Dylann Cohn-Emery

Almost every patient with mismatch repair-deficient colon cancer enrolled onto a multicenter clinical trial achieved some type of response when treated with the neoadjuvant combination of Opdivo (nivolumab) and Yervoy (ipilimumab), according to recently presented findings.

The data — which were unveiled at the 2022 

European Society of Medical Oncology Congress

 — also demonstrated that 98% of the 112 patients enrolled onto the trial received surgery within six weeks of starting treatment.

According to the National Cancer Institute, neoadjuvant therapy is an initial treatment that is given to patients to shrink their tumor before they undergo surgery.

Here, the investigators launched the NICHE-2 trial after observing a group of 32 patients with nonmetastatic, mismatch repair-deficient colon cancer achieve a 100% pathologic response (the disappearance of some or all traces of cancer in tissue samples removed during surgery) rate when treated with an immune checkpoint inhibitor. The same findings showed that of the responses to the treatment, 60% of patients derived a complete response, meaning all signs of disease were gone.

In the NICHE-2 trial, 112 patients were administered Opdivo plus Yervoy during their first cycle of treatment. Then, the patients received only Opdivo two weeks later followed by surgery within six weeks of enrolling onto the trial. Assessing the three-year disease-free survival (time after treatment has ended that a patient remains alive without signs or symptoms of their cancer) rate and safety of the neoadjuvant combination of Opdivo and Yervoy were the main goals of the study.

The authors also aimed to investigate the major pathological response rate, as well as the complete pathological response rate. A major pathologic response was defined as 10% or less residual tumor remaining following the completion of neoadjuvant treatment.

The findings from the NICHE-2 trial showed that treatment with Opdivo plus Yervoy for four weeks was associated with a major pathologic response rate of 95%.

This outcome, according to one of the study authors, is a major improvement over what has been seen in the past for these patients.

“This stands in stark contrast to data from neoadjuvant chemotherapy in this same patient population (that had) only 7% pathologic responses,” Dr. Myriam Chalabi, a medical oncologist at the Netherlands Cancer Institute in Amsterdam, said in her presentation of the data.

Additionally, 67% of patients demonstrated pathologic complete responses and none have had a disease recurrence as of the last evaluation of the data. The presurgical treatment with Opdivo plus Yervoy was also well tolerated, with investigators observing only 4% serious or severe immune-related side effects.

Immunotherapy helps boost a person's immune system to help the body find and destroy cancer cells, according to the American Society of Clinical Oncology. Since immunotherapy activates the immune system, it can cause inflammation in any of the organs within the body, which can lead to complications called immune-related side effects.

The median time from the first treatment with the combination of Opdivo and Yervoy to surgery was 5.4 weeks. The investigators noted that there were no new safety signals but explained that 21% of patients had a surgery-related side effect of any severity. Thirteen percent of those side effects were serious or worse.

The investigators observed a major pathologic response in 102 patients, and a pathologic complete response in 72 patients following neoadjuvant treatment with Opdivo plus Yervoy.

Overall, 61% of the patient population experienced an immune-related side effect of any severity. However, only two patients had an immune-related side effect that lead to a more than two week delay in surgery. The most common mild to moderate side effects included infusion reactions, dry mouth, over- or underactive thyroid function, fatigue and flu-like symptoms.

The findings from the three-year disease-free survival analysis are expected to be available next year. Chalabi noted that future studies may observe organ-sparing approaches for patients with mismatch repair-deficient colon cancer. An organ-sparing treatment approach aims to avoid invasive surgery and preserve the function of the affected organ.

“I believe that neoadjuvant immunotherapy has a very strong potential to become standard of care for patients with (mismatch repair deficient) colon cancer,” Chalabi concluded. “The future has never been brighter for this patient population, and for that, I urge the pharmaceutical companies to please strive for registration of neoadjuvant immunotherapy.”

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None of the more than 100 evaluable patients with mismatch repair deficient colon cancer have experienced disease recurrence after treatment with presurgical Opdivo plus Yervoy, according to study results.

Presurgical Opdivo-Yervoy Combo Has ‘Very Strong Potential’ to Be Standard of Care for Subgroup of Patients With Colon Cancer

The use of Calquence (acalabrutinib) was associated with fewer cardiovascular-related toxicities as well as a lower overall toxicity burden among patients with chronic lymphocytic leukemia (CLL), compared with Imbruvica (ibrutinib), according to recent findings.

The study authors conducted an analysis of data from the phase 3 ELEVATE-RR trial which had previously shown that treatment with the Bruton’s tyrosine kinase (BTK) inhibitor Calquence resulted in progression-free survival outcomes that were noninferior to those that occurred with Imbruvica — another BTK inhibitor — in patients with previously treated CLL.

This analysis, the results of which were presented at the recent 

2021 American Society of Hematology (ASH) Annual Meeting

, was conducted to further assess the occurrence of BTK inhibitor-associated side effects as well as the toxicity profiles of Calquence and Imbruvica.

Measuring progression-free survival (or the time during and after treatment when the patient lives without disease progression) was the main goal of the trial. Other goals included observing the incidence of atrial fibrillation (AFib)/flutter of any severity, as well as serious or severe infections and overall survival.

“Event-based analyses demonstrated a higher BTK inhibitor–related toxicity burden with ibrutinib in this head-to-head trial,” John F. Seymour, from the Peter MacCallum Centre and the Royal Melbourne Hospital in Melbourne, Australia, said in his presentation. “Exposure-adjusted assessments of AFib/flutter, hypertension, and bleeding events demonstrated a lower cardiovascular-related toxicity burden with acalabrutinib compared to ibrutinib. Cumulative incidences of hypertension and AFib/flutter were also lower with acalabrutinib in patients without a prior history of these events.”

After a median follow-up of 41 months, investigators assessed events of clinical interest in 268 patients receiving Calquence and 265 patients receiving Imbruvica. Of these events, the occurrence of AFib/flutter, hypertension and bleeding of any severity were statistically higher with Imbruvica. Exposure-adjusted incidence and exposure-adjusted time with these events were about 1.5 to 4.1 times higher with Imbruvica.

Other common BTK–related side effects noted for being significantly higher with Imbruvica in this analysis were any-severity diarrhea (46% vs 35%), joint pain (23% vs 16%), back pain (13% vs 8%), muscle spasms (13% vs 6%), and shortness of breath (12% vs 4%). Incidence of any-severity contusion and urinary tract infection (UTI) were also higher in those who received Imbruvica. Besides UTI, exposure-adjusted incidence and exposure-adjusted time with events were about 1.4 to 13.1 times higher with Imbruvica.

The only side effects with statistically higher incidence with Calquence were any-severity headache and cough, which occurred at rates of 35% and 29%, respectively, versus 20% and 21% with Imbruvica.

Investigators observed a longer median time to onset of any-severity AFib/flutter with Calquence versus Imbruvica, at 28.8 months and 16 months, respectively. Hypertension of any severity had a similar median time to onset for both therapies. Concomitant medication use for AFib/flutter or hypertension for all patients was less common in those administered Calquence.

The cumulative incidence of AFib/flutter and hypertension of any severity were consistently lower with Calquence up to 36 months, according to Seymour. Additionally, incidence of these two side effects was lower in patient subgroups regardless of the number of prior therapies, age, and having no prior history of AFib/flutter and hypertension. For patients with no prior history of AFib/flutter or hypertension, there was a lower cumulative incidence in patients receiving Calquence compared with Imbruvica.

There was, however, a similar time to onset for Calquence and Imbruvica in terms of inducing bleeding events of any severity. But incidence was lower for the Calquence group regardless of age and in patients with 1 to 3 prior lines of therapy. Few patients in either treatment group required dose modification due to bleeding events. Also, fewer patients given Calquence used concomitant medication for bleeding events than patients given Imbruvica. Moreover, the cumulative incidence of bleeding of any severity over 36 months was lower in those treated with Calquence.

At the data cutoff, 43% of patients on the ELEVATE-RR trial were still receiving treatment.

Treatment with Calquence resulted in fewer toxicities, including atrial fibrillation, flutter and hypertension, in patients with previously treated chronic lymphocytic leukemia, compared with Imbruvica treatment, according to findings from the analysis of a phase 3 trial.

Dylann Cohn-Emery

Presurgical Opdivo-Yervoy Combo Has ‘Very Strong Potential’ to Be Standard of Care for Subgroup of Patients With Colon Cancer

Calquence Linked to Fewer Heart-Related, Other Toxicities in Patients With CLL Than Imbruvica

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