MILAN, Italy—Patients with node-positive prostate cancer being treated with prostatectomy could derive benefit from early multimodality therapy combining androgen deprivation therapy (ADT) with radiotherapy (RT)—on top of surgery—if they have pathological features indicating high risk, according to findings reported at the European Multidisciplinary Meeting on Urological Cancers (EMUC).

 

Combining ADT with RT soon after prostatectomy improved overall survival as much as 40 per cent in the highest-risk patients according to analysis of data from studies conducted at three institutions—Memorial Sloan-Kettering Cancer Center in New York, the Mayo Clinic in Rochester MN and San Raffaele Hospital in Milan.

 

“It is the patients who are supposed—technically—to have the worst mortality from the disease that have the best survival when they receive the treatment,” said co-investigator Karim Touijer MD MPh, Attending Physician at the Department of Urology in the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan-Kettering Cancer Center in New York City.

 

He said that while the most common approach to node-positive disease after prostatectomy was observation—followed by treatment only if there was progression—his analysis suggested a potential net benefit from combining RT and ADT in patients who had additional risk factors on top of nodal spread.

 

He said studies were urgently needed to confirm any benefit since the natural history of patients with nodal disease after radical prostatectomy indicated that even—without further treatment—30 per cent of all patients were free from recurrence by 10 years. And this figure rose to 45 per cent among patients with only one or two nodes.

 

Pathological features can discriminate the 80 per cent of patients with nodal disease who had favorable characteristics and would be candidates for observation, he said. But it was important to identify those at the high risk because they could benefit from a multimodality approach, he said.

 

In his research from the three institutions patients with node-positive prostate cancer were divided into three groups after prostatectomy—those who had additional treatment with external beam RT, those who received the same RT combined with ADT, and patients assigned to no further treatment until relapse.

 

“We looked at a combined data set of nearly 1400 patients [who] received one of three strategies: Observed until they failed biochemically then treatment started, or: Automatically received hormonal therapy for life, or: Received the combination of hormonal and radiation therapy,” he said, adding that patients who received the combination of ADT and external beam RT started with the worst disease yet had the best overall survival.

 

Local Treatment Benefit

Touijer said they concluded there was great value in local control of the disease, despite the belief that if a patient had lymph-node metastases after radical prostatectomy the disease was already distant and systemic.

 

“What this data shows us is that maybe some patients are like that but not all of them, and not the majority, [and] that if we still focus—with all the treatments that we have available—to control the disease locally and regionally we can improve survival,” he said.

 

Not all Nodal Disease the Same

And analysis of the National Cancer Database (including 70 percent of all patients treated at US cancer centers) had given “external validation of these findings”.

 

“Close to 5 000 patients were treated by observation followed by treatment after failure, radiation alone, hormonal therapy alone, or a combination of hormonal and radiation therapy,” he said, noting that subcategories of patients with nodal disease clearly needed different treatment since there was a wide spectrum of risk and patients with the worst pathological features benefited the most from

Audio Journal of Oncology

AMSTERDAM—Women diagnosed with ductal carcinoma in situ (DCIS) of the breast were found to live longer than women in the general population according to a study from the Netherlands reported at the 2017 European Cancer Congress (ECCO).

Full Interview Transcript

LOTTE ELSHOF speaks with Peter Goodwin at the European Cancer Congress, ECCO 2017 in AMSTERDAM

Peter Goodwin

YOU WERE LOOKING AT CAUSE SPECIFIC MORTALITY IN PATIENTS WITH DCIS, WHAT WERE YOU TRYING TO DO IN THIS STUKDY?

Lotte Elshof

We looked at patients treated for DCIS – a potential precursor lesion to invasive breast cancer and we assessed cause specific mortality. So we looked at DCIS patients and during follow up see if they had died from what cause they had died and then we compared mortality with mortality in the general population. We wanted to look at [whether] DCIS patients had increased risk of dying.

 

WHY DID YOU WANT TO LOOK AT DCIS?

 

DCIS is a potential precursor to invasive breast cancer. So some DCIS lesions will progress into invasive breast cancer and invasive breast cancer can metastasise and then cause death so it’s an important thing to look at the outcomes of DCIS and there are a lot of uncertainties and anxiety associated with DCIS because many patients diagnosed with DCIS think they are diagnosed with breast cancer. But it’s not breast cancer, yet.

 

TELL ME WHAT YOU DID IN THE STUDY?

 

We looked at patients diagnosed with DCIS between 1989 and 2004 and we looked at the causes of death in this population and we compared these observed death numbers with the expected number of deaths.

 

QUITE A BIG GROUP?

 

Yes. Almost 10 000 women with DCIS

 

WHAT DID YOU FIND?

 

We found that DCIS patients older than 50 at diagnosis were at lower risk of dying compared to the general population. And—it may sound a bit counter-intuitive—but we think it is because these patients are mostly screen-detected so they go to the population-based screening program for breast cancer and these patients are likely to be more health conscious.

 

 

DETAILS—A THREE TIMES HIGHER RISK?

 

We saw that DCIS patients had lower risk of dying despite their increased risk of dying from breast cancer. So if you compare the risk of dying from breast cancer to the general population we see that they have an increased risk.   But then if we look at absolute numbers—the risk a woman [actually] had—then the risk is very low. So after ten years 2.5 per cent of the women died from breast cancer but compared to the general population this is only slightly increased risk.

 

AND YOU ALSO MENTIONED THAT THE RISK OF DEATH FROM BREAST CANCER WAS INDEPENDENT OF TREATMENT?

 

Yes we found that no matter what treatment the risk of mortality was so low. So we compared women treated with breast conserving therapy alone, breast conserving therapy with radiotherapy, and mastectomy and we saw no differences in breast cancer mortality.

 

PRACTICAL MESSAGES FOR DOCS?

 

This study provides accurate risk estimates—relative risks and absolute risks— which are important information to the patient. And I think these patients should be told they have a precursor lesion of invasive breast cancer but not yet invasive breast cancer and it should provide reassurance.

 

WHAT DOES THIS IMPLY FOR LOOKING FOR DCIS BECAUSE MANY WOMEN GET WORRIED BY THE DIAGNOSIS?

 

Yes. It’s a very worrying diagnosis. It’s associated with a lot of anxiety and confusion. It means that we sometimes find lesions that we would have rather not detected but because of screening we will find those lesions and the screening program also has a lot of benefits. So it’s not that we say that we don’t need to screen but there are always harms against benefits and some DCIS detection would be beneficial.

 

YOU DON’T WANT TO C

Audio Journal of Oncology, January 2, 2017

COPENHAGEN—Patients with metastatic non-small cell lung cancers (NSCLC) expressing the programmed cell-death ligand 1 (PD-L1) protein responded better to initial treatment with the anti-PD-L1 immunotherapy pembrolizumab—and lived longer with fewer toxicities—than to standard chemotherapy in the international KEYNOTE-024 (NCT02142738) study reported to the European Society for Medical Oncology 2016 congress. (Abstract LBA8_PR.)

http://annonc.oxfordjournals.org/content/27/suppl_6/LBA8_PR.full?sid=57db4b00-dd13-4ca0-ac50-086c77db63c0

Lead author Martin Reck MD PhD, a thoracic oncologist from the Grosshansdorf Lung Clinic near Hamburg in Germany, said the open-label, phase 3 study compared pembrolizumab checkpoint inhibition with platinum-doublet chemotherapy as first-line therapy for patients whose lung cancers had PD-L1 tumor proportion scores (TPS) of 50 percent or greater and did not have treatable epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations.

“These data are changing our management of patients with lung cancer,” he said adding that the results implied PD-L1 had emerged as an important predictive biomarker for treating patients with metastatic non-small cell lung cancer and that for patients whose tumors have it expressed pembrolizumab was an attractive new option in first-line treatment.

“The efficacy has been clearly better for pembrolizumab compared to chemotherapy, and the tolerability has been clearly better. So this tells us that we have to change our diagnostics for lung cancer. So besides the diagnostics for EGF receptor or ALK translocation we have to implement PD-L1 testing in our up-front diagnosis for lung cancer because we have got a completely new treatment option for this group of patients,” Reck told the Audio Journal of Oncology.

In the KEYNOTE-024 study patients with nonsquamous NSCLC were randomized either to 35 cycles of pembrolizumab, or between four and six cycles of investigators’ choice of platinum doublet chemotherapy (carboplatin or cisplatin plus pemetrexed, carboplatin or cisplatin with gemcitabine, or carboplatin plus paclitaxel) with optional pemetrexed maintenance.

The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate (ORR), and safety.

After a median follow-up of 11.2 months, nearly half of the 305 patients randomized to pembrolizumab chose to continue with their allocated initial therapy while only ten percent of those in the chemotherapy arm opted to continue with their initial treatment. Crossover was allowed, and when the disease progressed 44 percent of patients initially assigned to chemotherapy crossed over to pembrolizumab.

Disease Progression

Patients initially assigned to treatment with pembrolizumab lived a median of more than ten months before their disease progressed compared with only six months for those receiving chemotherapy. The immunotherapy was also associated with higher ORR (45percent compared with 28 percent) and longer duration of response —the median was not reached in the pembrolizumab arm and was 6.3 months with chemotherapy.

 Overall Survival

Six months after starting treatment 80 per cent of patients who started on pembrolizumab were alive compared with only 72 per cent for those initially allocated to chemotherapy. This was equivalent to a 40 per cent reduction of mortality risk for patients on pembrolizumab monotherapy—despite the high crossover rate.

Toxicities

Toxicities of any-grade were less common with immunotherapy (73 percent of patients had toxicities versus 90 percent with chemotherapy), and grade three-to-five treatment-related adverse events (AEs) were half as common with permbrolizumab. (27 percent versus 53 percent).

Stefan Zimmermann, MD, from Hôpital Fribourgeois, HFR Hôpital Cantonal, in Fribourg, Switzerland, who chaired a news bri

COPENHAGEN—Longer progression free survival (PFS) was achieved in patients with ALK-rearranged non-small cell lung cancer (NSCLC) previously treated with crizotinib randomised to treatment with the second generation anaplastic lymphoma kinase (ALK) inhibitor ceritinib rather than chemotherapy in the phase 3 ASCEND 5 study reported to the European Society for Medical Oncology (ESMO) 2016 Congress. (Abstract LBA42_PR

http://www.esmo.org/Conferences/ESMO-2016-Congress/Press-Media/Ceritinib-Provides-Longer-Progression-free-Survival-Than-Chemotherapy-in-Phase-III-Trial-of-ALK-Rearranged-Lung-Cancer-Treatment )

“We have another active agent that should be implemented in the clinical armamentarium for those patients with lung cancer that is ALK-positive—a preferred option over chemotherapy,” said Giorgio Scagliotti MD PhD, Professor of Medical Oncology at the University of Turin, Italy in an interview with the Audio Journal of Oncology (AJO).

“Ceritinib is a second generation ALK inhibitor that is much more potent than crizotinib and the study was [with] patients who were already exposed to crizotinib and cytotoxic chemotherapy looking at ceritinib versus the standard treatment—pemetrexed or taxotere (docetaxel),” Scagliotti said.

The open-label ASCEND-5 study included 231 patients with NSCLC who had received crizotinib. The median PFS in patients then treated with ceritinib was 5.4 months as compared with 1.6 months for those receiving chemotherapy—a hazard ratio of 0.49 for PFS. Compared to chemotherapy ceritinib increased overall response rate (39.1 percent compared with 6.9 percent) but there was no improvement in overall survival with ceritinib.

“In this selected patient population, where the target is present, this drug can give very interesting PFS in second, third, or fourth line—as long as the tumor is not resistant to [it],” said ESMO officer Solange Peters MD PhD, Médecin Cheffe in the Department of Thoracic Malignancies at Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Switzerland.

Stefan Zimmermann MD, from the Hôpital Fribourgeois, HFR Hôpital Cantonal, Fribourg, Switzerland noted that ceritinib had demonstrated an advantage over standard chemotherapy in second and further lines of therapy. “But the real question is: What do we have to use in first line?” he asked.

Scagliotti welcomed the addition of ceritinib to the family of tyrosine kinases for the small subgroup of patients who have the ALK translocation genomic alteration. “The first in class was crizotinib—a highly effective agent inducing 70 per cent response rate, improving survival over cytotoxic chemotherapy as shown in the PROFILE studies. But the issue with targeted therapies is that sooner or later you get relapse or progression of the disease and patients develop resistance,” he said.

Toxicities

The most frequent grade three to four adverse events with ceritinib were nausea (7.8 percent), vomiting (7.8 percent) and diarrhoea (4.3 percent), and with chemotherapy were neutropenia (15.5 percent), fatigue (4.4 percent) and nausea (1.8 percent). Ceritinib significantly improved patient-reported outcomes including lung cancer-specific symptoms and overall health status, compared to placebo.

“The toxicity profile was exactly what we were expecting from previous studies with ceritinib—with ALK treatment-naïve and ALK-pretreated patients having more gastrointestinal toxicities with ceritinib and some liver function test elevations that were not clinically relevant. In patients who received docetaxel hematological toxicities were much more commonly reported,” Scagliotti said.

But he said it was too early to give clear clinical guidelines about using ceritinib since there had not yet been head-to-head comparisons with crizotinib, and other ALK inhibitors were under investigation. “We need to wait a few months to identify the right sequence among these different treatment options,’ he said.

But he was opti

The Audio Journal of Oncology

Reporting from the 2016 Congress of the European Society of Medical Oncology

COPENHAGEN—The anti-PD-L1 (programmed cell death ligand-1) immunotherapy agent atezolizumab extended overall survival when compared head-to-head with docetaxel among patients with previously-treated non-small cell lung cancer (NSCLC) in the phase 3 OAK study reported at the European Society for Medical Oncology 2016 congress. (Abstract LBA44_PR http://annonc.oxfordjournals.org/content/27/suppl_6/LBA44_PR.short#)

Lead author Fabrice Barlesi MD PhD, Professor of Medicine at the Department of Multidisciplinary Oncology and Therapeutic Innovations of Assistance Publique Hôpitaux de Marseille, Aix-Marseille University in Marseille, France reported an overall hazard ratio of 0.73 in favor of immunotherapy among the first 850 patients—of whom those treated with atezolizumab lived more than four months longer than those receiving docetaxel (13.8 as compared with 9.6 months median).

Since the agent targets the PD-L1 protein it was expected to be more effective in patients testing positive for PD-L1, and the OAK study indeed found greater efficacy in this biomarker-positive group. Yet the drug clearly benefited patients in other subgroups too.

“The important message is that we have an immunotherapy treatment that works for all the patients in the second-line setting—whatever the PD-L1 status, and whatever the clinical characteristics—and it provides doctors and patients with a new strong therapeutic option,” Barlesi told the Audio Journal of Oncology.

ESMO officer Solange Peters MD PhD, Médecin Cheffe for Thoracic Malignancies at the Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne in Switzerland said the trial had brought clarification about the role of immunotherapy in lung cancer.

“What we knew from the other trials is that it’s better to give immunotherapy than docetaxel. In terms of survival [it is] very obviously better. This trial confirms that the higher PD-L1 is expressed the stronger is the benefit. But this trial clearly shows that patients without expression of PD-L1—the biomarker-negative population—still benefit from atezolizumab,” she said.

Barlesi said that the idea of using a PD-L1-directed drug arose because such “checkpoint inhibitors” work by cancelling one of the mechanisms cancer cells use to evade the immune system.

“The goal of this treatment is to allow the immune system to control and possibly eliminate cancer calls, so atezolizumab might be useful in a very large setting of different cancers,” said Barlesi.

The OAK study enrolled 1225 patients with previously-treated NSCLC and—after stratifying them according to PD-L1 status, number of prior chemotherapy regimens and histology—randomized them to intravenous atezolizumab (1200mg every three weeks) or docetaxel (75 mg/m2 every three weeks).

While the study was able to quantify the benefit from treatment with the PD-L1 checkpoint inhibitor in all patients the study was also designed to look at subgroups, with patients stratified according to their levels of PD-L1 expression.

Patients with more than one percent expression of the PD-L1 biomarker lived 52 percent longer if they received immunotherapy (15.7 months median compared with 10.3 months for docetaxel).

And patients in the highest group of PD-L1 expression treated with atezolizumab lived more than a year longer—to a median of 20.5 months as compared with 8.9 months for matched patients receiving docetaxel.

But even the patients who had no PD-L1 expression lived longer (12.6 as compared with 8.9 months median) with immunotherapy than with chemotherapy. And the improvements in overall survival were similar in patients with squamous and non-squamous histology.

Moderate to severe treatment-related adverse events occurred in 15 percent of patients treated with immunotherapy as compared with 43 percent of those receiving chemotherapy. There

COPENAGEN—Adding the PD-1 (programmed cell death protein 1) antibody pembrolizumab to standard first-line chemotherapy with carboplatin and pemetrexed for previously-untreated patients with advanced non-squamous non-small-cell lung cancer (NSCLC) and good performance status significantly improved objective response rate (ORR) and progression-free survival (PFS) in the phase II KEYNOTE-021 study reported at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen. (Abstract LBA46_PR)

“Pembrolizumab enables T cells to reactivate and accomplish what they are designed to do—facilitate tumor cell killing,” said principal investigator Corey Langer MD FACP, Professor of Medicine and Director of Thoracic Oncology at the Abramson Cancer Center, University of Pennsylvania in Philadelphia PA, commenting on the findings with this “checkpoint inhibitor” immunotherapy.

Langer told the Audio Journal of Oncology the study showed a “statistically significant and clinically meaningful improvement for both response and progression-free survival for the combination.”

The KEYNOTE-021 study randomized 123 patients with stage IIIB or stage IV, NSCLC to receive four cycles of carboplatin and pemetrexed (500 mg/m2 every three weeks), with or without 24 months treatment with pembrolizumab (200mg every three weeks).

After a median follow-up of 10.6 months, there was a significantly greater objective response rate (55 percent) in the patients who received pembrolizumab in addition to chemotherapy, compared to those treated with chemotherapy alone (29 percent).

PD-L1 (programmed cell death-ligand 1) expression was not used to select patients for treatment with the immune checkpoint inhibitor, but the investigators found a higher response rate (around 80 percent) for the combination in tumors with PD-L1 over-expression, consistent with the known and licensed activity of the agent in patients with metastatic NSCLC tumors testing positive for this biomarker.

Progression free survival was longer for patients treated with the pembrolizumab combination (median 13.0 months) as compared with those receiving chemotherapy (8.9 months). More than 90 per cent of patients lived longer than six months but there was no difference in overall survival between the two arms.

There were more grade 3 or 4 adverse events with the pembrolizumab combination (39 percent) than with chemotherapy (26 percent), but Langer said toxicity was readily manageable and did not affect rates of treatment discontinuation or treatment-related deaths.

“So even though toxicity may be a little bit worse it’s not a show-stopper,” he said, adding that he was encouraged by the findings. “With the judicious use of immunotherapy I believe we are moving the bar forward for this population,” he said.

ESMO congress officer Solange Peters MD PhD, Head of Medical Oncology and Médecin Cheffe of Thoracic Malignancies at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland said the KEYNOTE-021 finding reinforced the idea that every single patient should be exposed to immunotherapy at some time.

“On present [evidence] this should be sequential,” she said. “But I would advise doctors to keep an eye on these data about combination chemo and immuno-[therapies]—not only in lung, but in other diseases too, because it might be of great interest in the future.”

Peters said it was worth continuing to investigate combinations of chemotherapy plus immunotherapy as first line therapy for NSCLC since any worries that chemotherapy might damage T-cells had been lessened with the arrival of the KEYNOTE data.

“This combination was almost doubling the response rate as compared to chemotherapy alone—and the PFS [was] influenced positively by the combination. So it means that this is not a regimen that will damage the T-cell,” she said.

But she emphasized that we do not presently know if the benefits giving the two treatments concurrently were lik

COPENHAGEN—In a phase I study reported at the 2016 congress of the European Society for Medical Oncology (ESMO) six out of 15 patients with resectable early non-small cell lung cancer had “major pathological regression” to neo-adjuvant immunotherapy with nivolumab—the anti-PD1 …161116-ajo-esmo-forde-and-baas-production-master

Audio Journal of Oncology

COPENHAGEN, Denmark—In a phase 1b study patients with previously untreated stage IV pancreatic cancer responded or derived “clinical benefit” from a regimen in which a Wnt-signaling inhibitor—the humanized monoclonal antibody vantictumab—was added to nab-paclitaxel and gemcitabine chemotherapy. Colin Weekes MD PhD, Associate Professor at the University of Colorado in Denver, who reported findings from the trial at the 2016 European Society for Medical Oncology (ESMO) congress, discusses their clinical implications with Peter Goodwin. Debashis Sarker MD FRCP, Senior Lecturer and Consultant in Medical Oncology, at Guy’s, St Thomas’ and King’s College Hospitals, London, who was not involved with the study.

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COPENHAGEN, Denmark—Marked prolongation of progression free survival (PFS) in all groups of patients with platinum-sensitive recurrent ovarian cancer was reported at the European Society for Medical Oncology 2016 congress in findings from the double-blind phase 3 European Network of Gynaecological Oncology Trial groups (ENGOT-OV16/NOVA) trial of the oral poly adenosine-diphosphate–ribose polymerase (PARP) 1/2 inhibitor, niraparib, compared with placebo in patients with platinum-sensitive recurrent ovarian cancer.

Mansoor Raza Mirza MD, Chief Oncologist at Copenhagen University Hospital and Medical Director of the Nordic Society of Gynaecologic Oncology discusses the findings with Peter Goodwin.

http://www.nejm.org/doi/full/10.1056/NEJMoa1611310#t=articleTop

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