ASCO 2020: Research Report

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.¹ “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.

Cardiotoxicity

The first 2 abstracts that Ismail-Khan presented1 focused on results from the Pathways Heart Study,^2,3 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/m² 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.

Exercise

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.’”

References

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).¹

Identified more than 30 years ago, KRAS 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 KRAS mutation, called KRAS G12C, stood out: by itself, it accounted for 44% of KRAS mutations.¹ But in recent years, researchers at Amgen found a work-around for this problem. As outlined in Nature last fall,² they isolated the novel histidine 95 groove, which offered a way for molecules to selectively and irreversibly bind to KRAS G12C.

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 KRAS G12C mutation were present.³

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,⁴ as well as patients with multiple tumor types other than colorectal or NSCLC.⁵

COLORECTAL CANCER. 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 .⁴

OTHER TUMOR TYPES. 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.⁵

References

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. Nature. 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.¹

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.

References

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

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