Caroline Seymour

Treatment with Tecentriq (atezolizumab) following surgery was associated with a significant improvement in disease-free survival among patients with stage 2 to 3A non–small cell lung cancer (NSCLC), compared to the best supportive care.

Moreover, the data — which were presented during a news briefing prior to the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting — indicated that the benefit was particularly pronounced in patients who had a PD-L1–positive tumor.

“Though surgery can cure some patients with early-stage lung cancer, disease recurrence is still very common. Until this trial, the only treatment that was known to help reduce that risk for most patients was chemotherapy, or osimertinib [Tagrisso] for the small group of patients with tumors with an EGFR mutation,” said lead study author Dr. Heather Wakelee, a thoracic specialist and chief of the Division of Oncology at Stanford University Medical Center, in a news release. “These data show that personalized medicine with (Tecentriq) can reduce the chance of NSCLC returning after surgery for patients who have a tumor that expresses the biomarker PD-L1.”

Despite the progress that has been made for patients with early-stage disease who harbor EGFR sensitizing mutations, the standard of care remains platinum-based chemotherapy for most patients with resected NSCLC.

Patients had to have had completely resected stage 1B to 3A NSCLC to be enrolled onto the study. After 1,280 patients received between one and four cycles of the chemotherapy cisplatin plus pemetrexed, gemcitabine, docetaxel or vinorelbine, they were randomized to either Tecentriq every 21 days for 16 cycles (1,005 patients) or treatment with best supportive care (1,005 patients).

Measuring disease-free survival (the time after treatment without signs of cancer) in patients with stage 2 to 3A disease, as well as a PD-L1 expression of at least 1% on tumor cells, was the main goal of the study. Other goals included assessing overall survival and disease-free survival in patients with a high expression of PD-L1.

Among patients whose tumors expressed a PD-L1 expression of at least 1%, the data demonstrated that a median disease free survival (DFS) was not evaluable in 248 patients who received Tecentriq compared to a median DFS of 35.3 months in 228 patients treated with best supportive care. Two-year DFS rates were 74.6% in the Tecentriq group and 61% in the best supportive care group. Additionally, three-year DFS rates were 60% in those who received Tecentriq and 48.2% in the best supportive care group.

Treatment with Tecentriq in the other patients was associated with a median DFS of 42.3 months compared to 35.3 months in those who received best supportive care. Two-year DFS was 70.2% with Tecentriq and 61.6% with best supportive care. Additionally, the three-year DFS was 55.7% and 49.4%, respectively.

In terms of safety, 92.7% of 495 patients who received Tecentriq reported a side effect compared to 70.7% of 495 patients in the best supportive care group. Of note, 21.8% of the side effects in the Tecentriq group and 11.5% of side effects in the best supportive care group were considered serious or severe.

None of the patients in the best supportive care group had to withdraw from treatment because of their side effects, however 18.2% of those who received Tecentriq did.

More analyses of DFS and overall survival data are expected to continue as more data are collected over time.

“For the first time, we are seeing that an immunotherapy is effective when used to treat early-stage lung cancer. The IMpower010 trial demonstrates that, for certain patients, (Tecentriq) can delay progression to advanced disease, and perhaps even the need for more aggressive therapy. This could be an important advance in our understanding of immunotherapy and a step forward for many patients with lung cancer” noted ASCO chief medical officer and executive vice president Dr. Julie R. Gralow in the release.

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The data, according to an expert, show that treatment with Tecentriq could delay disease progression to an advanced stage, as well as the need for more aggressive therapy.

Tecentriq Significantly Improves Survival Outcome in Patients with Early-Stage Non-Small Cell Lung Cancer

Treatment with sapanisertib did not result in significant activity or a favorable safety profile in patients with refractory metastatic renal cell carcinoma, according to study results presented at the 2021 ASCO Genitourinary Cancers Symposium.

“Sapanisertib had poor tolerability and minimal activity in patients with treatment refractory metastatic (renal cell carcinoma), and there was no clear benefit among patients with (mechanistic target of rapamycin [mTOR]) or (phosphatase and tension homolog [PTEN]) alterations,” lead study author Dr. Bradley McGregor, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, said in a virtual presentation of the data.

Thirty-eight patients (median age, 62 years) with clear cell metastatic renal cell carcinoma who had received two or more previous lines of treatment and with non-clear cell metastatic renal cell carcinoma who received one or more previous line of treatment were enrolled onto the multicenter, phase 2 study.

Patients underwent a mandatory baseline biopsy that evaluated PTEN status and more than 477 genes, including TSC1, TSC2, mTOR, PIK3CA, and PTEN, prior to receiving 30 milligrams of oral sapanisertib weekly.

Measuring objective response rate (the proportion of patients who had a complete or partial response to treatment) was the main goal of the study. Additional goals included assessing progression-free survival, overall survival, safety and toxicity of the drug.

Most of the patient population had clear cell disease (73.7%), and the rest had non-clear cell renal cell carcinoma (26.3%). Moreover, most patients had intermediate-risk disease (76.3%), followed by favorable- (13.2%) and poor-risk disease (10.5%).

Treatment options following progression on a checkpoint inhibitor and VEGF tyrosine kinase inhibitor are limited for patients with metastatic renal cell carcinoma. Approved rapalogs (a drug class), which have modest activity in the disease, inhibit only mTORC1 (a specific protein), whereas sapanisertib inhibits the entire mTOR pathway by targeting mTORC1 and mTORC2.

Most patients received four or more prior lines of therapy (39.5%). Though, patients who received one (13.2%), two (21.1%), and three (13.2%) prior lines of therapy were also represented. There were five patients who had an unknown number of prior treatments.

After a median follow-up of 10.4 months, treatment with the study drug induced an objective response rate of 5.3%. Median progression-free survival was 2.5 months and the median overall survival was 11.2 months.

The data showed that two patients experienced an unconfirmed partial response, 15 patients had stable disease, 17 patients experienced disease progression and two were not evaluable.

At the time of data stopped being collected, two patients remained on treatment. Of the remaining 36 who discontinued treatment, 29 occurred because of progressive disease and four reached an unacceptable toxicity.

No clear benefit between mTOR and PTEN alterations and clinical benefit with sapanisertib was reported.

Side effects related to treatment with sapanisertib included, but were not limited to, nausea (50%), fatigue (39%), diarrhea (18%), constipation (11%) and dehydration (8%). There were no grade 4 or 5 (more serious or severe) side effects associated with the treatment.

“Additional work is needed to find new targets for patients with advanced RCC,” concluded McGregor.

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Treatment with sapanisertib was associated with limited activity and poor safety outcomes in patients with refractory metastatic renal cell carcinoma.

Novel Therapy Demonstrates Limited Activity and Poor Safety Outcomes in Patients With Metastatic Renal Cell Carcinoma

Clinical benefit from the addition of chemotherapy to endocrine therapy may be determined by menopause status in women with hormone receptor (HR)-positive, HER2-negative, lymph node-positive breast cancer and a recurrence score between 0 and 25, according to findings from an analysis of the phase 3 RxPONDER trial that were presented virtually during the 2020 San Antonio Breast Cancer Symposium.

In particular, the addition of chemotherapy to endocrine therapy led to an improvement in five-year invasive disease-free survival and overall survival (OS) in premenopausal but not postmenopausal women.

In premenopausal patients, the five-year invasive disease-free survival rate was 94.2% in the chemotherapy/endocrine therapy arm vs. 89% in the endocrine-alone arm. In postmenopausal patients, the five-year invasive disease-free survival rate was 91.6% and 91.9%, respectively.

“Postmenopausal women with one to three positive nodes and recurrence score between 0 and 25 can likely safely forego adjuvant chemotherapy without compromising (invasive disease-free survival),” said lead study author Dr. Kevin Kalinsky during a press briefing.

“This will save tens of thousands of women the time, expense and potentially harmful side effects that can be associated with chemotherapy infusions,” Kalinsky, director of the Glenn Family Breast Center and Breast Medical Oncology at Winship Cancer Institute, added. “(However,) premenopausal women with positive nodes and recurrence scores between 0 and 25 likely significantly benefit from chemotherapy.”

Patients with HR-positive, HER2-negative, lymph node-positive breast cancer have an increased risk for recurrence and are typically treated with chemotherapy.

To prevent potential overtreatment or undertreatment, the 21-gene Oncotype Dx Recurrence Score is used to identify which patients with lymph node-negative, HR-positive, HER2-negative disease can omit chemotherapy.

In lymph node-negative patients, exploratory findings from the phase 3 TAILORx trial suggested that women over the age of 50 with a recurrence score of 25 or less derive no benefit from chemotherapy, whereas patients age 50 or under with a recurrence score between 16 and 25 may derive benefit from chemotherapy. However, whether these results were generalizable to the approximately 20% of patients with nonmetastatic HR-positive, HER2-negative disease and one to three positive lymph nodes in the United States had not been previously defined.

To that end, investigators launched RxPONDER, in which 5,015 patients with a recurrence score between 0 and 25 were randomized to endocrine therapy alone or chemotherapy followed by endocrine therapy. Patients with a recurrence score of more than 25 were treated with chemotherapy followed by endocrine therapy.

Patients in the randomized portion of the trial were categorized by recurrence score (0-13 versus 14-25), menopausal status (pre versus post), and nodal surgery (axillary lymph node dissection versus sentinel lymph node biopsy).

Eligible patients included females 18 years of age or older with at least 1% estrogen receptor and/or progesterone receptor expression, HER2 negativity, one to three positive lymph nodes, recurrence scores of 25 or less without distant metastases and an ability to receive taxane and/or anthracycline-based chemotherapy.

Invasive disease-free survival, defined as local, regional, distant recurrence, any second invasive cancer or death due to any cause, served as the primary end point of the study. OS served as the secondary end point.

Additional results demonstrated that the invasive disease-free survival benefit also translated into an OS benefit in premenopausal patients. In this population, the five-year OS rate was 98.6% with chemotherapy/endocrine therapy vs 97.3% with endocrine therapy alone. However, in postmenopausal women, the five-year OS rate was 96.2% and 96.1%, respectively.

Providing additional perspective during the press briefing, SABCS co-director, Dr. C. Kent Osborne, founding director of the Dan L. Duncan Comprehensive Cancer Center and Dudley and Tina Sharp Chair for Cancer Research at Baylor College of Medicine, said, “The results clearly show no benefit to adding chemotherapy to standard endocrine therapy in postmenopausal patients, despite having positive nodes, emphasizing that node positivity, while an important prognostic marker, is not a predictive marker of chemotherapy sensitivity.”

“In premenopausal patients, a different result was obtained. Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” Osborne concluded.

Premenopausal women with HR-positive, HER2-negative, lymph node-positive breast cancer and a risk for recurrence experienced benefits with chemotherapy plus endocrine therapy, with improvements in five-year invasive disease-free and overall survival. 

Chemotherapy With Endocrine Therapy Shows Clinical Benefit With Improved Survival in Breast Cancer 

received a diagnosis of colorectal cancer (CRC), it’s crucial to ask for testing to determine the tumor’s genetic mutations or other aberrations.

That’s because CRC is a very heterogeneous group of cancers, meaning it differs greatly among patients. Testing allows for individualized therapy by helping to inform doctors about which drugs to use and which to avoid.

The many subsets of CRC include those with and without the BRAF and RAS family of mutations. Then there are CRCs that overexpress the protein HER2, which helps drive the cancer. Another crucial aberration: mismatch-repair deficiency or microsatellite instability (MSI)-high status. This means that the cancer has trouble repairing its own DNA when damaged; over time, these tumors develop a large number of mutations that render them sensitive to immunotherapy. Although a type of immunotherapy known as immune checkpoint blockade does not work for all CRCs, mismatch-repair/MSI-high tumors are more sensitive to it, and this subset has a Food and Drug Administration (FDA)-approved treatment.

Previously, some of these mutations were only useful in determining prognosis. Now, there are treatment options for patients with BRAF V600E gene mutations and also those with NTRK gene fusions, and clinical trials are testing anti-HER2 drugs, according to Pashtoon M. Kasi, M.D., M.B.B.S., M.S., an assistant professor of oncology and medi&shy;cine at the University of Iowa. “We’re increasingly moving toward individualizing therapy for each patient,” he said.

In practice, genetic testing of these patients typically involves sampling and analyzing tumor tissue in a standard biopsy procedure. But liquid biopsies, which test blood for circulating tumor DNA, are increasingly used both in clinical trials and in practice and are expected to play a growing role in guiding treatment for people with CRC. Already, liquid biopsies are helping to identify both clini&shy;cally relevant mutations and changes that happen over time, which can direct future treatment decisions, Kasi said.

®, Kasi discussed the potential for liquid biopsies and provided an overview of treatment advances being made for CRC based on the molecular makeup of tumors.

Liquid biopsies, or circulating tumor DNA testing, have rapidly made their way into research and now into practice. The most recent guidelines, issued by a panel of experts from the American Society of Clinical Oncology and the College of American Pathologists in March 2018, summarized the promising ongoing research and studies on circulating tumor DNA. However, they’re not ready for prime time: The only FDA-approved indication for liquid biopsies is in the sphere of lung cancer.

Still, if you look at all the papers and abstracts that came from the 2018 American Society of Clinical Oncology Annual Meeting and now the 2019 ASCO Gastrointestinal Cancers Symposium, there is a great enthusiasm for the approach because of its sensitivity and specificity — at least in the metastatic setting. For early-stage cancers, it’s still early in research. In the metastatic setting in CRC, these biopsies are able to pick up the presence of all the relevant mutations &mdash; BRAF V600E and non-V600E, RAS family or its absence, as well as HER2, which can be present at base line or acquired. Additionally, these assays are now reporting on microsatellite instability.

Employing liquid biopsies as part of practice to help complement tissue-based testing is useful and practical in many ways. First, often we see patients whose tissue biopsy is not available. Next, it is not uncommon to encounter situations where tissue biopsy is not sufficient or safe to be done or repeated. Additionally, we know that these tumors, while on therapy, especially targeted therapies, evolve and change over time, explaining why these treatments may stop working.

Specifically, liquid biopsies help us identify tumors that initially don’t have RAS or EGFR mutations or HER2 or MET amplifications but acquire them during treatment. Those are things you can pick up on a liquid biopsy that you wouldn’t be able to pick up on tissue testing. That’s because a standard biopsy is done at the outset of treatment, and it’s not feasible to do these again and again. Liquid biopsies, on the other hand, are noninvasive blood tests and, therefore, can be repeated periodically as treatment progresses.

It is also important to know that not all actionable aberrations are detected by all assays and that the timing of circulating tumor DNA testing is key. Ideally, for patients with metastatic CRC, doing a liquid biopsy at base line when they have not begun treatment is the most informa&shy;tive and reliable time. It also serves as a base line with which to compare results down the line.

Could you elaborate on ongoing research efforts in this area? 

One of the most exciting things, in terms of using this approach in the metastatic setting, is clinical trials. One of them is a master protocol called COLOMATE (NCT03765736), or Colorectal Cancer Liquid Biopsy Screening Protocol for Molecularly Assigned Therapy, where each treatment arm may be determined by the patient’s liquid biopsy results. The study is being led by many academic institutions, with each arm being a separate clinical trial.

As of right now, different arms, or testing groups, are being developed based on the aberration found in each patient. We already have the HER2 arm open (NCT03043313), where tucatinib (ONT-380) and Herceptin (trastuzumab) (a kinase inhibitor and an antibody, respec&shy;tively, that work in different ways to inhibit the activity of the HER2 protein) will be given together to patients based on HER2 amplification detected in circulating-tumor DNA testing.

Other ongoing research, more for patients with stage 2 or stage 3 CRC, involves the use of liquid biopsies to determine which patients will benefit from chemotherapy after surgery and which may not need it. However, the sensitivity of these assays has to be very high, since the stakes are a lot higher in the curative-intent setting for earlier-stage patients.

Are there other ways that under&shy;standing gene mutations can be used to guide treatment? 

Pharmacogenomics — or genetic testing of the indi&shy;vidual, not the tumor &mdash; is underused in CRC patients; it can guide treatment dosing and adjustment based on variations in genes that affect the metabolism of various drugs. Historical analyses have shown that some patients do far worse in terms of side effects when they get chemo&shy;therapy because they harbor an aberration in certain genes. One of the barriers is that it’s underestimated how many patients have these aberrations.

Additionally, previously there was a delay — usually weeks &mdash; in getting back some of these results. We have shown that incorporating this testing into practice is feasible. Now you can get the results back within three to five days and make a treatment decision in real time.

The other barrier was figuring out how to interpret these results. Now there are guidelines available from Clinical Pharmacogenetics Implementation Consortium that tell you how much chemotherapy should be considered if a patient has an aberration in a certain metabolism gene.

By using pharmacogenomics testing preemptively rather than reactively, we could avoid severe side effects in patients. For patients with CRC and other gastrointestinal cancers, it is particularly of value since the genes that metabolize the two most commonly used chemotherapies are already known and well described. It’s going to help bridge that gap in terms of individualizing care. That will be very helpful, because chemotherapy is still the mainstay for first-line therapy and beyond for all of our patients. To be able to give them treatment in a way that is safer and more tolerable without compromising efficacy would affect the care of these patients.

The BEACON CRC trial is one of the most exciting trials that we had updates for at the 2019 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. It is focused on patients with BRAF V600E-mutated CRC and is led by Scott Kopetz, M.D., Ph.D., FACP, of The University of Texas MD Anderson Cancer Center, and Axel Grothey, M.D., of West Cancer Center. These patients represent an unmet need; their survival in the second-line setting or beyond is about four to six months. Outcomes in these patients are up to three times worse than those of patients who don’t have the BRAF V600E mutation. Historically, BRAF inhibitors didn’t work. The combination of BRAF inhibitors with MEK inhibitors did not show much promise, either.

Those efforts showed that we had to block the cell-signaling pathway at three levels due to the upregulation of the protein EGFR and overac&shy;tivation of that pathway. Doing so with the BRAF protein inhibitor Braftovi (encorafenib), MEK inhib&shy;itor Mektovi (binimetinib) and the anti-EGFR monoclonal antibody Erbitux (cetux&shy;imab) has demonstrated remarkable results. The median estimated overall survival is now around 15 months, and about 48 percent of patients with BRAF V600E-mutated CRC responded to the regimen. In this subset, even stable disease is an important clinical end point, because these patients would otherwise die of their disease. Even the progression-free survival (the time from first treatment until disease progression) is outperforming some of the historical overall survival rates.

Many patients who respond tend to show (relatively long-lasting) responses, and the regimen is well-tolerated. It received an FDA breakthrough therapy designation (to speed development) in August 2018 for the treatment of patients with metastatic BRAF V600E-mutant metastatic CRC after one or two lines of treatment. Hopefully, this will become an option this year. A sister trial, ANCHOR, will evaluate for the use of the combination in the first-line setting.

What is the ongoing research in the HER2 space? 

One of the key advances in CRC is looking at these aberra&shy;tions at base line and what happens to these tumors over time. One of the classic examples is the evolving recognition of HER2-positive CRC. At base line, it confers resistance to some anti-EGFR therapies. It’s not part of guidelines yet, but HER2 may be another aspect to check for in patients before considering anti-EGFR therapies. If found, we may not consider an anti-EGFR therapy for them. HER2 can also be an acquired mechanism of resistance; you can pick it up later either through liquid biopsy or tissue testing. For those 3 to 4 percent of patients, you can enroll them in anti-HER2- based therapy trials.

Data with the anti- HER2 and EGFR drug Tykerb (lapatinib) and the anti-HER2 monoclonal antibody Herceptin (trastuzumab) look promising. There are data and ongoing trials with the dual anti-HER2 blockade that combines Herceptin and another HER2-targeting antibody, Perjeta (pertuzumab). These are studies where it is important to know HER2 status at base line and also at progression so that we can pick the right trials for patients. It won’t be long before a biologic becomes available for these patients, in addition to anti-VEGF and anti-EGFR agents. Antibody-drug conjugates such as trastuzumab deruxtecan (DS-8201), which links an anti-HER2 drug to a chemotherapy, are also being used to treat CRCs with HER2 expression; a trial of this conjugate (NCT03384940) is in progress. Meanwhile, the MOUNTAINEER study (NCT03043313) of tucatinib (ONT-380) and Herceptin employs the addition of a novel small-molecule HER2 inhibitor and is also open and (accepting patients).

An expert discusses genetic profiling and other advances in the treatment of colorectal cancer.

Caroline Seymour

Tecentriq Significantly Improves Survival Outcome in Patients with Early-Stage Non-Small Cell Lung Cancer

Novel Therapy Demonstrates Limited Activity and Poor Safety Outcomes in Patients With Metastatic Renal Cell Carcinoma

Chemotherapy With Endocrine Therapy Shows Clinical Benefit With Improved Survival in Breast Cancer

Looking Beneath the Surface in Colorectal Cancer

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