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COLORECTAL CANCER

Targeting HER2amplifi cationsPage 4

BREAST CANCER

Prof. Christos Sotiriou talks about KEYNOTE-522Page 4

IMMUNOTHERAPY

‘Living’ anticancer medicines: has a new era started?Page 7

Opinion: Dr Emmanouil Saloustros

Precision medicine in adolescents and young adultsPage 8

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Promising data prompt new questions in breast cancer treatment

By Dr Carmen Criscitiello

Editorial

CDK 4/6 inhibitors in combination with endocrine therapy are confi rmed to improve the outcome of patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer, across different trials, in any treatment line, and regardless of which endocrine therapy is used.

All three CDK 4/6 inhibitors previously demonstrated improved progression-free survival (PFS) in some lines of treatment for HR-positive/HER2-negative metastatic breast cancer, in combination with either a non-steroidal aromatase inhibitor (NSAI) or fulvestrant.

Now, results from the MONARCH 2 and MONALEESA-3 trials show that overall survival (OS) in patients with HR-positive/HER2-negative metastatic breast cancer is improved by the combination of fulvestrant with abemaciclib and ribociclib, respectively. Similar data, although not formally statistically signifi cant, were seen with palbociclib within the PALOMA-3 trial.

These three trials included patients with different degrees of endocrine resistance, so they should be compared

Two CDK 4/6 inhibitors prolong survival in HR+/HER2- breast cancer in pre- and postmenopausal womenAt yesterday’s Presidential Symposium, results from the MONARCH 2 trial reported an overall survival benefi t of 9.4 months with abemaciclib plus fulvestrant. In the MONALEESA-3 trial, consistent survival benefi ts were also shown in the fi rst- and second-line setting with ribociclib.

METASTATIC BREAST CANCER

CDK 4/6 inhibitors in combination with endocrine therapy are confi rmed to be benefi cial in patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer across the board, as results from two phase III trials presented yesterday at the Presidential Symposium showed.

Late-Breaking Abstract presentations from the MONARCH 2 trial with abemaciclib and the MONALEESA-3 trial with ribociclib demonstrated substantially improved overall survival (OS) in patients with HR-positive/HER2-negative metastatic breast cancer. Complementing similar positive data from the PALOMA-3 trial with

Results from the PRODIGY and RESOLVE trials could infl uence clinical practice in Asian countries

Interview Data presented yesterday from two trials in patients with locally advanced, resectable gastric cancer—PRODIGY and RESOLVE—demonstrated the benefi t of perioperative chemotherapy regimens, as reported by Prof. Ian Chau from The Royal Marsden Hospital NHS Foundation Trust, Sutton, UK.

Prof. George Sledge from Stanford University School of Medicine, Stanford, CA, USA, who presented results from the MONARCH 2 trial

2

Daily Reporter Monday 30 September 2019

Two CDK 4/6 inhibitors prolong survival in HR+/HER2- breast cancer in pre- and postmenopausal women

METASTATIC BREAST CANCER

...Continued from page 1

palbociclib presented at the ESMO Congress last year and subsequently published,1 oncologists can now count on three CDK 4/6 inhibitors in this setting, although the choice of which agent to use and at which stage remains an open question. “When we look at statistics from tumour registries, median OS for HR-positive/HER2-negative metastatic breast cancer is still 2.5–3 years,” says Prof. Nadia Harbeck from the University of Munich (LMU), Germany, as she comments enthusiastically on the results. “Findings from these studies demonstrate that the combination of CDK 4/6 inhibitors plus endocrine therapy provides almost an extra 1.5 years of median life expectancy. We have reached the point where a lot of patients can achieve long-term stabilisation of their metastatic disease and this is fantastic news.”

Previous reports from the MONARCH 2 trial have shown that abemaciclib plus fulvestrant signifi cantly improves progression-free survival compared with placebo plus fulvestrant in more than 650 pre- or postmenopausal women

pre-treated with endocrine therapy.2

Yesterday, an advantage in OS was demonstrated for the fi rst time for this agent. Abemaciclib plus fulvestrant was shown to be associated with an OS benefi t of 9.4 months—median OS was 46.7 months in patients treated with abemaciclib plus fulvestrant compared with 37.3 months in those who received placebo plus fulvestrant (hazard ratio [HR] 0.757; 95% confi dence interval [CI] 0.606–0.945; p=0.0137) (Abstract LBA6_PR). No surprising safety signals were recorded with abemaciclib.

OS data were also presented from the MONALEESA-3 trial comparing ribociclib plus fulvestrant versus placebo plus fulvestrant as fi rst- or second-line treatment of 726 postmenopausal women with HR-positive/HER2-negative metastatic breast cancer (Abstract LBA7_PR). Ribociclib plus fulvestrant signifi cantly prolonged OS versus placebo plus fulvestrant (median not reached [NR] versus 40.0 months; HR 0.724; 95% CI 0.568–0.924; p=0.00455). Notably, the OS benefi t was observed in both the fi rst-line setting (median NR versus 45.1 months; HR 0.700; 95% CI 0.479–1.021) and in patients with early relapse or who

were receiving second-line treatment (median 40.2 versus 32.5 months; HR 0.730; 95% CI 0.530–1.004). The safety profi le of ribociclib was similar to previously published analyses.

“Taken together, these are remarkable and consistent fi ndings,” says Harbeck. “With the results of MONARCH 2, we

can now say that all three CDK 4/6 inhibitors—palbociclib, abemaciclib and ribociclib—in combination with endocrine therapy, provide a survival advantage compared with endocrine therapy alone. In addition, MONALEESA 3 has confi rmed fi ndings from MONALEESA-7, presented earlier this year, and demonstrated that the survival benefi t is consistent in pre- and postmenopausal women, and occurs in the fi rst- and second-line settings.”

“CDK 4/6 inhibitors should be used as early as possible in the disease course based on the first-line results seen in MONALEESA-3 and the consistent overall survival benefit observed in the second-line setting in MONARCH 2, as presented here in Barcelona,” highlights Prof. Nadia Harbeck.

Given these noteworthy results, Harbeck believes that CDK 4/6 inhibitors will become part of the standard-of-care. But how

with caution. For instance, in the MONARCH 2 and MONALEESA-3 trials, patients had previously received no more than one line of endocrine therapy and no chemotherapy in the metastatic setting, while in the PALOMA-3 trial there was no limit for previous endocrine therapies and one prior chemotherapy was allowed too. Moreover, the MONALEESA-3 trial also included a unique subgroup of postmenopausal patients who received ribociclib plus fulvestrant as fi rst-line therapy. This is the fi rst study to show an OS benefi t in postmenopausal patients and in combination with fulvestrant. So far, the only study of a CDK 4/6 inhibitor to have shown an OS benefi t was the MONALEESA-7 trial, which enrolled premenopausal patients

treated in the fi rst-line setting with endocrine therapy—either tamoxifen or NSAI plus goserelin—with or without ribociclib.

These new data confi rm CDK 4/6 inhibitors as the preferred treatment option in the management of HR-positive/HER2-negative metastatic breast cancer, with remarkable and consistent results. In addition, the results of the MONALEESA-3 trial in the fi rst-line setting suggest that CDK 4/6 inhibitors should be used as early as possible in the disease course. However, there are still open questions. Firstly, is there a preferred CDK 4/6 inhibitor in any specifi c disease setting? Secondly, based on the MONALEESA-3 trial results, should an aromatase inhibitor or fulvestrant be used as the preferred endocrine partner in the

Promising data prompt new questions in breast cancer treatment

Editorial fi rst-line setting? Thirdly, which is the best treatment sequence? In other words, if we treat patients with CDK 4/6 inhibitors plus fulvestrant in the fi rst line, which regimen should we choose for further lines?

This latter question might be particularly relevant for patients with PIK3CA-mutant tumours, who might be considered for the combination of fulvestrant and alpelisib. The choice of the best CDK 4/6 inhibitor should be tailored case by case, considering individual patient characteristics, previous treatment, and the slightly different toxicity profi les of each agent. Data presented yesterday at the Presidential Symposium, together with previous data, reinforce the indication for CDK 4/6 inhibitor plus endocrine therapy as standard-of-care for patients with HR-positive/HER2-negative metastatic breast cancer, but at the same time defi ne new clinical and research questions for treatment tailoring and optimisation.

...Continued from page 1

MONARCH 2: Overall survival

to choose the right inhibitor and which is the optimal treatment sequencing? “There are subtle differences in the safety profi les and management requirements of these treatments. The choice of the most appropriate CDK 4/6 inhibitor should be based on individual patient characteristics and previous treatment but, in general, adverse events related to these agents are all manageable with the right training,” concludes Harbeck. “Not every patient will receive second-line treatment—some are too ill or do not want to receive more treatment—and we should not withhold these agents, now we know they have a proven clinically meaningful impact on survival. Multinational efforts are required to generate evidence, such as from the ESMO-Magnitude of Clinical Benefi t Scale (ESMO-MCBS), to determine the potential benefi t of these agents in the fi rst-line, real-life setting and aid their availability and reimbursement across Europe.”

1. Turner NC, et al. N Engl J Med 2018;379:1926–36

2. Sledge GW Jr, et al. J Clin Oncol 2017;35:2875–84

Overall survivalThe reduction in relative risk of death with RIB was 28%

RIB + FUL PBO + FUL

Events/N 167/484 108/242

OS, median (95% CI), mo NR (42.5-NR) 40.0 (37.0-NR)

HR (95% CI) 0.724 (0.568-0.924)

P value 0.00455

Landmark Analysis

• The P value of 0.00455 crossed the prespecified boundary to claim superior efficacy (P <0.01129)

KM Estimate

RIB + FUL

PBO + FUL

36 months 67.0% 58.2%

42 months 57.8% 45.9%

Ove

rall

Surv

ival

, %

RIB + FUL

PBO + FUL

0

20

40

60

80

100

484 470 454 444 436 428 414 402 397 389 374 365 348 334 326 309 300 287 237 159 92 41 14 20242 233 227 223 218 213 207 199 194 187 184 174 169 159 155 147 141 134 107 64 37 14 3 0

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

No. of patients still at risk

PlaceboRibociclib

Time, months

3

NSCLC

Could ctDNA be used to detect mutational changes in NSCLC before disease progression occurs on treatment with osimertinib? Results presented yesterday from an exploratory analysis using circulating tumour DNA (ctDNA) to monitor patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC) in the FLAURA study showed that not only was early detection of disease progression possible, but so was the detection of mutational changes before clinical progression was evident (Abstract LBA85).

Detection of ex19del, L858R or T790M EGFRmutations in ctDNA from plasma samples was performed before, during and after treatment. ctDNA was monitored for T790M or C797Sresistance mutations during and after treatment.

Of 122 patients who had their ctDNA monitored, ctDNA progression preceded or occurred concurrently with clinical disease progression in 66% of patients with a median lead time of 2.7 months.

Median progression-free survival (PFS) was 9.5 months. Acquired C797S or T790M resistance mutations were detected in 8% and 74% of patients with ctDNA progression in the osimertinib and comparator arms, respectively. The median time to detection of these mutations was longer in the osimertinib arm than in comparator arms (16.7 months and 8.4 months, respectively), which refl ected the divergence in overall median PFS results.

Research into ctDNA monitoring for the early detection of non-EGFR-mediated mutations is planned. “The investigators showed that, on average, tumour detection in the blood was 2.7 months earlier than radiological progression. It is also valuable that the type of resistance mechanism could be determined. Knowing sooner that resistance is present and about the type of resistance will, for sure, be impactful in the future. We need studies to confi rm if these fi ndings can change outcomes, but this is a very interesting start,” explains Prof. Olivier Michielin from Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

In addition to the FLAURA analysis, two additional studies presented yesterday provide insight into the use of liquid biopsies for the early detection of disease and resistance mechanisms. Here, Prof. Olivier Michielin from Centre Hospitalier

Universitaire Vaudois (CHUV), Lausanne, Switzerland, discusses the fi ndings and next steps for further progress in the use of liquid biopsies.

How far has the use of liquid biopsies come? What new information can liquid biopsies provide on disease detection?We are living in an exciting time for tumour DNA blood interrogation—we now have very sensitive technology to detect and sequence tumour DNA in the blood compartment. We can use these techniques to follow therapy, to look at resistance mechanisms, and as we saw in the late-breaking analysis from the Circulating Cell-free Genome Atlas and STRIVE observational studies, we can now detect early disease from multiple tumour types with high certainty. What is very interesting is that this new method is based on DNA methylation and the tumour type can be assigned with quite a high level of confi dence.

Further advances in the capabilities of liquid biopsies are reported in two studies in different tumour types

Interview

Interview

DON’T MISS TODAY!

Proffered Paper 2 – Gastrointestinal Tumours, Colorectal

08.30 – 10.00, Barcelona Auditorium (Hall 2)

ESMO-SIOPE/AYA Collaborative Session: Genetics and Precision Medicine for AYA with Cancer

08.30 – 10.00, Salamanca Auditorium (Hall 3)

Proffered Paper 2 – Non-Metastatic NSCLC and Other Thoracic Malignancies (Mesothelioma and Thymic Carcinoma)

10.15 – 11.45, Pamplona Auditorium (Hall 2)

Proffered Paper – Immunotherapy of Cancer

10.15 – 11.45, Barcelona Auditorium (Hall 2)

Caloric Restriction Mimetics, Autophagy and Cancer

12.00 – 12.45, Madrid Auditorium (Hall 2)

Proffered Paper – Sarcoma

14.45 – 16.40, Malaga Auditorium (Hall 5)

Presidential Symposium III

16.30 – 18.15, Barcelona Auditorium (Hall 2)

What further insight does the PADA-1 trial provide on resistance mechanisms?The authors looked at mechanisms of resistance to aromatase inhibitors and specifi c mutations in the oestrogen receptor in an exploratory analysis of the PADA-1 trial. It was very interesting that the investigators were able to distinguish between early primary resistance and later adaptive resistance. In the fi rst 6 months, resistance mechanisms via oestrogen receptor mutations were infrequent, whereas after months, it was much more common, showing the dynamics of tumour adaptation through blood DNA analysis.

Watch the full interview onlinedailyreporter.esmo.org

Results from the PRODIGY and RESOLVE trials could infl uence clinical practice in Asian countries

...Continued from page 1

What are the results from the PRODIGY and RESOLVE trials?The PRODIGY trial was conducted in Korea and randomised patients with newly diagnosed cancer to neoadjuvant docetaxel, oxaliplatin plus S-1 (DOS) followed by D2 resection and then S-1, or control, consisting of D2 resection fi rst, followed by S-1. There was a signifi cant improvement in the study’s primary endpoint, progression-free survival, in favour of neoadjuvant DOS, with an absolute improvement of around 6% at 3 years. This translated to a hazard ratio of 0.70. At the moment, the overall survival data are immature.

Performed in China, the RESOLVE trial compared three treatment arms: 1) D2 resection followed by oxaliplatin plus capecitabine; 2) D2 resection followed by S-1 plus oxaliplatin (SOX); and 3)

Watch the full interview onlinedailyreporter.esmo.org

SOX followed by D2 resection, adjuvant SOX then S-1. Neoadjuvant and adjuvant SOX signifi cantly improved the primary endpoint of 3-year disease-free survival. It was also shown that adjuvantSOX was non-inferior to adjuvant capecitabine plus oxaliplatin.

How could these results infl uence clinical practice?While the survival data from PRODIGY are not yet mature, there was a signifi cant improvement in progression-free survival, and because of this positive outcome, it will likely add weight to the evidence in Asian patients supporting neoadjuvant chemotherapy.

In the RESOLVE trial, only patients with T4 tumours—so quite locally advanced cancer—were recruited. Since neoadjuvant SOX improves progression-free survival, this regimen should be considered a new standard treatment option, at least in countries where post-operative adjuvant chemotherapy is administered.

What do these trials tell us about the timing of chemotherapy in the advanced gastric cancer setting? The results of PRODIGY and RESOLVE bring into line the data for Asian and Caucasian patients on the perioperative use of chemotherapy. Perioperative chemotherapy is considered the standard-of-care in Caucasian patients. In the past, the standard for Asian patients with D2 resectable disease was post-operative chemotherapy, but what these two trials show is that the use of neoadjuvant chemotherapy brings additional benefi ts.

What are the challenges and next steps for the use of liquid biopsies?Our techniques for detecting tumour DNA are improving and the detection limit is going down, but we still have a lot to learn. There are differences among tumour types and, even for a given tumour type, the amount of DNA that is shed can differ quite a lot and we have to factor this in.

There are lots of unknowns, but these studies really show that we are getting there. We are able to measure meaningful parameters in the blood, but the next challenge is to integrate these developments into patient care.

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Daily Reporter Monday 30 September 2019

COLORECTAL CANCER

There were mixed results yesterday for dual-targeted therapy in HER2-amplifi ed KRAS wild-type metastatic colorectal cancer (mCRC). The HERACLES-B trial (Abstract LBA35) did not reach its primary endpoint but encouraging (ORRs) were reported from the TRIUMPH sub-study, GOZILA (Abstract 526PD) and the MOUNTAINEER trial (Abstract 527PD).

In the open-label phase II HERACLES-B trial of pertuzumab plus trastuzumab emtansine (T-DM1) (n=30), the ORR was 10%. However, many patients (70%) did experience stable disease and higher HER2 immunohistochemistry scores were associated with objective response/stable disease ≥4 months (p=0.03). Dr Elizabeth Smyth from Cambridge University Hospitals NHS Foundation Trust,

UK, provided her insight into the results: “It is unclear why response rates are lower than expected in HERACLES-B,” she says comparing these fi ndings with the ORR of 30% in the HERACLES-A trial with trastuzumab and lapatinib reported some years ago.1 “T-DM1 used in HERACLES-B combines a cytotoxic payload with trastuzumab and it would be reasonable to expect higher response rates than with the non-cytotoxic combination of trastuzumab plus lapatinib used in HERACLES-A. However, it is possible that mCRC is less sensitive to emtansine chemotherapy—which is a microtubulin inhibitor—than breast cancer, the disease in which T-DM1 has previously been shown to be effective. Alternatively, it could be that blocking EGFR with lapatinib was also helpful for these tumours.”

In contrast to HERACLES-B, GOZILA and MOUNTAINEER achieved their primary endpoints, with ORRs ≥30%. “Considering that the patients enrolled in GOZILA and MOUNTAINEER were previously chemorefractory, the results are impressive,” says Smyth. “Response rates to second-line chemotherapy in mCRC are around 20% and these results for anti-HER2 therapy appear to exceed that, although we need to be cautious not to over-interpret the results of small datasets.”

In the GOZILA sub-study, HER2 amplifi cation was confi rmed by analysis of tumour tissue and/or circulating tumour DNA (ctDNA): 14 patients had HER2 amplifi cation in both tissue and ctDNA; HER2 amplifi cation was confi rmed by tissue alone in 3 patients and in ctDNA alone for 1 patient. Investigators found that trastuzumab plus pertuzumab was associated with an ORR of 35% in tissue-positive patients and 33% in ctDNA-positive patients. The antitumor activity seen in GOZILA is in line with the results from the MyPathway study investigating the same combination in HER2-amplifi ed mCRC by tissue profi ling.2

“It is reassuring that there was substantial overlap when HER2 amplifi cation was assessed in ctDNA and tissue, indicating that either method could be used for patient selection,”

Targeting HER2 amplifi cations in metastatic colorectal cancer: searching for the most active combination therapy?With positive objective response rates (ORR) from three phase II studies, research takes another step toward targeting these rare genetic abnormalities with the right regimens.

remarks Smyth. “Additionally, the effi cacy of trastuzumab plus pertuzumab was similar for both methods, which suggests that there is no difference in the sensitivity of ctDNA- or tissue-detected HER2-positive mCRC to anti-HER2 therapy. Liquid biopsy, or measurement of ctDNA in plasma could, in future, decrease the need for tissue confi rmation of HER2 status.”

In the MOUNTAINEER trial, the ORR was 52% in the 23 evaluable patients who received tucatinib plus trastuzumab. Furthermore, median progression-free survival was 8.1 months and median overall survival (OS) was 18.7 months. Smyth is excited by these fi ndings. “This is a very encouraging response rate for a novel HER2 tyrosine kinase inhibitor and antibody combination,” she says. “Unlike trastuzumab and pertuzumab, tucatinib crosses the blood–brain barrier and has the potential to treat brain metastases, which can occur even in patients with good systemic disease control who are treated with anti-HER2 therapies.”

It emerges that there is a group of patients with HER2-amplified CRC who are oncogenically addicted to HER2 signalling. The priority now should be to identify them and enrol them in larger registration trials.

“The median OS of over 18 months in a chemorefractory population shows the power of treating this sensitive population with the right specifi cally targeted therapies,” highlights Smyth.

“In future, moving anti-HER2 therapy to earlier lines of mCRC treatment may lead to even higher response rates. We also need to consider the best time to measure HER2 amplifi cation in mCRC. Is the amplifi cation an inherent tumour characteristic or is it acquired, for example, after anti-EGFR therapy? Is response to anti-HER2 therapy different in these two scenarios? Also, as HER2 overexpression seems to predict worse outcomes in Ras wild-type patients treated with anti-EGFR therapy, should we be using HER2 overexpression as a negative selection biomarker for anti-EGFR therapy in mCRC? This is the topic of much debate.”

To conclude, Smyth says, “It is challenging to work on trials where the genetic abnormality is rare, but if we consider NTRK, ALK or ROS1 fusions, and now HER2amplifi cation, we can see what is possible. Results from these phase II trials suggest that in the next few years we will be able to treat patients with HER2-positive mCRC with the right agents, and possibly even with chemotherapy-free combinations—this is great news for patients.”

1. Sartore-Bianchi A, et al. Lancet Oncol 2016;17:738–462. Meric-Bernstam F, et al. Lancet Oncol 2019;20:518–30

A Late-Breaking Abstract presentation of results from the KEYNOTE-522 trial in yesterday’s Presidential Symposium saw pembrolizumab become the fi rst anti-PD-1 therapy to signifi cantly improve pathological complete response (pCR) rates regardless of PD-L1 status when used in combination with chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC) (Abstract LBA8_PR).

TNBC is a particularly aggressive form of breast cancer, which shows a tendency for early recurrence. The standard treatment approach is neoadjuvant chemotherapy followed by surgery and the better the pCR, the greater likelihood there is of the patient being cured.

In this phase III, randomised, double-blind trial, 1,174 patients with early TNBC were randomised 2:1 to receive neoadjuvant treatment with chemotherapy—with anthracyclines, taxanes and platinum—in combination with either pembrolizumab or placebo for 5–6 months. Following surgery, patients received 9 cycles of adjuvant treatment with pembrolizumab or placebo, respectively. The dual primary endpoints were pCR and event-free survival (EFS).

At a median follow-up of 15.5 months, analysis in the first 602 patients showed a 13.6-percentage point increase in the pCR rate with pembrolizumab compared with placebo (64.8% versus 51.2%, p=0.00055).

Dr Ramón Salazar from L´Hospitalet de Llobregat, Barcelona, Spain, invited discussant for the HERACLES-B, GOZILA and MOUNTAINEER trials

BREAST CANCER

Neoadjuvant pembrolizumab plus chemotherapy improves pCR in TNBC irrespective of PD-L1 status

Preliminary data from an interim analysis of EFS were also encouraging, showing a trend in favour of pembrolizumab, with a hazard ratio of 0.63 (95% confi dent interval 0.43–0.93).

Grade ≥3 treatment-related side-effects with pembrolizumab and placebo occurred at similar rates (78.0% versus 73.0%) but, as expected, the rate of potentially immune-related adverse events were higher in the pembrolizumab arm (42% versus 21%).

Commenting on the results, Prof. Christos Sotiriou from Institut Jules Bordet, Brussels, Belgium, says, “This is a positive fi nding for this phase III study. Showing that neoadjuvant treatment with pembrolizumab leads to an improvement in the pCR rate, it is the fi rst real indication that immunotherapy works in early-stage TNBC. Now, before we can move ahead with pembrolizumab in this setting, we have to work out which patients will get the most benefi t from this type of treatment. In so doing, we can direct therapy to those patients who can be expected to respond well to treatment while at the same time avoid exposing patients unlikely to respond to the side-effects

associated with immunotherapy. Areas to be investigated include the impact of tumour-infi ltrating lymphocytes and tumour mutational burden. And we must remember that TNBC is not a single disease, so looking at the different subtypes will also be important.”

Prof. Christos Sotiriou from Institut Jules Bordet, Brussels, Belgium, discussing the KEYNOTE-522 trial

5

SUPPORTIVE CARE

Cancer has dozens of common symptoms and adverse events—such as pain, fatigue, nausea, vomiting, neuropathy, mouth sores, appetite problems, taste problems, anxiety and sleeplessness—which may be interpreted differently by patients and healthcare professionals. Patient-reported outcomes (PROs) that focus on symptoms and quality of life (QoL) are very important to improve cancer care and may help to re-align the major concerns and needs of patients with the perspectives of healthcare professionals.

PROs encourage patient-centred care. “Sometimes, patients need encouragement to describe their symptoms. They may be hesitant to do so for several reasons, including a reluctance to be perceived as complaining, or fear that treatment will be discontinued. Systematic tracking of PROs can help patients and clinicians to partner so that they stay on

top of symptoms, which in turn can improve treatment effectiveness and the patient experience,” explains Prof. Deborah Schrag from the Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA, who will discuss the ‘Relevance of patient reported outcomes’ at the Challenge your Expert Session this afternoon (15.00 – 16.00, Salamanca Auditorium [Hall 3]). “In turn, clinicians can reassure patients that there are ways to address these symptoms. Also, during treatment, healthcare teams can tell patients what symptoms to expect, how long these are likely to last and suggest coping strategies.”

Having a convenient way of recording patient-reported outcomes can help patients to better describe their symptoms, not just in the clinician’s office, but also when patients are at home.

As cancer survival rates increase due to advances in preventative strategies, diagnostic tools and treatments, PROs are likely to play a central role in the future of cancer care. Cancer survivors can experience a variety of problems related to the disease itself or its treatment, and these issues may continue to have a detrimental impact on patients during or immediately after treatment, or even many years later. “We need to pay greater attention to survivorship and exactly how patients will survive, not just focus on their treatment,” says Prof. Manuela Eicher from the University of Lausanne, Switzerland, an oncology nurse whose research is focussed on supportive care in cancer. QoL in survivorship is the focus of today’s ‘Surviving a cancer diagnosis’ Educational Session (08.30 – 10.00,

Closing the clinician–patient gap with patient-reported outcomesIn an era when surviving a cancer diagnosis is becoming more commonplace, accurate reporting of the symptoms, needs and concerns of patients will help to provide guidance on decision making to improve care and quality of life.

Santander Auditorium [Hall 3]). Eicher continues, “We have strong evidence to show that oncology healthcare professionals underestimate the impact that the symptoms and adverse events of cancer and its treatment have on patients’ lives. The inclusion of PROs in clinical care can help us identify what is important for their symptom management and, more broadly, QoL, and set the basis for future clinical decision making.”

Recently, efforts have been made to integrate PRO data into patient electronic health records, although research is ongoing regarding the most appropriate way of doing this. While technological advances provide numerous means of recording PROs, combining the information into a single, convenient record can be problematic.

“We can easily record PROs with various apps, but more important than this is having supportive care expertise to provide relevant information and education, including coaching,” comments Schrag. “Good supportive care includes nurses with expertise in symptom management—sometimes called nurse navigators—who are skilled at coaching patients and addressing symptoms early, before they escalate and require acute care.” Schrag thinks that this can encourage patients to feel empowered and optimistic, which contributes to their overall sense of wellbeing. “In my clinical practice, I have found that the majority of patients are open and receptive, and immediately recognise the value of reporting their symptoms because they understand that this may help them feel well,” concludes Schrag.

6

Daily Reporter Monday 30 September 2019

ENDOMETRIAL CANCER

PORTEC-3: tumour molecular characterisation predicts recurrence-free survival with combined adjuvant chemotherapy plus radiotherapyMolecular characterisation of endometrial cancer has a strong prognostic value in identifying patients with endometrial cancer and high-risk features who may benefi t from adjuvant chemotherapy plus radiotherapy, as reported in a Late-Breaking Abstract presentation yesterday (Abstract LBA63).

Following the previous positive reports of overall survival from the phase III randomised PORTEC-3 trial with combined adjuvant chemotherapy plus radiotherapy versus radiotherapy alone in patients with high-risk endometrial cancer, this analysis evaluated the relationship between outcomes and chemotherapy according to previously defi ned molecular subgroups.

Molecular characterisation using immunohistochemistry and DNA sequencing was performed on tissue samples from 410 patients with stage I–III endometrial cancer who participated in the PORTEC-3 trial. In total, 22% of patients had mutant p53, 33% had defi ciencies in mismatch repair

proteins, 13% had ultramutated polymerase-epsilon (POLE) and 32% had no specifi c molecular profi le. Five-year recurrence-free survival (RFS) rates were 50%, 74%, 98% and 76%, respectively (p<0.0001). Patients with p53 mutations had signifi cant improvements in 5-year RFS with chemotherapy plus radiotherapy versus radiotherapy alone (61% versus 37%, p=0.017), whereas patients with POLE mutations had high rates of RFS regardless of regimen (100% versus 97%, respectively, p=0.632). Patients with mismatch repair defi ciencies did not seem to benefi t from the addition of chemotherapy to radiotherapy (72% versus 76%, p=0.687). For patients with no specifi c molecular profi le, 5-year RFS was 81% with chemotherapy plus radiotherapy versus 70% with radiotherapy alone (p=0.311).

These fi ndings suggest that further investigation of molecular classifi cation as a prognostic indicator to target specifi c patient subgroups is warranted.

Surufatinib signifi cantly improves progression-free survival in patients with non-pancreatic NETsLate-Breaking phase III data from the SANET-ep trial presented yesterday showed that investigator-assessed median progression-free survival (PFS) was 9.2 months with surufatinib versus 3.8 months with placebo (hazard ratio 0.334; 95% confi dence interval 0.223–0.499; p<0.0001) in patients with progressive, advanced neuroendocrine tumours (NETs) (Abstract LBA76). The SANET-ep study met its pre-defi ned primary endpoint of PFS and was stopped early.

The study enrolled 198 patients who were randomised to oral, daily surufatinib or placebo until disease progression or intolerable adverse events. At disease progression, treatment crossover was permitted. Most patients (84%) had pathological grade 2 NETs, with many (47%) originating from the gastrointestinal tract.

Overall survival (OS) data, which were immature at data cut-off (18.7% OS events), are eagerly awaited. The overall response rate was 10.3%—comprising 11 confi rmed and 2 unconfi rmed

partial responses—with surufatinib versus 0% with placebo (p=0.0051). Among responders, the duration of response was 5.6 months.

The most common grade 3 or worse treatment-emergent adverse event was hypertension, occurring in 36.4% of surufatinib-treated patients and 13.2% of placebo-treated patients. Other common adverse events were proteinuria (19.4% for surufatinib and 0% for placebo) and anaemia (7.0% for surufatinib and 2.9% for placebo). Discontinuations due to adverse events were reported in 17.8% of surufatinib-treated patients versus 5.9% of placebo-treated patients.

Surufatinib is an angio-immuno kinase inhibitor that specifi cally targets the tyrosine kinase activity related to vascular endothelial growth factor receptor, fi broblast growth factor receptor and colony-stimulating factor-1 receptor. It is also under investigation for pancreatic NETs.

NETS

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Surufatinib arm

Placebo arm

Dr Robert L. Coleman from the University of Texas MD Anderson Cancer Center, Houston, TX, USA, invited discussant for the PORTEC-3 trial

7

IMMUNOTHERAPY

The benefi ts of adoptive T-cell therapy—where T-cells are given to induce a specifi c immune response—are moving closer to reality for patients with solid tumours. Studies presented at ESMO 2019 over the past few days refl ect the diversity of immunotherapies currently under investigation. At the beginning of what is likely to be a new era in cancer care, researchers have the technical expertise to use this approach for solid tumours, but it is yet to be determined which are the best targets and T-cell administration techniques.

Presented on Saturday, a phase I study in 9 patients with NY-ESO-1-expressing solid tumours who received T-cells genetically engineered to express a high affi nity NY-ESO-1-specifi c T-cell receptor (TCR), reported persistence of modifi ed T-cells. Three patients had detectable cells for more than 100 days post infusion and partial responses (n=2) were associated with signifi cantly higher frequencies of CD45RA+ CCR7+ CD8+ T-cells (Abstract 1183PD). “These results support data from previous trials and confi rm the validity of NY-ESO-1 as a therapeutic target,” says Dr Aurélien Marabelle from Gustave Roussy Cancer Center, Villejuif, France. “The most frequently used approach in this area is to transfer mixed populations of cells to patients. This study shows that effi cacy appeared to be driven by a subset of T-cells with a clear phenotype and this perhaps highlights the importance of selecting the correct cells for treatment. We now need to know if there is any impact of the conditioning regimen—in this case cyclophosphamide—on response to treatment, and this will be indicated by the durability of responses,” continues Marabelle. “With clear, durable responses, you can be confi dent that the T-cell therapy is likely to be active.”

Also on Saturday, antigen-specifi c T-cells induced by vaccination with blood-derived myeloid and plasmacytoid dendritic cells were reported to improve radiological progression-free survival (18.8 months versus 5.1 months in patients without immunological response, p=0.02) in a phase II trial in 21 patients with castration-resistant prostate cancer (Abstract 1179PD). Marabelle comments, “The fi nding that modifi ed dendritic cells have an impact on survival is important. Improving ways of assessing effi cacy, rather than just relying on survival outcomes—which requires large cohorts of patients and long follow-up times—may help to expedite investigation of new approaches.” In this respect, advances in circulating tumour DNA technology—which were discussed at multiple sessions in Barcelona and covered in the Daily Reporter yesterday—may provide a solution to this, allowing oncologists to monitor treatment-associated changes in tumour kinetics and to adjust treatment accordingly.

Findings from today’s poster session could help to overcome the limitation of the single-target specificity of T-cell therapies, which can lead to relapses in patients harbouring subclones of target-negative cancer cells.

Marabelle discusses the very preliminary fi ndings of a study being presented today, which reports that HPV16 TCR-T and anti-PD-1-armoured HPV16 TCR-T-cells were safe and were associated with clinical activity in patients with advanced HPV16+HLA-A2+ cervical cancer (Poster Display Session 3, 12.00 – 13.00, Poster Hall [Area 4]; Abstract 1227P). “The important point about this trial in a virus-induced cancer is the co-expression in the same adoptive

cells of an HPV-specifi c TCR and an anti-PD-1 short chain FV (scFV),” he says. “It is hoped that such genetically modifi ed T-cells will be more effi cacious as they will benefi t from an intrinsic PD-1 blockade without the systemic adverse events of a regular anti-PD-1. On a separate note, targeting of a virus-specifi c epitope in this study is a good way to avoid antigens that are expressed in healthy tissues, which may help to explain the low toxicity of this treatment.”

According to Marabelle, while results look promising, major limitations of many of these early studies are the very small numbers of patients and

‘Living’ anticancer medicines: has a new era started?The technical expertise to use T-cells to treat patients is already here, but many of the studies are small with short follow-up times.

short follow-up times. There are a variety of hurdles to be overcome before we see broad benefi ts from adoptive T-cell therapies for solid tumours in the clinic. These include issues related to T-cells ‘homing’ to the tumour—which might be overcome if T-cells are used ‘locally’; (Abstract 1226P); cancer cell recognition and destruction, and the heterogeneity of metastatic solid tumour cells. Cost is also a consideration but, as with any innovation, initial high costs are driven down by competition and newer innovations, allowing the fi eld to move forward. Despite the challenges, the oncology community is likely to see signifi cant progress in this area in the next few years.

Early results in targeting RET alterations in thyroid cancer are promising

NETS

In the LIBRETTO-001 study, LOXO-292 promises to address an unmet need in patients with this disease, but data on effi cacy and tolerability are still preliminary.

Late-Breaking results presented yesterday demonstrated the marked antitumour activity of the highly selective RET inhibitor, LOXO-292, in patients with RET-altered thyroid cancer included in the fi rst-in-man phase I/II LIBRETTO-001 study (Abstract LBA93).

“Genetic aberrations in RET are found in most cases of hereditary and in 50–60% of sporadic medullary thyroid cancer, as well as in 20% of papillary thyroid cancer, and are associated with aggressive biology,” explains Prof. George Pentheroudakis from the University of Ioannina,

Greece. “Until now, there have been no specifi c RET-targeting agents and RET-altered tumours have been treated with multitargeted kinase inhibitors, which have some activity against RET alterations, but they are not selective.”

The LIBRETTO-001 study included patients with advanced RET fusion or mutation-positive solid tumours, including differentiated thyroid and medullary thyroid cancer. In the primary analysis set of 55 patients with RET-mutant medullary thyroid cancer who had received prior cabozantinib and/or vandetanib treatment, the

investigator-assessed objective response rate with LOXO-292 was 56% (95% confi dence interval 42–70, with 2 partial responses pending confi rmation). With a median follow-up of 10.6 months, the median duration of response had not been reached. Similar effi cacy was also observed in 26 pre-treated patients with differentiated thyroid cancer.

Dry mouth, diarrhoea, hypertension and increased liver transaminases were the most common adverse events, but the majority were grade 1–2 and the rate of discontinuation was very low (1.7%).

Pentheroudakis thinks the results are encouraging. “Most of the responses are ongoing with a median follow-up of almost 1 year and that is good news. The effi cacy and tolerability data are very promising, but they are preliminary, and I would like to see more mature data on progression-free survival, overall survival and quality of life in a larger cohort.” He continues, “Overall, in thyroid cancer and also RET-altered non-small-cell lung cancer, the selective RET inhibitors LOXO-292 and BLU-677 have produced excellent early results, demonstrating that targeting RET alterations is a feasible and worthwhile approach.”

Pentheroudakis concludes with some of the questions that need to be answered to further the progress of RET inhibitors. “We should now consider testing for RET aberrations—what is the best testing method and when should we test? It is also important to determine the best time to start therapy with RET inhibitors—should we wait until after treatment with multitargeted kinase inhibitors or use selective RET inhibitors in the fi rst-line setting? How do we combine RET inhibitors with other targeted agents in order to prevent the emergence of resistance?”

Elements of CAR-T cell immunotherapy

8

Daily Reporter Monday 30 September 2019

Clinical implications of precision medicine in adolescents and young adults with cancer

As genetic analysis becomes cheaper and more widely available, oncologists are getting close to an era where tumour—somatic—and germline testing will form a greater component of the management of adolescents and young adults (AYA) with cancer. But before this can become common practice, more research is needed.

From the genomic profi ling of tumours in this age group, although limited, it has emerged that cancers in AYA have fewer somatic mutations, the mutations are disease specifi c and only 30% of the signifi cantly mutated genes overlap with those in adult pan-cancer analyses. In the ESMO–

By Dr Emmanouil Saloustros University Hospital of Larissa, Greece and Co-Chair of the ESMO–SIOPE AYA Working Group

Opinion

European Society for Paediatric Oncology (SIOPE) Collaborative Session, the up-to-date clinical implications of precision medicine will be presented, including measures to improve diagnosis (e.g., methylation profi ling to characterise CNS tumours), the stratifi cation of disease (e.g., medulloblastoma, acute lymphoblastic leukaemia) and treatment with molecular-targeted therapies (e.g., BRAF inhibitors in CNS tumours).

It has emerged recently that around 8% of paediatric patients and young adults with cancer have germline mutations in genes predisposing to cancer. Crucially, however, as we cannot identify those individuals by a family history of cancer, identifi cation of these germline mutations is vital. We must remember that genomic analysis and genetic counselling go hand in hand, so, if we increase our use of genomic analysis, we will also

need to make sure that we have enough trained healthcare cancer professionals in place to help these young patients understand their test result, treatment options and potential outcomes.

Precision medicine is the goal of genomic analysis and this targeted treatment approach has changed the landscape of treatment for adults. It should be the same for AYA but sadly, it is not. This is largely because of the outdated age-limit criteria of the majority of clinical trials in Europe, which exclude a substantial proportion of our patients from studies of novel medicines. Efforts like the joint Innovative Therapies for Children with Cancer (ITCC)–SIOPE initiative, ACCELERATE Platform, are hoping to address this to some extent by strengthening international cooperation for drug development and by giving the opportunity of novel therapy to our patients who are not children but are not adults

either. Also, the ESMO–SIOPE Cancer in AYA Working Group was formed 4 years ago with the main aim of promoting education about the unmet needs facing our AYA patients.

I think that, as a community, we must offer the best possible cancer care to every AYA with cancer. We need to fi nd ways to obtain the resources and create the collaborations that will enable us to expand our understanding of the disease in this age group—including the genomic characterisation of their tumours—and provide better treatments to improve their outcomes.

This morning’s ESMO–SIOPE/AYA Collaborative Session, ‘Genetics and precision medicine for AYA with cancer’ (08.30 – 10.00, Salamanca Auditorium [Hall 3]) will discuss current knowledge in this area.

9

SUPPORTIVE CARE

How prevalent is the use of complementary medicines among trial participants?Complementary medicine use was revealed to be high among participants in phase III trials, but there was no evidence for a detrimental impact on outcomes.

In a Poster Discussion Session on Saturday, the Canadian Cancer Trials Group revealed how they investigated the use of complementary medications in 3,707 patients included in six international phase III trials in colorectal cancer (43.3%), lung cancer (39.1%) and breast cancer (17.6%) (Abstract 1758PD).

One-fi fth of patients (20.2%) enrolled in these trials were found to be taking complementary medications according to trial records. Complementary medications—defi ned as products found on natural databases—most frequently used by patients were other herbal\natural products (n=158), dietary supplements (n=88), fi sh oils (n=85) and glucosamine (n=52). Patients using complementary medications tended to be younger and have better performance status. The use of complementary

medications did not appear to affect the time to global deterioration of quality of life (hazard ratio [HR] 1.07; 95% confi dence interval [CI] 0.94–1.21; p=0.94), but was associated with less improved subjective EORTC-QLQ-C30 ratings for pain, constipation and role functioning. However, patients using complementary medications reported fewer adverse events than those who did not (50.0% versus 61.6%, p=0.0002).

Use of complementary medications did not appear to adversely affect overall survival in patients with lung cancer (HR 0.80; 95% CI 0.68–0.94; p=0.005), colorectal cancer (HR 0.87; 95% CI 0.75–1.02; p=0.08) or breast cancer (HR 0.85; 95% CI 0.61–1.19; p=0.35). While the impact of complementary medication use on overall survival seemed to be positive and signifi cant in lung cancer, the investigators tempered this fi nding by mentioning the retrospective and post-hoc nature of the analyses, and the more favourable baseline characteristics of those taking complementary medications.

Taking steps to close the gender gap in oncologyYesterday, the Women for Oncology (W4O)–Young Oncologists Committee (YOC) joint Forum was held at ESMO 2019. “W4O is committed to monitoring the gender disparity situation and creating awareness through forums and publication of data from our studies,” stated Prof. Solange Peters from Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, and Chair of the ESMO W4O Committee, introducing the Forum. “We are also delighted to be working closely with the YOC in addressing gender issues.” An outcome of the collaboration has been the inclusion of mentorship roundtables held as part of this year’s W4O–YOC joint Forum. Peters continued, “We want to plant the seeds for gender balance among the next generation of doctors and scientists.”

WOMEN FOR ONCOLOGY

SUSTAINABILITY

‘A train to ESMO’ for the climate: an environmentally-friendly initiativeAchieving sustainable cancer care in a sustainable world. This is the idea that prompted Dr Joakim Crona, from the University Hospital Uppsala Akademiska Sjukhuset, Sweden, to run an initiative—‘A train to ESMO’ for the climate—encouraging the oncology community to take a train rather than an aeroplane to reach main events in the fi eld in Europe. Alongside 6 of his colleagues, Crona travelled by train to Barcelona for ESMO 2019. “The main purpose of our project was to reduce our carbon footprint by avoiding travelling by aeroplane. We also aimed to raise awareness around this issue in order to start a discussion among our colleagues on how we, as individuals, can contribute to a sustainable future,” explained Crona. “We were only a group of 7 travelling by train, but the response was quite overwhelming, and I got so much input from people, prompting new discussions. We wanted to compel others to think how they could manage to live their lives well, enjoy successful meetings but still be environmentally friendly.”

Prof. Solange Peters from Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, with the W4O-YOC Forum’s speakers and some of the members of the W4O Committee

10

Daily Reporter Monday 30 September 2019

CONTROVERSY SESSION

Neoadjuvant vs. adjuvant therapy or combination for locoregional/oligometastatic melanomaYesterday, Dr Ana Arance moderated a Controversy Session where Dr Alexander van Akkooi provided arguments in favour of neoadjuvant therapy, while Prof. Mario Mandalà upheld the view for continued use of adjuvant therapy as the standard for resectable melanoma. Following the presentations and fi nal vote, the consensus of opinion appeared to support van Akkooi’s case and a positive role for neoadjuvant therapy.

Does neoadjuvant therapy provide an advantage over adjuvant therapy in patients with resectable melanoma?

73.0%Yes

15.6%Don’t know

No11.5%

Mandalà was pleased that the majority vote refl ected the audience’s positive outlook, “since oncology is based on hope and belief.” The take-home messages were that neoadjuvant therapy represents a very promising approach but that there are still several issues to consider such as toxicity management, timing, logistics and patient selection, and further evidence is needed from large phase III trials.

Sex-based heterogeneity matters for immunotherapy and immunotherapy–chemotherapy combinations

IMMUNOTHERAPY

Having shown that treatment with immune checkpoint inhibitors was more effective for men than women,1 investigators from the European Institute of Oncology IRCCS, Milan, Italy, sought to determine whether there was sex-based heterogeneity when anti-PD-1 or anti-PD-L1 agents were combined with chemotherapy (Abstract 1285P). In today’s Poster Display Session (12.00 – 13.00, Poster Area [Hall 4]), the investigators will show that in this instance, the tables were turned, with women deriving even greater benefi t than men from the addition of chemotherapy to anti-PD-1/PD-L1 agents.

A meta-analysis was performed of 16 phase III trials testing anti-PD-1 or anti-PD-L1 monotherapy versus standard chemotherapy in 9,291 patients—8 trials in non-small-cell lung cancer (NSCLC), 2 trials in melanoma, 2 in head and neck squamous cell carcinoma, 2 in gastric cancer, and 1 each in kidney and urothelial cancer. In 15 out of 16 trials, the overall survival benefi t was larger for men (pooled

hazard ratio [HR] 0.73; 95% confi dence interval [CI] 0.69–0.78) than women (HR 0.86; 95% CI 0.78–0.94; p=0.0079 for heterogeneity).

A second meta-analysis was performed of 5 phase III trials comparing the combination of chemotherapy plus anti-PD-1/PD-L1 agents versus chemotherapy alone in 2,979 patients—4 trials in NSCLC and 1 trial in small-cell lung cancer. In all 5 trials, the overall survival benefi t with the combination was larger for women (pooled HR 0.50; 95% CI 0.41–0.60) than men (HR 0.76; 95% CI 0.66–0.87; p=0.0003 for heterogeneity).

These data are intriguing and support the need for different therapeutic strategies to be tested in male and female populations in prospectivetrials to further improve the use of immunotherapeutic strategies.

1. Conforti F, et al. J Natl Cancer Inst 2019; May 20. pii: djz094

11

Supervisor• Stefan Zimmerman,

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Editor-in-Chief• Markus Joerger,

Kantonsspital St. Gallen, Switzerland

Associate Editors• Branislav Bystrický,

Faculty Hospital Trenčín, Slovakia

• Carmen Criscitiello, Istituto Europeo di Oncologia, Milan, Italy

• Alessandra Curioni-Fontecedro, University Hospital Zürich, Switzerland

• Rodrigo Dienstmann, Vall d'Hebron Institute of Oncology, Barcelona, Spain

• Ignacio Duran, Hospital Universitario Marques de Valdecilla, Santander, Spain

The ESMO 2019 Daily Reporter is published by ESMO with support from TMC Strategic Communications.

Editorial TeamFrom left to right: Carmen Criscitiello, Alessandra Curioni-Fontecedro, Stefan Zimmerman, Branislav Bystrický, Rodrigo Dienstmann and Markus Joerger