for patients who are ineligible for immunotherapy or have autoimmune disease. In these patients with intermediate- or poor-risk disease, data shows that Cabometyx delayed disease progression compared with Sutent, he said.

In addition, Cabometyx is being studied in combina- tion with novel drugs to treat kidney cancer. One trial pairs it with CB-839, a glutaminase inhibitor. “It is impressive that there is no increase in toxicities (when CB-839 is added), but there is a great disease control rate,” McGregor said. He added that a HIF-2 inhibitor has also been paired with Cabometyx in trials.

“What we really need are novel approaches,” he said. “Unfortunately, even with the great responses of these combi- nations in the front-line setting, there are still patients who don’t respond. We need novel agents and rational combinations. Looking for new targets to help those patients who don’t respond to what we have is going to be critical.”

Drug duos that hit kidney cancer with immunotherapy and targeted treatment offer a better alternative to single agents.

Gina Columbus

3 Drug Treatment Puts Some Patients With CLL On the Road to Remission

FDA Panel Unanimously Supports Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma

Patient-Doctor Duo: The Basics of Myeloproliferative Neoplasms

A One-Two Punch in Kidney Cancer

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