Highlights from ASCO 2018: Immunotherapy for Endometrial Cancer, Benefits of Exercise, and Promising New Targeted Drugs

By Matthew Tontonoz,

Monday, June 4, 2018

Crowded hall with ASCO signage
Summary

Memorial Sloan Kettering researchers unveiled the results of more than 300 studies at this year’s American Society of Clinical Oncology annual meeting. These are a few of the highlights.

Every year, cancer doctors and scientists from around the world converge on the sprawling McCormick Place in Chicago for the annual meeting of the American Society of Clinical Oncology (ASCO). They come in search of up-to-the-minute information about cancer and ways to treat it. This year’s meeting theme is “Delivering discoveries: Expanding the reach of precision medicine.”

Among the studies highlighted in the ASCO press program were several led by Memorial Sloan Kettering researchers:

MSK experts also weighed in on results from a study evaluating whether chemotherapy is beneficial for women with intermediate-risk breast cancer.

medical oncologist Larry Norton
Some Women with Early Breast Cancer May Not Need Chemotherapy, Study Says
Learn about the results of a trial showing that women with intermediate-risk breast cancer may not need chemotherapy.
Learn more

But there were many other important studies that shouldn’t be overlooked. Here’s a roundup:

Immunotherapy Combo for Endometrial Cancer

Immunotherapy has transformed the care of several types of cancer — melanoma, lung cancer, and bladder cancer especially. But so far, immune therapies for gynecologic cancers have had more limited success. Some people respond well, but the numbers are small.

Research at MSK and elsewhere suggests that some immunotherapy drugs can be more effective if they are combined with drugs that alter the area surrounding the tumor. This region is referred to as the microenvironment.

MSK medical oncologist Vicky Makker is leading an early-phase clinical trial of one such combination in women with advanced endometrial (uterine) cancer. The trial is testing an immune checkpoint inhibitor called pembrolizumab (Keytruda®) in combination with a targeted drug called lenvatinib (Lenvima®). Pembrolizumab blocks a molecule called PD-1, boosting immune responses. Lenvatinib blocks several enzymes, including those that help tumors grow blood vessels.

Research suggests that some immunotherapy drugs can be more effective if they are combined with drugs that alter the area surrounding the tumor.

As of August 2017, 54 women with endometrial cancer were enrolled in the study. Women with all endometrial tumor types were allowed to join, as were women whose tumors had a specific genetic defect called mismatch repair (MMR) deficiency. (Previous research has shown that tumors with MMR deficiency tend to respond better to immunotherapy.)

According to Dr. Makker, the combination demonstrated “encouraging activity” in advanced endometrial cancer regardless of MMR status. After 24 weeks, the response rate was 40%. The most common side effects were high blood pressure, fatigue, diarrhea, thyroid problems, and decreased appetite.

Based on these results, the investigators believe that a randomized phase III study comparing this combination to chemotherapy is warranted. They expect to open a trial at MSK at the end of August, followed by other institutions around the world.

“Given that there are no currently approved treatments for people with high-grade advanced endometrial cancer, these encouraging results suggest that the combination of lenvatinib and pembrolizumab could be an important option,” Dr. Makker says.

Read more about immunotherapy for gynecological cancers.

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Exercise, Mortality, and Well-Being in Childhood Cancer Survivors

Compared with their peers in the general population, adult survivors of childhood cancer are at a higher risk of dying early from a number of causes. MSK exercise scientists Jessica Scott and Lee Jones and colleagues sought to find out whether exercise could lower this risk. They analyzed data from 15,450 adults in the Childhood Cancer Survivor Study (CCSS), a large National Cancer Institute–sponsored study that tracks participants’ health from year to year. The investigators looked specifically at self-reported answers to questions about vigorous exercise that makes you sweat or breathe hard.

The researchers found that over approximately ten years, there was a significant inverse relationship between the amount of exercise and the risk of death. That is, those who exercised the most had the lowest risk of death from any cause.

Among 5,689 survivors in this group, those who increased the intensity of their exercise over an eight-year period had a 40% reduction in their mortality rate compared with those with a low level of exercise. The authors conclude that vigorous exercise is associated with a lower risk of late mortality in adult survivors of childhood cancer.

“More and more data are showing the increasing importance of exercise after a cancer diagnosis,” says Dr. Scott, the lead author. “Our findings indicate that a relatively small increase in vigorous exercise — about 40 minutes per week — confers significant benefit for adult survivors of childhood cancers regardless of age, weight, or cancer treatment.”

A paper reporting these results was published simultaneously in the journal JAMA Oncology

Even small amounts of vigorous exercise — 20 minutes a week — may have lasting psychological benefits.
Emily S. Tonorezos
Emily S. Tonorezos Clinical Director of MSK’s Adult Long-Term Follow-Up Program

In a separate study, MSK physician Emily Tonorezos, Dr. Jones, and colleagues looked at whether exercise could reduce the risk of psychological distress among cancer survivors. The problems they looked at included depression and anxiety, as well as trouble thinking and processing information. Dr. Tonorezos, who is Clinical Director of MSK’s Adult Long-Term Follow-Up Program, and her team looked at data from 6,199 adult participants of the CCSS. They compared answers on a baseline questionnaire to ones given seven years later.

Of those not engaged in vigorous exercise, 76% had mental health concerns. By contrast, 69% of people who exercised vigorously had these issues. The investigators concluded that vigorous exercise is associated with less emotional distress and less trouble thinking and processing information in long-term survivors of childhood cancer.

“For survivors,” Dr. Tonorezos says, “even small amounts of vigorous exercise — 20 minutes a week —  may have lasting psychological benefits.”

Read more about how MSK researchers are studying the ways that exercise can benefit people with cancer.

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New Hope for a Rare Sarcoma

Sarcomas are cancers of the bone, muscle, or connective tissue. There are as many types as there are different varieties of these tissues in the body. Tenosynovial giant cell tumor (TGCT) is a rare sarcoma of the joint and the tendon sheath for which no approved systemic therapies are available. Surgery is the main form of treatment.

Doctors do know something about what causes the disease, however. It is associated with the overproduction of a molecule called colony-stimulating factor 1 (CSF-1), a cellular growth factor. Pexidartinib is an investigational drug made by Daiichi Sankyo that acts as a selective inhibitor of the receptor for CSF-1 and related molecules. Preclinical work and early clinical trials have suggested it may benefit people with TGCT.

A team of clinician-scientists led by MSK’s William Tap conducted a phase III trial of this drug. The adults with TGCT who participated did not have surgery because it would have been associated with potentially worse function or complications due to the tumor’s location.

A total of 120 patients were randomized to receive either pexidartinib or a placebo. The primary endpoint of the study, dubbed ENLIVEN, was an overall response rate (ORR) at week 25. For the pexidartinib group, the ORR was 39%; for the placebo group, it was 0%.

After a median follow-up time of six months, none of those who responded to pexidartinib saw their disease worsen. “The results are pretty striking,” Dr. Tap says.

The drug does have some side effects, including rare cases of liver toxicity. Other side effects included hair color changes, vomiting, fatigue, altered taste, and swelling around the eyes.

According to Dr. Tap, “If approved, pexidartinib would be the first drug we’ve ever had to treat this rare disease.”

If approved, pexidartinib would be the first drug we've ever had to treat this rare disease.
William D. Tap
William D. Tap medical oncologist
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Precision Drugs Find Another Target

At last year’s ASCO meeting, it was announced that larotrectinib was effective at treating a broad swath of cancers with the TRK fusion mutation. People with few other options who received the targeted therapy, made by Loxo Oncology, benefited from significantly longer life.

This year, Loxo announced results from a phase I study of LOXO-292. This targeted drug is a potent inhibitor of a mutated form of the protein RET, which is found across many different types of solid tumors. Unlike prior RET inhibitors, the new medication is even more precise.

The purpose of this global phase I trial was to establish the safety of the drug and a maximum tolerated dose. People with any type of RET-altered cancer were allowed to participate. Many patients had already been treated with older therapies that target RET, and some had brain metastases. The most common cancer types represented were non-small cell lung cancer (NSCLC), papillary thyroid cancer (PTC), and medullary thyroid cancer (MTC).

LOXO-292 is an inhibitor of a mutated form of the protein RET, which is found across many different types of solid tumors.

So far, 78 people have been treated with LOXO-292. No dose-limiting toxicities have occurred, and side effects have been minor. The overall response rate in patients with a RET mutation was 77%. This includes people with brain metastases, NSCLC, PTC, and pancreatic cancer. In those with RET-mutant MTC, the overall response rate was 45%, including two people with complete responses.

The study authors conclude that LOXO-292 is “well-tolerated and had marked antitumor activity in patients with RET-altered cancers.”

MSK medical oncologist Alexander Drilon, Clinical Director of the Early Drug Development Service, was the principal investigator of the trial. He says, “These results are highly encouraging, especially considering that to date there is no approved drug for RET-altered cancers. The fact that LOXO-292 was active regardless of cancer type or RET alteration type once again underscores the utility of a tumor-agnostic approach to drug development.”

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