Tiragolumab Plus Atezolizumab Improves Objective Response in CITYSCAPE Trial

Blocking TIGIT, a T-cell immunoreceptor, benefi ts patients with non—small cell lung cancer in that it can restore their immune system’s antitumor response, leading to a greater objective response and progression-free survival, noted 

associate director for lung cancer research at Sarah Cannon Research Institute and partner in Tennessee Oncology, in discussing the results of the CITYSCAPE trial.

At the American Society of Clinical Oncology (ASCO) meeting, you presented findings from CITYSCAPE. Can you provide some background on this trial, as well as its notable results?

CITYSCAPE is a randomized phase 2 trial. We enrolled 135 patients who were newly diagnosed with metastatic non—small cell lung cancer. They were negative for 

 alterations, and their tumors expressed PD-L1 at least 1% or higher as tested using the Dako 22C3 assay. That assay could be done locally or centrally. Patients were randomized to receive tiragolumab, an anti-TIGIT antibody, plus atezolizumab, a PD-L1 antibody, versus placebo plus atezolizumab.

The primary end points were objective response rate and progression-free survival (PFS). The trial results showed that patients who received the combination of tiragolumab plus atezolizumab had improved objective response as well as PFS compared with patients who were treated with placebo plus atezolizumab.

What particular mechanism of action of the anti-TIGIT immunotherapy is important in the lung cancer space?

Understanding the Benefits of Zanubrutinib on Cardiac Effects

TIGIT is another inhibitory checkpoint. It works similarly to PD-L1. TIGIT is expressed on immune cells, T cells, and natural killer cells, and when it binds to its ligand, PVR, on tumor cells or antigen-presenting cells, it can blunt the immune response. In a similar way to blocking PD-1 or PD-L1, when you block TIGIT with the anti-TIGIT antibody, tiragolumab, you can restore the antitumor immune response and activate infl ammatory cells to fight the cancer.

Compared with ibrutinib, the second-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib appears to have more of a benefi t for patients in that it is associated with less atrial fi brillation and hypertension, and fewer other cardiac eff ects, explained 

clinical hematologist, Peter MacCallum Cancer Centre in Melbourne, Australia. He discussed fi ndings from the initial ASPEN study and updated results presented at ASCO.

What is it about the second-generation BTK inhibitors that might tend to cause less of these cardiac effects?

We think it’s how clean the targeting is. We don’t really know what causes hypertension and atrial fibrillation. We look at congenital BTK deficiency—humans born without BTK&mdash;and they don’t really get atrial fibrillation or hypertension. So, presumably, you can dispense with BTK and be okay from a vascular point of view. We think that ibrutinib causes some of these AEs because it’s not totally clean. So, it’s like TEC, and EGFR, and JAK3 and a whole group of other enzymes, which are structurally related to BTK.

Now, with either zanubrutinib or acalabrutinib, you get less off -target enzyme inhibition [than with ibrutinib]. And I don’t think anyone can actually put a finger on it and say, “This enzyme is causing it.” But we just know that the cleaner it is, the better the profile.

And it wasn’t just hypertension: Fibrillation and a whole multitude of other AEs, like muscle spasm, peripheral edema, pneumonitis, and pneumonia were reduced with zanubrutinib compared with ibrutinib. And I think a lot of the [cases of] sudden pneumonia were in fact pneumonitis, because there’s no real reason why there should be such a big diff erence in infective pneumonia.

Overall, the ability to stay on a drug longer seems to favor zanubrutinib. Is that a benefit of it over ibrutinib?

AstraZeneca's Kilcoyne Claims Paradigm Shift in Lung Cancer Treatment

Yes; the drug is easier to take. Fewer AEs, (adverse events) less dose reduction—people can stay on it for longer. Also, we actually examined the cumulative risk of atrial fi brillation and hypertension over time. You see that for zanubrutinib, essentially, most of the events happen in the fi rst 12 months and then it sort of plateaus. Conversely, with ibrutinib, we’ve seen an increasing cumulative pattern. This suggests that if you are going to take one of these drugs for, let’s say, 3 or 5 years, zanubrutinib may be a bit better because it has no cumulative effect on the vascular system, whereas ibrutinib appears to have one.

 vice president of US Medical Affairs and Health Economics Outcomes Research for Oncology at AstraZeneca, discusses a paradigm shift in lung cancer treatment due to the overwhelming efficacy of  a EGFR—tyrosine kinase inhibitor (TKI) treatment. 

A lot of excitement was generated by the news that ADAURA would be unblinded due to the overwhelmingly efficacy of the EGFR-TKI treatment. Can we expect the results to be paradigm shifting?

Absolutely. As you’re aware, we’ve had some great results with osimertinib (Tagrisso) already in the metastatic setting. So, we feel there’s great promise in bringing it earlier into the disease paradigm. When we look at the ADAURA study, this is very much earlier in the longer-term curative setting; it’s in the early stages, stage IB to IIIA, meaning these are the resectable populations. What we’ve been able to demonstrate is compelling.

When any study is stopped 2 years early, that has to be done for a very good reason. As you can imagine, these data are compelling in terms of the disease-free survival benefi t we’re seeing, but they are important in a number of ways. One, the data are telling us that if you hit cancer early, well, you can have  very compelling results in lung cancer. This may drive people to want to identify disease earlier, which is really important, too. The second thing is that while all these patients had surgery, not all of them had adjuvant chemotherapy. Half did, half didn’t, and regardless of that you’re seeing signifi cant benefit. So, in my

view, there will be a paradigm shift. I think you’ll see [osimertinib] will become standard of care.

Three is the question: Do you also need to give chemotherapy? And again, we don’t have enough data; we have to wait for referrals, [more] data, etc. But I think those 3 areas will see very significant changes in clinical care. 

Osimertinib is already approved in the United States for the frontline setting in metastatic non—small cell lung cancer. What can we expect to see in the adjuvant setting after ASCO?

So after ASCO—and I think I’ve touched on some of the things already said&mdash;in the frontline metastatic setting, which is late-stage, disease stage IV, we have seen great results with Tagrisso. It really has become the standard of care for all intents and purpos es.…At AstraZeneca, we’re very much committed to really eliminating cancer as a cause of death, and we do understand the best chance of achieving that is to treat early, [by] identifying the right patients early. This is what ADAURA is allowing us to do: treat patients early. Now if we think about the stage IBs, those are pretty early lung cancers, and right through to stage III&mdash;that’s a broad group of patients. But if you look at those groups individually, we’re seeing benefi ts in each group. So, this is incredibly compelling for

Video Conference Interventions Are an Invaluable Resource for Those Who Choose to Participate

physicians now to be able to treat their very early lung cancers, which would probably have a good chance of cure with just resection. Still, a huge proportion of these [surgical] patients will relapse. So, for me, this is going to be a huge change in clinical care.

Being part of a multidisciplinary team of oncologists, health care providers, caregivers, and patients benefits all members—not least the patients themselves&mdash;and telehealth-based interventions can help to foster these relationships. However, we should understand when patients do not want to involve their families in their care, noted 

, the Gertrude Perkins Oliva Professor in Oncology Nursing and associate dean for research at the Frances Payne Bolton School of Nursing at Case Western Reserve University in Cleveland, Ohio.

The theme for this year’s virtual meeting was “Unite and Conquer: Accelerating Progress Together.” How does your poster on video conference interventions for distance caregivers of patients with cancer reflect this theme?

That’s such an interesting question. To be honest, I didn’t even know that was the theme of this year’s conference. So, it’s a very appropriate question. My answer, as I thought about it, is that I really think this study represented all of the good and the positive that come when all the members of the team unite for the benefit of the patient. In this research study, we had to rely on the oncologist and health care providers to participate and be involved, as well as the patient, the local caregiver, and the distance caregiver. By all of us sort of working together in conjunction with the researchers, we were able to test an intervention that’s not only going to help the distance caregiver but will potentially help patients as well.

Did you find that people were eager to participate, or were they reticent?

All of the physicians were very interested in participating. This is one of the few intervention studies I’ve done where people didn’t, you know, run and hide when they saw me coming, you know? They were very interested and engaged, as were other members of the health care team. Our refusal rate for participation was about 20%, which is less than what we usually see….It was interesting that sometimes the distance caregiver didn’t want to participate. Then again, sometimes, the patient didn’t want them to participate.

Experimental Glioblastoma Therapy Has Promise in Treatment-Resistant Cancers

[I couldn’t help but notice something] when I would be involved in talking to a patient about whether or not they were interested in the study, and then in asking if they’d give us permission to reach out to their distance caregiver. I recognized that sometimes our family members are distant for a reason. Not all families want to be together, want to share information, etc. And so I think—although some of the health care providers were very surprised at times&mdash;when a patient did not want their extended family involved, it’s very understandable. Each family unit is diff erent, and so we did have some patients and some distance caregivers who were not interested in participating.

An experimental glioblastoma therapy with promising 12-month results may also have potential with other treatment-resistant cancers, according to 

vice president of clinical development, Inovio Pharmaceuticals, Inc. Inovio’s experimental therapy, INO-5401, in combination with PD-1 checkpoint inhibitor cemiplimab, has shown promising results in glioblastoma.

Inovio’s experimental therapy, INO-5401, in combination with PD-1 checkpoint inhibitor cemiplimab, has shown promising results in glioblastoma. When can we expect to learn about 18-month findings?

We’re really excited about our 18-month overall survival (OS) data. As we’ve just released the OS data at 12 months, we anticipate that by the end of this year, certainly fall or winter, we will have all of the data for our 18-month OS. That’s really exciting to us.

If the 18-month findings are as exciting as the 12-month findings, then what will the next steps be?

We’re very excited to move on to a more pivotal study, for which we’ll be speaking with our potential partners. With this study, we’re collaborating with Regeneron and [its] cemiplimab, the PD-1 inhibitor that we are utilizing. We hope to continue those conversations with our collaborator, and we will move to designing a larger study and one that potentially will bring benefit to more patients.

Is there the potential for the combination of Inovio’s experimental therapy, INO-5401, and immunotherapy to work in other treatment-resistant cancers the way you’ve shown it can work in glioblastoma?

It’s key that INO-5401 is made up of 3 diff erent DNA plasmids, which make up the 5401 DNA medicine. These 3 plasmids are proteins that are often overexpressed in human tumors. It is true that specifi cally for glioblastoma, these particular proteins are important. For example, human telomerase is often—if not almost always&mdash;overexpressed in glioblastoma. But the same can be said for 2 other proteins: WT1, or Wilms’ tumor 1, protein, as well as for prostate-specific antigen. And so together, we really do have a program that has the opportunity to be studied in many other human cancers.

First, thank you very much for allowing me to share my excitement about Inovio’s therapies. I think that Inovio’s DNA medicines really have the opportunity to change the way we are treating not only patients with cancer, but patients with precancerous conditions, potentially infectious diseases, as well. And we’re really excited about the immunology and safety [data,] but most important, the efficacy data that we are seeing from our programs.

Articles

Evidence-Based Oncology

Interviews on presentations made during the 2020 Virtual meeting of the American Society of Clinical Oncology, featuring Drs Melissa L. Johnson, Constantine S. Tam, Adrian Kilcoyne, Sara L. Douglas, and Jeffrey Skolnick.

ASCO 2020: AJMCtv Interviews

How Does Cardiotoxicity Present Itself in Patients With Cancer?

A  trio of abstracts presented at this year’s annual meeting of the American Society of Clinical Oncology focused on cardiotoxic effects of cancer treatment and how cardiac disease remains a barrier to eff ective cancer therapy among patients with cancer and survivors.

“There’s a 3-pronged approach in cardio-oncology. We describe short-term and delayed cardiotoxic effects of cancer treatments,” noted Roohi Ismail-Khan, MD, MSc, medical oncologist and co-director of the cardio-oncology program at H. Lee Moffitt Cancer Center.

 “We explain strategies for screening and monitoring of cancer patients for cardiovascular toxicity before, during, and after cancer treatment. And lastly, we would like to outline a multidisciplinary approach between cardiologists and oncologists to manage cardio-oncology patients using recommendations and optimizing survivorship outcomes.”

Five-year survival rates noticeably improved across a variety of cancers between 1971 and 2011, Khan pointed out. Among the cancers with the most significant improvements are prostate, non-Hodgkin lymphoma, and leukemia. However, longer survival times mean that late-term adverse effects are becoming more

common. These include cardiovascular disease (CVD), especially among patients with early-stage breast cancer who are beginning to die more from CVD than the cancer itself.

The first 2 abstracts that Ismail-Khan presented1 focused on results from the Pathways Heart Study,

 from the National Cancer Institute and Kaiser Permanente Northern California (KPNC), which is examining CVD and its risk factors among women with breast cancer, women with no history of the disease, and survivors.

Patient data came from KPNC electronic health records for all cases of invasive breast cancer diagnosed from 2005 to 2013. 

CVD was classified as major (eg, ischemic heart disease, heart failure, cardiomyopathy, stroke) or other (eg, arrhythmia, cardiac arrest, valvular disease, etc). In addition to statistical analyses, subgroup analyses looked at differences among patients who received chemotherapy, radiation, and hormonal therapy.

There were 14,942 women in the breast cancer cohort and 74,702 in the control group (no breast cancer), with an average age of 62 years and an average body mass index of 28.3 kg/m

 at diagnosis. The average follow-up was 7 years.

The overall results show an increased risk of both hypertension and diabetes:

• Hypertension: HR, 1.18 (95% CI, 1.13-1.24)

• Diabetes: HR, 1.25 (95% CI, 1.18-1.33)

Treatment for breast cancer with chemotherapy, left-sided radiation therapy, and endocrine therapy was also shown to increase the risk of cardiotoxic effects. In particular, chemotherapy increased the risk of heart failure and cardiomyopathy. Ismail-Khan noted, however, that other factors infl uence these outcomes in patients with cancer, and these include genetics, cancer type, and lifestyle factors.

The third abstract4 Ismail-Khan presented focused on using exercise to improve heart health among patients with testicular, breast, and colon cancers as well as non-Hodgkin lymphoma (NHL) who have undergone treatment. They were randomized to a 24-week exercise intervention either during chemotherapy (n¨=¨131) or when it finished (n = 135). The primary outcome was the eff ect on peak oxygen uptake (VO2 peak), adjusted for baseline values at diagnosis (T0), with additional measures taken after chemotherapy (T1), post-exercise intervention (T2), and 1-year post-exercise intervention (T3).

The average ages of the patients were 33 years for testicular cancer, 52 years for breast cancer, and 64 years for both colon cancer and NHL.

Although both groups benefi ted, the results showed that the early-exercise cohort fared signifi cantly better, with less of a decline in their VO2 peak and quality of life. The early exercisers also had less overall general (P = .002) and physical fatigue (P < .0001) at the first time point.

At the second time point, VO2 peak (P = .9), quality of life (P = .7), general fatigue (P = .3), and physical fatigue (P = .7) were comparable between early and postchemotherapy groups. A supervised exercise program is best, Ismail-Khan noted, but “the earlier we introduce exercise in our chemotherapy adjuvant patients, the better.

“These cardio-oncology studies are looking at modifying multiple areas, so we can have better outcomes for our cancer survivors,” Ismail-Khan concluded. “When I see my patients, I tell them, ‘While we are curing your cancer, we don’t want to increase your risk of dying from yet another disease. So, while we are curing your cancer, we have to concentrate on preventing heart disease at the same time.’”

1. Ismail-Khan R. To the heart of the matter: understanding and improving cardiovascular health in cancer. Presented at: ASCO20 Virtual; May 29-31, 2020. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/188934/video

2. Greenlee H, Iribarren C, Neugebauer, et al. Risk of cardiovascular disease in women with and without a history of breast cancer: the Pathways Heart study. Presented at: ASCO20 Virtual; May 29-31, 2020. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/188171/abstract

3. Kwan ML, Iribarren C, Neugebauer R, et al. Onset of cardiovascular disease risk factors in women with and without a history of breast cancer: the Pathways Heart study. Presented at: ASCO20 Virtual; May 29-31, 2020. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/188346/abstract

4. van der Schoot GGF, Ormel HL, Westerink N-DL, et al. Effect of a tailored exercise intervention during or after chemotherapy on cardiovascular morbidity in cancer patients. Presented at: ASCO20 Virtual; May 29-31, 2020. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/187836/abstract

More Positive Signs for AMG 510, Inhibitor of KRAS Mutation That Stymied Scientists for Decades

The 2020 annual meeting of the American Society of Clinical Oncology (ASCO) featured updates on AMG 510, the fi rst-in-class small-molecule inhibitor of the KRAS p.G12C mutation, which is implicated in multiple solid tumor cancers including 13% of non—small cell lung cancers (NSCLCs).

 is one of the most frequently mutated oncogenes, but over the years, it was considered “undruggable” because the protein lacked surfaces where a small molecule could bind to impede its function. One type of 

 G12C, stood out: by itself, it accounted for 44% of KRAS mutations.

But in recent years, researchers at Amgen found a work-around for this problem. As outlined in 

 they isolated the novel histidine 95 groove, which offered a way for molecules to selectively and irreversibly bind to 

Following results at the 2019 ASCO Scientifi c Program involving AMG 510 in patients with previously treated metastatic NSCLC, the FDA granted fast-track designation to the drug for individuals with this cancer if the 

At the 2020 ASCO Virtual Scientifi c Program in May, researchers presented data from CodeBreak100, involving AMG 510 in patients who had a poor colorectal cancer prognosis,

 as well as patients with multiple tumor types other than colorectal or NSCLC.

 Researchers released an update of a phase 1 trial involving 42 patients with colorectal cancer, including 12 women. The median age was 57.5 years, and 19 patients had received at least 3 prior lines of therapy. Patients were tested with doses of 180, 360, 720, and 960 mg; 25 patients were selected for the expansion phase of the trial at 960 mg. As of January 8, 2020, median follow-up was 7.9 months (range, 4.2-15.9 months); 13 patients had died (31.0%), and 8 patients (19.0%) were still on treatment, with 22 (52.4%) and 8 (19.0%) on treatment for more than 3 and 6 months. Disease progression was the most common reason for stopping treatment. Of the group, 20 patients (47.6%) had treatment-related adverse events (TRAEs), and 2 (4.8%) had a grade 3 TRAE.

Overall, the objective response rate (ORR) was 7.1% and the disease control rate was 76.2%. With the 960-mg dose, the ORR was 12.0% and the disease control

rate was 80.0%. Three patients with partial responses had a duration of response of 1.5, 4.2, and 4.3 months, which were ongoing at the time of data cutoff .

. Other results from CodeBreak 100, reported in a separate abstract, involved mutant solid tumors in pancreatic, endometrial, bile duct, small bowel, melanoma, and other cancers. The primary end point was safety and secondary end points were pharmacokinetics and ORR. The same dose-escalation schedule was used. As of January 8, 2020, 25 patients (9 women; median age, 60 years) reported results. Of the group, 23 received the 960-mg dose, including 20 (80%) who had received at least 2 prior lines of therapy. At data cutoff on January 8, 2020, 13 patients (52.0%) were still on treatment, with 9 patients (36.0%) and 3 (12.0%) on therapy at least 3 and 6 months, respectively. 

Median follow-up was 4.3 months. TRAEs were seen in 9 patients, and 2 patients had grade 3 TRAEs. Of the group, 22 were followed for at least 7 weeks, including

3 partial responses, 13 with stable disease, and 6 with progressive disease.

1. Amgen’s KRAS G12C research could bring hope to some patients with lung, colorectal and pancreatic cancers. Amgen. Accessed June 22, 2020. www.amgen.com/media/featured-news/2019/10/amgens-kras-g12c-researchcould-bring-hope-to-some-patients

2. Canon J, Rex K, Saiki AY, et al.¢The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

2019;575:217-223. doi:10.1038/s41586-019-1694-1

3. Cortez MF, Flanagan C. Amgen slips as gene-targeting drug misses some lofty hopes. Bloomberg. September 9, 2019. Accessed June 23, 2020. www.bloomberg.com/news/articles/2019-09-08/amgen-s-gene-targeting-drugshrank-54-of-lung-tumors-in-study 

4. Fakih M, Desai J, Kuboki Y, et al. CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. J Clin Oncol. 2020;38:(suppl; abstr 4018). doi: 10.1200/JCO.2020.38.15_suppl.4018

5. Hong DS, Kuo J, Sacher AG, et al. CodeBreak 100: phase¢I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). J Clin Oncol. 2020;38:(suppl; abstr 3511). doi: 10.1200/JCO.2020.38.15_suppl.3511

Safety Edge Is Seen for Lurbinectedin Over Topotecan in Combined Data Set

A pooled safety analysis comparing single-agent lurbinectedin, a selective oncogenic transcription inhibitor, with topotecan, a topoisomerase I inhibitor, has found that patients using lurbinectedin had fewer hematological toxicities and were less likely to need supportive treatments, including therapies with granulocyte colony-stimulating factor.

Data presented at the American Society of Clinical Oncology evaluated data from a phase 2 basket study that featured 335 patients treated with lurbinectedin across 9 indications, including 105 patients treated for small cell lung cancer (SCLC). These results were pooled with data from the phase 3 CORAIL trial, which studied topotecan in patients with platinum-resistant ovarian cancer. The CORAIL trial included 219 patients taking lurbinectedin and 87 who took topotecan.

The most common adverse events (AEs) with lurbinectedin were grade 1/2 fatigue, nausea, and vomiting. Patients taking topotecan were more likely to have treatment adjustments and serious AEs, as follows:

• dose reductions: lurbinectedin, 22.9%; topotecan, 48.3%;

• treatment delays: lurbinectedin, 25.8%; topotecan, 52.9%;

• serious AEs, grade 3 or higher: lurbinectedin, 15.0%; topotecan, 32.2%;

• discontinuations: lurbinectedin, 3.2%; topotecan, 5.7%;

• deaths: lurbinectedin, 1.3%; topotecan, 1.5%; and

• use of granulocyte colony-stimulating factor drugs: lurbinectedin, 23.8%; topotecan, 70.1%.

The investigators concluded that within the limitations of indirect comparisons, the analysis found patients taking lurbinectedin were less likely to experience hematological toxicities and treatment adjustments or discontinuations than those taking topotecan.

When the analysis was presented at the American Society of Clinical Oncology on May 29, 2020, topotecan was the only approved second-line therapy for SCLC. Since then, on June 16, the FDA granted lurbinectedin accelerated approval for second-line treatment of SCLC, based on results for the 105 patients in the basket trial.2 Lurbinectedin, developed by PharMar and Jazz Pharmaceuticals, is sold as Zepzelca.

1. Leary A, Gaillard S, Vergote I, et al. Pooled safety analysis of single-agent lurbinectedin versus topotecan (Results from a randomized phase III trial CORAIL and a phase II basket trial). 

 2020;38(15): suppl; abstr 3635. doi:10.1200/JCO.2020.38.15_suppl.3635

2. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label phase 2 basket trial. 

2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1

Selected abstracts in cardio-oncology, findings for AMG 510, and lurbinectedin as a second-line treatment in SCLC.

ASCO 2020: Research Report 

Genetic Testing Can Guide Treatment, but Access and Counseling Are Essential, Results Say

Advances in genetic testing increasingly connect cancer patients with treatments that work—and help them avoid those that won’t. But providers have a responsibility to make sure they are ordering the right tests and using the results correctly, said Erin Hofstatter, MD, associate professor adjunct and co-director of the Cancer Genetics and Prevention Program at Yale School of Medicine.

Getting the full picture means patients should have access to genetic counselors who can evaluate individual risk, Hofstatter said during the virtual session, “Cancer Risk, Genetics, and Prevention,” held May 30 during the¢American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

Hofstatter highlighted 4 studies that she said amplify the 3 components of using genetic testing in cancer treatment and prevention: (1) understanding the germline component of a tumor test, (2) broadening access to genetic counselors with video sessions, and (3) making sure risk assessment of each patient is accurate, so that patients do not have unnecessary surgeries.

. Tumor tests typically look for acquired mutations—somatic testing&mdash;to select targeted therapies. MSK-IMPACT evaluated the value, or clinical utility, of adding germline profi ling, for inherited mutations, for patients with advanced cancer, through next-generation sequencing.

 From a study population of 11,975 patients, investigators identified 2043 (17.1%) who had pathogenic or likely pathogenic germline variants, including 777 patients (6.5%) who had genes for which targeted therapies were available. Most of these were for BRCA mutations (n = 416) or for Lynch syndrome (n = 149). Of importance, Hofstatter said, is the share of patients with advanced disease who received a targeted therapy: The authors reported the share was 45.3% of 554 patients.

But Hofstatter noted that such findings are essentially a moving target. “If emerging genes of interest in homologous recombination repair are included, prevalence rose to 8.6%,” she said. “With the emergence of novel targeted treatments, it’s important to realize that the therapeutic actionability of germline variants is likely to increase signifi cantly over time,” Hofstatter noted. Increasingly, she said, the advanced setting is where germline testing will be indicated to select a cancer treatment. “It’s important to know your test. Remember that tumor sequencing is not a substitute for control. Hence of germline testing, and it should be considered separately to achieve the best results,” Hofstatter reminded.

 Despite broader availability of germline testing, uptake is poor. For instance, only about 2% of Lynch syndrome carriers have been identifi ed, Hofstatter said. Lack of knowledge, cost, inconvenience, and a shortage of genetic counselors—some payers require a counseling session before testing&mdash;have all been barriers.

Two studies presented during ASCO examined whether there was any disadvantage for patients if counselors met with them via telemedicine—a method that has taken off in recent months due to the coronavirus 2019 pandemic. The ProGen study, led by Huma Q. Rana, MD, of Dana-Farber Cancer Institute, was a randomized trial that compared the eff ectiveness of video visits with traditional genetic counseling among men diagnosed with prostate cancer.

—The study reported high uptake by both groups: 88% of the eligible men in the traditional counseling group agreed to be tested, compared with 93% of those eligible in the video group.

Testing completion rates were 99% in both groups who agreed to be tested, and according to initial survey results, patients in both groups were equally satisfied with the process. Over 2 years, 604 patients were tested and pathogenic variants were identified in 79 of them (13.2%).

However, Hofstatter noted that ProGen took place in a highly controlled setting. What, she wondered, would be the result in a study that reflected real-world conditions? For this answer, she turned to the MAGENTA study,

—which recruited many of its participants over social media. The study aimed to learn whether pre- and posttest genetic counseling is needed to best guide genetic testing for women at risk of hereditary breast and ovarian cancer.

All counseling took place online. Of 3822 patients randomized, 3111 were placed in a family-history cohort and 711 in a cascade cohort, where someone in the family was known to have a mutation. Among those completing genetic testing, 173 participants (7.2%) had a mutation in a breast or ovarian gene;

this included 114 patients (5.7%) in the family history cohort and 59 (14.2%) in the cascade cohort. Hofstatter explained the results, which focused on distress level among patients: It was lowest among those who had neither pre- nor posttest counseling. Overall, 318 participants (18%) had high levels of distress, and there was little difference whether their test was ultimately positive or negative.

Both studies, Hofstatter said, “demonstrate high uptake rates with pretest video education, and they truly represent new models of genetic counseling, breaking down barriers and improving accessibility to testing.

“And it would be very tempting,” Hofstatter continued, “to have our major take-home message being that pretest counseling is really [superfluous]—

that ‘Less is more,’ or at least that no counseling ‘is just as good.’ [Some could say,] ‘Let’s get rid of the counselors] altogether.’” However, “test completion 

or uptake of testing cannot be our only goal,” she said. “Truly, it’s what you do with the information from testing that counts. Certainly uptake, satisfaction,

distress, and intention-to-share are essential.”

For a view of how information is used, Hofstatter turned to the PROMPT study, which examined how many women completed oophorectomy based on results of multipanel genetic testing. While the results included some self-reported statements from the patients, the findings highlight the concerns payers have had about genetic testing without proper counseling or education for providers: The testing may lead to unnecessary or even harmful procedures.

Of the 1566 women in the PROMPT registry who reported having oophorectomy, 487 (30.7%) reported having cancer treatment and 432 reported benign disease (27.6%). Another 186 (12.8%) reported pathogenic variants associated with risk of ovarian cancer. The majority of women had no family history of ovarian cancer, and most of the women having surgery were not yet aged 50 years. The study found that 10% to 15% of the women who had surgery had a pathogenic variant or a variant of unknown signifi cance, and thus were reporting having a procedure without a clear indication.

The study, Hofstatter said, “serves as a cautionary tale, especially when we’re thinking about omitting or limiting the availability of genetic counseling as part of genetic testing.” Increased access to testing—a good goal&mdash;in combination with less counseling would invite “the inevitable potential for misinformation and possible mismanagement.”

A provider may have good intentions in streamlining the process, but Hofstatter said treatment management decisions “must be based on accurate risk assessment. And certainly, with less availability and less use of genetic counselors, the burden is going to be increasingly on the provider to make sure that

they understand the implications of testing results.”

1. Stadler ZK, Maio A, Kemel Y, et al. Targeted therapy based on germline analysis of tumor-normal sequencing (MSK-IMPACT) in a pan-cancer population. J€Clin Oncol.Š2020;38(15 suppl; abstr 1500). doi:10.1200/JCO.2020.38.15_suppl.1500

2. Rana HQ, Stopfer JE, Petrucelli N, et al. A randomized controlled trial of video-education or in-person genetic counseling for men with prostate cancer (ProGen). J Clin Oncol. 2020;38(15 suppl; abstr 1507). doi:10.1200/JCO.2020.38.15_suppl.1507

3. Swisher EM, Rayes N, Bowen D, et al. Results from MAGENTA: a national randomized four-arm noninferiority trial evaluating pre- and post-test genetic counseling during online testing for breast and ovarian cancer genetic risk. J Clin Oncol.Š2020;38(15 suppl; abstr 1506). doi:10.1200/

4. Domchek SM, Brower J, Symecko H, et al. Uptake of oophorectomy in women with findings on multigene panel testing: results from the Prospective Registry of Multiplex Testing (PROMPT). J Clin Oncol. 2020;38(15 suppl; abstr 1508). doi:10.1200/JCO.2020.38.15_suppl.1508

MD Anderson’s Lu: MAGENTA Highlights Need to Use Genetic Counselors in "Most Effective Way Possible"

Women who undergo genetic testing for hereditary breast and ovarian cancer are often advised to speak with a genetic counselor before and after they take the test, even if the result is ultimately negative for a mutation that would indicate a greater risk. 

But results presented virtually at the 2020 annual meeting of the American Society of Clinical Oncology suggest that an online educational video about genetic testing may be suffi cient, and that women often don’t need to speak in person with a genetic counselor in the context of this type of testing. “We were surprised by the findings,” said Karen H. Lu, MD, the study’s principal investigator and chair of the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center, in an interview.

“I would hate for anyone to say, ‘We don’t need genetic counselors—they are not necessary,’” Lu added. “I think what [we] need to do is use them in the most effective way possible.” 

Lu and her colleagues presented findings from MAGENTA (Making GENetic Testing Accessible), a 4-arm study that included 3111 women with a family history of hereditary breast and ovarian cancer and another group of 711 women with a family member whose genetic test results were positive for a risk-conferring mutation. Women enrolled in the trial watched an online educational video about genetic testing. Lu explained that women in the control arm of the study then spoke with a genetic counselor by telephone before and after they took the genetic test, which was an at-home “spit kit” test that involves collecting saliva sample for DNA testing. (The MAGENTA study website describes it as “the study of genetic testing from your living room.”)

Others arms of the study included genetic counseling only before the genetic test, only after, and no genetic counseling either before or after.

However, if the test came back positive for a risk-conferring mutation, genetic counseling was given regardless of which arm of the study the woman was in. Among the participants who completed testing, 173 (7.2%) had a positive test.

The primary outcome was “cancer risk distress” at 3 months. Lu and her colleagues measured distress among the women in 3 groups with more limited genetic counseling—including the group that didn’t receive any counseling if their results were negative. These results were noninferior to those of the group that received counseling before and after the test, the scenario which Lu described as the current standard of care. Analysis of data on secondary end points such as anxiety, depression and “decisional regret” painted a similar picture of no difference among the 4 arms. However, test completion was highest in the no-counseling arm (86.4%) and lowest in the control arm (60.6%).

Lu said genetic counselors provide “a wonderful service” to patients, but she added that there aren’t enough of them, particularly as testing becomes more prevalent and the results become more instrumental in making treatment decisions. She said the most effective way to use counselors may be to focus their efforts on people who test positive for risk-conferring mutations and those with a strong family history of cancer.

The overarching concern is making genetic testing more accessible, so women at high risk are identified and monitored or treated early, said Lu. “As a whole, [the results] really show that this type of testing—which is available commercially&mdash;can be used,” she said.

Study Shows How NGS, Precision Medicine Benefited Patients at Community Cancer Clinic 

In oncology, precision medicine is already well established, with targeted therapies approved based on the patient’s genetic makeup or genetic variants of their tumor. Now, a combination of precision medicine, next-generation sequencing (NGS), and diagnostics is making its way into community cancer clinics. Study outcomes revealed during the American Society of Clinical Oncology 2020 Virtual Scientifi c Program analyzed NGS testing results in a community cancer care clinic in coordination with a precision medicine program.

With decreasing costs—of NGS to identify both germline and somatic pathogenic variants, and of other technological advancements&mdash;there is a critical need for curation and interpretation of these results, the study authors noted, as clinicians often order the tests simultaneously.

The retrospective review examined germline NGS results from patients who were seen since 2001 by the Hereditary Cancer Program at Hoag Family Cancer Institute in Newport Beach, California. Researchers also compared those who had both positive genetic testing results for germline and somatic variants and those who had tumor molecular profiling. The cancer program saw a total of 8239 patients; of those, 6100 had germline testing done, and approximately 50% had multigene panel testing (MGPT).

Results showed that 15% of the patients with germline testing had a pathogenic or likely pathogenic mutation. Of those patients with positive results, 71% had breast or ovarian cancer, while 29% had other cancer types.

The researchers also analyzed NGS results for 713 tumors tested in 1 year through a commercial laboratory. All cases were subject to the authors’ secondary annotation. That analysis resulted in additional recommendations in 40% of cases, beyond what was in the commercial report. The secondary annotations also provided additional clinical trial options in 30% of cases.

The cancer clinic had also begun a new program in the past year that led to the researchers examining tumor profi ling results for indications of possible germline mutations. By analyzing those results, the authors said they made recommendations for genetic counseling in 91 cases (12.8%). The results show the importance of genetic counseling and MGPT in a community setting in patients with personal and/or family histories of cancer, the authors wrote.

Physicians at the center have an increased understanding of the clinical utility of molecular testing, which benefi ts patients, the authors said.

Darabi S, Braxton DR, Homer J, et al.ŠPrecision medicine, genetics and genomics in a community cancer clinic. 

. 2020;38(15 suppl; abstr e13511). doi:10.1200/JCO.2020.38.15_suppl.e13511

Four studies were highlighted that amplified the 3 components of using genetic testing in cancer treatment and prevention: (1) understanding the germline component of a tumor test, (2) broadening access to genetic counselors with video sessions, and (3) making sure risk assessment of each patient is accurate, so that patients do not have unnecessary surgeries.

ASCO 2020: Genetic Testing

Bispecific antibodies received plenty of attention at last year’s meeting of the American Society of Hematology, and the momentum continued in late May during the virtual annual meeting of the American Society Society of Clinical Oncology (ASCO). As the name suggests, these therapies are manufactured proteins that can bind to 2 separate antigens at the same time, bringing extra power to the fight against cancer.

During ASCO, Janssen presented results from the CHRYSALIS study on amivantimab,

 a bispecific antibody being developed to treat non—small cell lung cancer (NSCLC). The pharma giant, along with its parent company, Johnson & Johnson (J&J), had previously received a breakthrough therapy designation in December for teclistamab, another bispecific antibody indicated for potential treatment of multiple myeloma.

Mark Wildgust, PhD, vice president of Global Medical Affairs/Oncology at Janssen, who leads a team of scientists and physicians developing new, targeted therapies for oncologic and hematologic conditions, expounded on the similarities and differences of these 2 novel dual-targeted therapies with 

Wildgust explained that intervening earlier in the premalignant setting is a primary goal. To that end, Janssen has 6 bispecific antibodies in development—all first-in-class therapies. He also touched upon medication aff ordability, noting that availability and regulatory approval are moot points if a drug is not accessible, because although it is proven safe and eff ective, patients can’t benefi t from a treatment if they can’t get it.

This interview has been edited slightly for clarity.

: Two bispecific antibodies in development, amivantamab for NSCLC and teclistamab for multiple myeloma, have some similarities, but one is being developed for a solid tumor and the other for hematologic cancer. Can you discuss the similarities and differences?

Both are built on the same duobody platform, which is what we call it. Bispecifics are essentially monoclonal antibodies that bind to 2 different targets—that’s why we call them bispecific. The method by which we make them is the same, but they are actually quite distinctly different.

Let’s take teclistamab. We actually create 2 individual antibodies: 1 targets CD3 and 1 targets BCMA. We then break those apart and glue them back together so that they can basically target CD3 and BCMA. So, that’s teclistamab.

Now, the same process is used for making amivantamab as well: 1 [antibody] targets 

 and 1 targets c-MET. We break these 2 antibodies apart and glue them back together and create that single bispecific. So, the similarities kind of end there. Then we get into the diff erences. Teclistamab binds to BCMA. BCMA is essentially an antigen target that’s almost ubiquitously expressed on myeloma cells. Then you have CD3. Why CD3? CD3 is essentially picking up T cells, which express CD3. The BCMA-CD3 teclistamab is really what we would call a T-cell redirector. It essentially picks up the T cell on the monoclonal antibody and then it binds to the BCMA antigen that’s expressed on the myeloma cells. And so, you’re essentially bringing the T cell to the cancer cell to kill it. So, that’s how teclistamab works. Amivantamab, though, targets 

 and c-Met, so it’s not redirecting T cells. With amivantamab you’re targeting 2 distinct antigen targets. And then there’s a variety of immune-type mechanisms by which binding of 

 or binding of c-Met separately kills the cancer cell. Why should you target 

When you think about NSCLC, there are those cases that are driven by driver mutations and those that are not. Those that are driven by driver mutations are things like 

 is quite distinct as a driver mutation. Lots of different compounds are out there for EGFR-expressing NSCLC, like gefitinib and erlotinib [Tarceva] and osimertinib. But we’ve learned over the last 10-plus years that in many 

 lung cancers, one primary mechanism of resistance is through c-Met.

 and c-Met is that potentially, you can target both the driver of the cancer and the resistance mutation, too.

/c-Met that’s unique as well. The different kinase inhibitors I just mentioned—like osimertinib and gefi tinib and Tarceva&mdash;target 

 from an intracellular perspective, and amivantamab targets it in an extracellular manner.

When you think about lung cancer and exon 20 insertion, why don’t the classical 

 inhibitors work in that space? They don’t work because they don’t have the ability to bind within the conformational pocket. By targeting the receptor from an extracellular perspective, you don’t have that issue. We know that about 10% of 

 lung cancers are of the exon 20 insertion type. They currently have no standard of care. By targeting 

 extracellularly, we can target that and potentially address something where current 

So, similarities, but quite a few more differences.

Are these therapies meant to be curative? 

 That’s a good question. Let’s take multiple myeloma for a second, a highly complex, heterogeneous disease. Once patients become refractory, we know that their overall survival is quite poor. I think in the refractory setting it’s very unlikely that we will give patients cure, but what we’re really trying to do is achieve really deep, durable responses, for as many patients as possible, with the idea that if we can get deep, durable responses, we can give them a meaningful amount of time.

In the relapse setting, I think that it’s about harnessing the immune system, harnessing those T cells to be able to try to target those cancer cells. As we learn more about teclistamab, I think the question will be, how can we use it to build curative-type regimens? One of our focuses at J&J and Janssen is to develop individual molecules or compounds, but at the same time, we’re very much interested in building curative regimens. So, I think for teclistamab in its current setting, unfortunately, I don’t think there is the potential for cure, mostly because of the disease complexity and heterogeneous nature. I think that teclistamab has the potential to be part of a regimen for cure in the earliest setting, and that’s certainly something that we will explore.

Now, in terms of amivantamab, there are a couple of places to think about it. The first is where we just got the breakthrough designation, for patients with the exon 20 insertion. A patient with lung cancer who has an 

 exon 20 insertion unfortunately has a survival of probably about a year and a half. Their outcomes are very poor.

I don’t think it’s really about cure, but more about trying to build regimens right now that can give patients more time. For patients with exon 20 insertion, for patients who have progressed after initial therapy—that’s where the breakthrough designation is for amivantamab. Once a patient has had initial therapy and progresses with exon 20, their median life expectancy is probably less than a year. What we’re trying to do now is give them more time. That’s the goal.

Ultimately, we would love to get to cure, and that’s part of our overall initiative. We actually have an ongoing lung cancer initiative across J&J; we brought the 3 different parts of the company together to look at how we can intervene earlier in the premalignant setting and premalignant stage. That’s the place

where we can think, potentially, about cure for some of these patients, and that’s part of our overall approach in terms of disease intervention.

: Especially for lung cancer, because it’s so often diagnosed in such a late stage that by the time it’s caught, it has metastasized.

Unfortunately, most patients are caught at stage IV because it’s relatively asymptomatic. Most patients might have a cough. It may seem like they have something that seems quite benign, so unfortunately, most patients get caught late. More than 1.8 million patients die a year from lung cancer worldwide,3 and the median life expectancy for a patient with newly diagnosed stage IV lung cancer is less than 2 years.

You saw some of the quite exciting data that came out at ASCO on one of the other compounds, looking at a checkpoint inhibitor in chemotherapy, and we’re heralding the outcomes of that. But we’re talking about moving survival by a couple of months. Median survival is still less than 2˜years, right? For 

-driven disease, the outcomes are a little bit better, but still, the outcomes are very poor. We’ve got a long way to go to help patients with lung cancer....

During ASCO, Janssen presented results from the CHRYSALIS study on amivantimab, a bispecific antibody being developed to treat non–small cell lung cancer (NSCLC). The pharma giant, along with its parent company, Johnson & Johnson (J&J), had previously received a breakthrough therapy designation in December for teclistamab, another bispecific antibody indicated for potential treatment of multiple myeloma.

July 2020

ASCO 2020: AJMCtv Interviews

ASCO 2020: Research Report

ASCO 2020: Genetic Testing

Janssen's Wildgust Breaks Down Bispecific Antibodies in Development for Non-Small Cell Lung Cancer and Multiple Myeloma

Access to Care: Burris Says United With Our Patients, We Accelerate Progress Together

ASCO 2020: Clinical Updates

COVID-19 and Cancer: NCI's Sharpless Says COVID-19 Could Halt Streak of US Cancer Mortality Gains