Prostate Genomics—Which Patients Will Die?20 Apr 2017
MILAN, Italy—Genomic profiling could help reduce the risk of over-treatment in primary prostate cancer (PC) by identifying patients and healthy individuals whose genes put them at greatest risk of developing dangerous disseminated disease said Norman J Maitland PhD, Professor of Molecular Biology and Director of the Cancer Research Unit at York University, UK. He was speaking at the 2016 European Multidisciplinary Meeting on Urological Cancers (EMUC).
He interpreted data from several recent studies—investigating the influence gene mutations had on prostate tumor development—that infer gene arrays could soon distinguish patients with dangerous tumors from those whose disease does not need aggressive management.
He discusses his findings n the Audio Journal of Oncology Interview with Peter Goodwin: “We don’t know which [patients] are going to die of prostate cancer and which ones can be left untreated for the rest of their lives,” he said. “Genetics is one tool to allow us to understand that.”Norman Maitland AJO PRODUCTION Master
MILAN, Italy—The first choice of therapy for patients with metastatic kidney cancer who have failed VEGF therapy has changed according to experts at the 2016 European Multidisciplinary Meeting on Urological Cancers (EMUC) who assessed phase 3 study data on two different agents—each of which showed clinically meaningful improvements to outcomes.
“There is a new treatment algorithm for individuals who have failed VEGF-targeted therapy,” said Thomas Powles, MBBS MRCP MD, Director of Barts Cancer Centre at St Bartholemews Hospital in London, UK.
“Both the ESMO and EAU guidelines are [now] supporting nivolumab and cabozantinib rather than—[as] previously—supporting axitinib and everolimus.”
He based his comments on observations from the METEOR and CheckMate 025 studies which found that therapy with cabozantinib or nivolumab improved overall survival compared to everolimus.
Peter Goodwin discusses the details of the METEOR findings with him.Thomas Powles 1 EMUC PRODUCTION Master
Karim Touijer, MD MPh, Sidney Kimmel Center for Prostate & Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York.
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 combining surgery, ADT and RT.
“We did statistical risk groups based on Gleason grade, clinical stage, invasion of the seminal vesicles, T4 disease, positive surgical margins—all the elements which have been shown to be predictive in most prostate cancers in many series. And the worse these features are the better the separation and the advantage in overall survival if we added radiation and hormone therapy,” he said.
The three-institutional data set revealed no difference in overall survival between patients who were observed and those treated with lifetime ADT.
“When we tried to look in detail at cancer-specific survival we saw that there was an advantage to androgen deprivation therapy. But when we looked at death from other causes—not cancer causes—we saw that there was [also] a detriment,” he said.
Node-positive patients assigned after prostatectomy to RT alone lived longer than patients allocated to ADT alone.
“The assumption is that thorough surgery followed by radiation therapy is controlling the source of the disease and seems to make a difference in terms of survival. [But] the combination of both [ADT and RT] seems to give the best result.”
But Touijer repeated that prospective clinical trials were needed to remove potentially confounding variables in these retrospective data, warning that these therapies could also have deleterious effects.
“One always has to balance the risk and benefit. But in terms of survival it looks like multimodality therapy has a clear advantage,” he said.
“A prudent way forward is for surgeons to reach out to radiation therapists and medical oncologists when they are dealing with patients [who] have lymph node metastases after radical prostatectomy and happen to have a Gleason 8, 9 or 10, pathological stage T3b or T4, positive surgical margins, and a higher nodal count and really carefully look at the value a multimodality approach for these patients—because it may alter their survival.”
Karim Touijer EMUC AJO PRODUCTION Master
MILAN, Italy—Genomic testing combined with clinical assessment could be the best way to identify patients with prostate cancer who can benefit from early radiotherapy after prostatectomy, according to a study in The Lancet Oncology reported at the European Multidisciplinary Meeting on Urological Cancers (EMUC).
“A certain sub-population of patients would benefit from having early postoperative radiotherapy, and the genomic test will hopefully help identify that subset,” said one of the investigators Jeffrey Karnes MD, a urologic oncologist at the Mayo Clinic in Rochester MN.
Under senior author Felix Feng MD, from the University of California in San Francisco, the study reported on the use of genomic classifiers to help therapy decision-making in patients being treated with prostatectomy.
Since around half of all patients do not have recurrences after radical prostatectomy Karnes said the study was needed to help identify those with aggressive prostate cancers who do—and who could therefore benefit from early postoperative radiotherapy.
“We identified four risk factors—stage T3b or 4, lymph-node invasion, Gleason score 8, 9 or 10 and high genomic risk. Patients benefited from adjuvant radiotherapy if they had at least two of those risk factors,” he said.
The study assessed the use of a combination of clinical factors and genomic classifiers in the Post-Operative Radiation Therapy Outcomes Score (PORTOS).
Patients with high PORTOS had marked reductions of metastasis over ten years from adding radiotherapy to their prostatectomy.
Among the 39 patients with high PORTOS (out of an overall cohort of 197) only five percent of the 20 men who had radiotherapy had metastases by ten years postoperatively compared with 63 percent of the 19 patients who did not have radiotherapy.
Not all patients
However, the benefit of radiotherapy was not seen in the 157 patients who had low PORTOS among whom the metastasis rate by ten years was nearly doubled in those who had radiotherapy—57 percent, as compared with 31 percent among patients having no adjuvant therapy.
The study concluded that treatment with postoperative radiotherapy should now be considered in patients with high PORTOS but that the use of PORTOS as a predictive tool still needed to be investigated further in additional independent cohorts.
Karim Touijer MD MPh, from the Sidney Kimmel Center for Prostate and Urologic Cancers, at the Memorial Sloan-Kettering Cancer Center in New York, said that including genomic classifiers gave “good discrimination in selecting patients” and he described Karnes’ data as “a great signal” to be subjected to careful statistical analysis—mainly decision curve analysis—which he considered would be “of great value” to help optimize the use of adjuvant radiation therapy by integrating clinical and genomic features.
Quoting the new data Karnes made a strong case for the combined use of genomic classifiers from tumor specimens together with clinical features for predicting prostate cancer response to radiotherapy.
In the genomic research he said the original aim had been “to better prognosticate patients who had high-risk prostate cancer” by quantifying the risk of metastasis at five years and at ten years. But the technique had proved to have predictive value too.
He explained that the standard clinical criteria had not been sufficient to decide on post-surgical radiotherapy.
“At the end of the day we [were] still left with this dilemma: Do we actually give radiation early—maybe [with] the consequence that the patient may not recover fully—versus waiting for PSA progression?”
Karnes noted that by incorporating genomic classifiers into an overall predictive assessment it was now clear that there were some men for whom the earlier radiation was given the better. And he said this had already affected his practice.
“In my practice [for patients with clinical risk factors] I reflexively get a genomic test. If it’s high I immediately refer that patient for radiotherapy,” he said.
More evidence came from another study Karnes was involved with led by Ashley Evan Ross, MD, PhD, Assistant Professor of Urology, Oncology and Pathology at the James Buchanan Brady Urological Institute at Johns Hopkins Hospital in Baltimore MD, which allocated four groups of patients on the basis of PSA levels to be treated with adjuvant radiotherapy, early salvage radiotherapy, salvage radiotherapy or no radiotherapy at all.
“We did show that the higher the genomic score the more separation in the curves. When the genomic score was low the metastasis rate at 10 years didn’t differ that much. The higher the genomic score the more separation. Patients benefit from early or adjuvant radiotherapy the higher the genomic complexity,” said Karnes.
The study concluded, however, that any decision about the timing and the need for additional local therapy after surgery was “nuanced and requires providers and patients to balance risks of morbidity with the improved oncological outcomes.”
While patients at high risk were candidates for clinical trials, adjuvant treatment could safely be avoided by men who are found to have low-risk when assessed by combined clinical and genomic scoring.
“It does improve what we call the “area under the curve.” By using our usual clinical-pathologic parameters, adding genomic information does allow us to prognosticate or rightfully assign therapy better,” Karnes said, noting that the higher the PORTOS the more likely the benefit of incorporating “multi-modal therapy” including post-operative radiation.
Although there were no data yet on overall survival Karnes said there was a balance to be weighed against the risk of adverse side-effects of adjuvant radiotherapy in any individual patient.
But he was optimistic about the future of genomically-guided therapy decision-making in prostate cancer.
“We’re seeing genomics utilized in the entire prostate cancer spectrum from very localized disease to metastatic castration-resistant disease,” he said. “The higher the genomic complexity the more likely the patient is to benefit from early salvage or adjuvant radiotherapy.”
161124 Jeff Karnes AJO PRODUCTION Master
April 15, 2017
Active Surveillance for Renal Cell Cancer
MILAN, Italy—Criteria for withholding aggressive therapies early in the course of renal cell cancer were updated at the 2016 European Multidisciplinary Meeting on Urological Cancers (EMUC) by Phillip M Pierorazio MD, Assistant Professor of Urology and Oncology at Johns Hopkins University, Baltimore MD.
“In clinically localized small masses—four centimeters or smaller—the first-line option is non-surgical management—active surveillance—for many patients,” he said, and he went on to discuss the latest evidence on minimizing the risk of unnecessary treatment emerging from his group’s registry of patients with renal tumors.
While there has been much encouraging news about new treatments for advanced and resistant renal cancer there was need to reassure many patients that they do not need to treat early stages of the disease urgently, Pierorazio said. Most patients could take time to allow teams to gather the clinical data needed to make considered decisions based on risk/benefit assessment.
Many Tumors Not Dangerous
“What we try to impart is that most small renal masses are not dangerous. In fact upwards of 20 to 30 percent are benign. The majority of the cancers are low-grade indolent tumors or not dangerous cancers,” he said.
He recognized that some patients particularly wanted to avoid surgery and—for them—an active surveillance management strategy was viewed as a completely safe option—at least in the short term.
Pierorazio said there were penalties for proceeding with active therapy.
“No kidney surgery is without risk. The kidney is a very vascular organ. It gets a quarter of the body’s blood-flow per minute. So temporarily stopping blood-flow, removing tumors [and] reconstructing kidneys subjects patients to risks that they may not necessarily need.”
During surveillance, however, there were triggers for intervention, he said.
“We image every six months for two years then annually thereafter. Historically the biggest trigger for intervention has been a growth rate of greater than half a centimeter per year. But that’s probably not the right trigger.”
He highlighted, instead, the importance of overall tumor size, pointing out that a marked upswing of risk that a patient will have a serious cancer—from below one percent to the order of two to three percent—typically began at around a diameter of four centimeters. So he regarded monitoring tumor size as a key factor in decision-making.
When he was asked about outcomes following active surveillance as compared with more aggressive approaches he said that in his group’s registry study of patients with early renal cancer only two out of 500 patients died of kidney cancer, both of whom had up-front surgery.
“None of the patients in the active surveillance cohort has developed metastatic disease or died of kidney cancer. 30 per cent of them “progressed”—meaning their tumors grew, but only about 15 percent of them crossed over into intervention,” he said.
Best Candidates for Active Surveillance?
“We know that tumors of less than two centimeters are really indolent,” said Pierorazio. “We do not miss a window of opportunity for treatment or cure if we allow them to grow and keep an eye on them, and most of them will not grow or change.”
Although teams have traditionally regarded older patients who have comorbidities as candidates for active surveillance there was, in fact, another distinct group. “Any patient with a small tumor is certainly eligible for active surveillance,” he said.
“Active surveillance is a safe option for all patients with clinical T1A tumors—four centimeters or less. It really should be our first-line management for patients who are older with co-morbidities, but it can be considered first-line management for any patient with a tumor less than two centimeters.”
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
YOU WERE LOOKING AT CAUSE SPECIFIC MORTALITY IN PATIENTS WITH DCIS, WHAT WERE YOU TRYING TO DO IN THIS STUKDY?
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 COMMIT YOURSELF WHETHER IT’S BETTER TO HAVE KNOWLEDGE OF YOUR DCIS?
No. We cannot conclude that. We need more studies. More prospective studies and also we need to wait for the prospective studies on active surveillance of DCIS because at this moment we don’t have this information.
WHAT IS THE TAKE HOME MESSAGE FOR CANCER CLINICIANS?
Accurately explain the diagnosis of DCIS. Tell the patient what it is. And these women with screen-detected DCIS can be reassured that they have the same life expectancy as other women.
Women With DCIS Live Longer Than General Population
By Peter M Goodwin
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).
“It may sound a bit counter-intuitive—but we found that DCIS patients older than 50 at diagnosis were at lower risk of dying compared to the general population,” said Lotte Elshof, MD PhD Student Associate of the Departments of Surgery, Epidemiology and Molecular Pathology at the Netherlands Cancer Institute in Amsterdam.
“We think it is because these patients are mostly screen-detected so they go to the population-based screening program for breast cancer and are likely to be more health conscious,” she said.
The findings she reported were associated with the on-going randomized, non-inferiority phase III “LORD” trial being conducted in the Netherlands by the BOOG (Borstkanker Onderzoek Groep) team under principal investigator Jelle Wesseling MD PhD, Consultant Breast Pathologist at the Netherlands Cancer Institute in Amsterdam looking at “management of low grade ductal carcinoma in situ: active surveillance or not?” https://www.boogstudycenter.nl/studie/276/lord.html
Elshof explained that they looked at patients being treated for DCIS because it was a potential precursor lesion to invasive breast cancer.
“If [patients] had died we assessed cause-specific mortality [to] see from what cause they had died. And then we compared [their] mortality with mortality in the general population,” she said.
The study found that patients with DCIS had lower risk of dying of all causes combined compared to the general population and “seem to represent a generally healthy subgroup.”
Also, their absolute risk of breast cancer death was low—3.9 percent at 15 years—and the risk of dying from breast cancer among women treated for DCIS alone was only slightly higher than that in the general population.
The suggestion was that “a history of primary DCIS has no negative effect on overall survival.”
The study looked at 9,799 women treated for DCIS in the Netherlands from 1989 to 2004. 1,429 deaths occurred over a median follow-up of 10 years of which 368 were due to cardiovascular disease (4 percent of the total population) and 284 deaths were due to breast cancer (3 percent).
These data revealed an overall risk of dying of all causes that was significantly lower combined compared to the general population.
“There are a lot of uncertainties and anxiety associated with DCIS because many patients think they are diagnosed with breast cancer. Some DCIS lesions will progress into invasive breast cancer and can metastasize and then cause death. So it’s an important to look at the outcomes,” Elshof said.
Breast Cancer-Specific Risk
Although the study confirmed that patients with DCIS were at increased risk of dying from breast cancer they still had a lower risk of dying overall despite this.
“If we look at absolute numbers the risk is very low,” she said. “After ten years 2.5 percent of the women died from breast cancer—but compared to the general population this is only a slightly increased risk.”
Intriguingly the study also found that the risk of dying from breast cancer was independent of the type of treatment patients received.
“We found that no matter what treatment, the risk of mortality was low. 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,” she said.
When she was asked what was the practical message for cancer clinicians she said the study provided accurate estimates of relative and absolute risk which she regarded as important information for the patient.
“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,” she said.
“[DCIS is] 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 find those lesions and the screening program also has a lot of benefits. So it’s not that we say we don’t need to screen but [that] there are always harms against benefits. And some DCIS detection would be beneficial,” said Elshof.
She concluded that doctors could now accurately explain the diagnosis of DCIS, and tell patients what it is and reassure them they have the same life expectancy as other women.
Philip Poortmans MD PhD, President-elect of ECCO and head of the Radiation Oncology Department at Radboud University Medical Center in Nijmegen, in The Netherlands said that although ductal carcinoma in situ should be considered as being clearly different from breast cancer treatments had side-effects.
“This research provides reassurance for women with DCIS because it shows that they are as likely to be alive ten years after the diagnosis as people in the general population who did not have DCIS. This is also reassuring with regards to the potential risks of side-effects,” he said.
“However, we have to recognize that in one fifth of patients who die, the cause is breast cancer—which is likely to result from progression of the DCIS they were diagnosed with. Therefore, we are eagerly waiting results of further research to identify factors—including age, as clearly shown in this study—that contribute to the risk for recurrence and progression from DCIS for each individual patient.”
Poortmans thought it was remarkable that the increased risk of dying from breast cancer was completely offset by a lower risk of dying from other causes compared to women in the general population.
“This might be explained by the generally better health and socioeconomic status of women who regularly participate in breast cancer screening. This could also be tested in the on-going research,” he said.
Elshof INTERVIEW Production MASTER
Nuclear War: The Facts Today8 Feb 2017
Hans Kristensen, Director of the Nuclear Information Project, Federation of American Scientists, Washington DC and co-author of “The Growing Threat of Nuclear War and the Role of the Health Community” (World Medical Journal, 2016) tells Peter Goodwin why we need to take the threat of nuclear war seriously.
NUCLEAR DETERRENCE HAS HELD THE PEACE FOR 70 YEARS—WHAT’S WRONG WITH IT?
“It comes with a terrible risk, obviously, which is that you have to threaten other countries to behave and so through that threat you—literally— have to plan for their destruction and you have to plan for your own destruction as well.
So this is an ironic “peace” to have over so many decades.”
DOES IT WORK?
“Nuclear weapons are very dangerous and very scary. So there is a deterrence effect, absolutely, the question is whether it works always—and [whether] we can count on it—and that’s where people get a little concerned that you can get into very dicey crisis situations. And it’s not a given that nuclear weapons would not be used because they’re scary.”
WHAT ARE THE ARSENALS, WHERE ARE THEY, HOW MANY WEAPONS ARE THERE AND HOW ARE THEY PLANNING TO BE USED?
15 000 Warheads, Nine Countries
“Today there are nine countries that have nuclear weapons. The United States and Russia have the most. China, France, Britain and India and Pakistan, and Israel and North Korea [have the rest]. And all together, if you count everything they have in their nuclear arsenals—the weapons that can be used, plus the ones they’re working on dismantling but nevertheless not quite done—altogether we’re close to 15 000 nuclear weapons.”
THIS MEANS WHAT?
“Try to put 15 000 “X”s on a map. How would you use them? If you just take the portion of them that are in the military arsenals—a little less than 10 000—those are the ones there are plans for. So there are “X”s on the maps where military facilities [are], command and control centers, storage sites, missile silos—you name it—harbors, airfields. There are plans in all these countries for where these weapons would land.”
Real Military Plans
“It’s a real effort. It’s a real strategic intention. It’s not just something that you have in your basement that could be a scary thing.”
IF YOU TARGET A LEGITIMATE MILITARY TARGET, AIRFIELD OR WHATEVER, WHAT ARE THE CONSEQUENCES FOR THE REST OF THAT COUNTRY?
“Depending on the size of the weapons you use they are “bad” or “really bad”! The point being that there’s no such thing as a “clean nuclear attack”. They’re all aimed at destroying facilities. And if you want to destroy a facility you have to obliterate it. And that is done either by:
If it is an underground facility—you dig a giant hole and it’s really dirty because a lot of material is blown up into the atmosphere and falls over great distances.
“You can try more clean attacks, so to speak (even though that’s a bad word) where you explode the weapon more precisely in the air so the pressure wave more precisely destroys the facilities. But in all of these cases it’s dirty business.”
HOW EASY IS IT TO ACHIEVE A MILITARY OBJECTIVE?
“Well generally targeteers (sort of) joke that if the weapon arrives over the target it will be destroyed. The point being that the uncertainty seems to be more in the delivery – that missiles can go wrong. Or there can be atmospheric interference, or what have you.”
“But if the missile manages to deliver the weapon over the great distance, and it survives the re-entry through the atmosphere, and it gets to the point over the target where it has to detonate, and [if] the fuse works, then it will destroy the target.”
“Sometimes they have to layer. Sometimes they have to use two or three nuclear warheads to destroy a target, depending on how “hard” it is. But generally speaking we’re talking about one or two weapons per target.”
SO WHAT WOULD RUSSIA AND AMERICA DO?
“The way they talk about their intentions in a war is [that it is planned to be] very much in phases. That you have a crisis that deepens and turns into a shooting war—a conventional war at first. And it gets hotter and at some point they—for various reasons—decide to “escalate” (people call it)—escalate to nuclear use.”
“That would probably start—at least according to the plan—gradually. That they would begin to signal that: “We are serious about this. We’re using a few weapons here and if you don’t back down we’ll go further.”
“Now the other side may not buy it. They might decide: “Yeah. Well we’re here too. We can do things as well.” And counter attack. That counter attack might be comparable, or they might decide to go much bigger, and then basically settle the battle.”
War à la Carte
“What I’m saying is there are lots of different nuances in the war plans. Some are a few weapons. Some are hundreds of weapons—depending on what you are trying to inflict on the adversary.”
SUPPOSING JUST A FEW WEAPONS ARE USED BETWEEN RUSSIA AND AMERICA. WHAT HAPPENS?
A Few Small Nukes?
“Well if a few weapons are used they would most likely be used in (sort-of) periphery scenarios—in a region, for example, where the forces are battling each other. Then they would use a “nuke” against the other side in an airfield or battle group or whatever it might be.”
“And so the impact of that is: If it’s on the ground you would have radioactive fallout wherever that weapon is used. And we’ve done some simulations where you could see how that fallout would drift over Europe if just six weapons were used—a very small attack.”
Chernobyl on Steroids
“If they escalate to bigger use you’re talking about broad sweeps of countries and continents that would be contaminated with radioactive fallout.”
SUPPOSING A MORE LIMITED WAR TOOK PLACE: CHINA, INDIA, PAKISTAN OR KOREA — WITH RELATIVELY FEW WEAPONS. WHAT WOULD HAPPEN IN A LIMITED WAR?
The Big Two
“Different nuclear weapon states think differently about potential use. They come from a different place, so to speak. The United States and Russia are engaged in a many decade long Cold War. And where nuclear planning went insane, it was at all levels. So Nuclear War fighting was very central to their thinking about it.”
Other countries didn’t go so far. China, certainly, has had a much more relaxed nuclear posture. It hasn’t really entertained the thought of nuclear war fighting. It thinks about the role of its nuclear weapon more in (sort of): “We have a big hammer and if you do something that’s really bad we’re going to hit you with it.”
“That’s not to say that China is going to stay like that for ever. They may be influenced to update or modify their nuclear thinking as well. But there is a clear difference so far in the way small nuclear weapons states think about potential use.”
“India and Pakistan are particularly dicey because the two countries are in a very long-term border dispute and again-and-again get into these border fights that could go bad and escalate.”
“And we’ve just had one just a few months ago, again where they were shooting at each other with conventional weapons and leaders on both sides starting to refer to nuclear weapons. [This is] a sort of reminder. “We have this if you go further and do something bad.”
So people are worried that if something could turn into a nuclear use it could very well start in the Pakistan Indian scenario.
HOW MIGHT COUNTRIES LIKE FRANCE AND THE UNITED KINGDOM BE PLANNING TO USE THEIR WEAPONS?
“Well France and Britain are (sort of) in the shadow of the United States—to some extent—within NATO. Both countries, of course, insist that they have there own independent deterrent, but their thinking about it is very much in the context of US-Russia, East-West scenarios.”
“Britain in particular, of course, is very coordinated with the United States in terms of how it thinks of using its nuclear weapons. France is a little more independent, and are thinking about an all-around—360 degrees so to speak (as they talk about it)—“deterrence thinking”—it could be anywhere, so to speak. So they’re a little more open-minded geographically about where potentially it could be used.”
Threaten First Use
“But neither Britain nor France are very happy about (sort-of) “rattling the nuclear sword”. They’re more—you could say—traditional about holding it in reserve in the very far background.”
DO HOW DANGEROUS IS ALL OF THIS, IN YOUR VIEW?
Safer, but not safe
“It depends on what you compare with, of course. Because if you compare with the Cold War where East and West literally held a gun to each other’s head—and things [were ready] to blow any minute—we lived thirty minutes from annihilation every day. That was the reality in those days.”
“And the stakes were enormous, and people were willing to go far because of those stakes.”
“We’re not in such a situation today, even though there are still risks. The risk today is more that you could have nuclear use coming out of an accident or a misinterpreted crisis escalation where the two sides read each other wrong, or something like that.”
“Or you could have smaller nuclear powers like India and Pakistan that get into a shooting war that escalates to nuclear that then draws in bigger nuclear powers because they want to back the side of their potential ally.”
Creepy Nuclear War
“So you can have those sorts of creepy escalation scenarios.”
Terrorist, Rogue State
“And the last one, of course, is (sort-of) the wild card—a crazy scenario, involving North Korea, for example—where the leadership somehow decides that all is lost and we’ll just have to use a nuclear weapon against something, or even sell a nuclear weapon to a terrorist group or something like that.”
DO YOU THINK THEN THAT NUCLEAR WEAPONS ARE MAKING THE WORLD A MORE STABLE, BALANCED PLACE – LESS LIKELY TO BE DANGEROUS IN THE FUTURE? OR OTHERWISE?
Fight Fire with Fire?
“That’s a really tough call—because it is [just] because of nuclear weapons threatening us that we feel afraid and have to spend out resources on maintaining our nuclear weapons and threatening others. That cycle seems to be alive and well, unfortunately.”
“But if you’re thinking about World War Two types of scenarios—where big powers suddenly go at each other and they battle with conventional forces for years and years—that type of scenario is much harder to imagine and we haven’t—thank God— had one for a long time now—70 some years.”
Do Bombs Preserve Peace?
“There are people who will argue that it is because of nuclear weapons that we haven’t had those big wars. But, mind you, we’ve had plenty of small wars and we’ve also had plenty of proxy wars where nuclear powers were directly involved and proxy powers were battling each other.”
Proxy Mid-East War
“We have a situation in Syria right now where several nuclear powers are in direct military contact with each other.”
Russia v. America?
“Russian forces are there. US forces are there. They’re not there with nuclear weapons but they’re there militarily and you can imagine an escalation of such a conflict that gets both countries at each others’ throats directly and escalates from there—broadens from there.”
MANY PEOPLE ARE PASSIONATE ABOUT THEIR ATTITUDES TO NUCLEAR WEAPONS BUT– SOMETIMES IN COMPLETELY OPPOSITE DIRECTIONS. HOW DO YOU RECONCILE THE DIVERGENCE OF VIEWS?
“It’s one of the biggest puzzles about nuclear weapons. Because they’re so scary—because they’re so frightening—they lead to two fundamentally opposing solutions. One is that, [as] some people say: “They’re terrible and we need to get rid of them all.” The other is: “They’re so terrible, therefore we need them!”
“So from the same fear comes two fundamentally different solutions. One is you live with it. And the other is you try to get rid of it! “
“It depends who you talk to. Some countries say they’re very basic and fundamental to their security—global peace and stability. There are other countries—most countries—that are really opposed to them. They would like to see them just go away.”
Ban the Bomb?
“So we’re having right now a very interesting dilemma along those lines in the United Nations, where a vast majority of countries have voted a resolution that says we need to have a treaty that bans nuclear weapons, and we need to begin to negotiate the content of that treaty and: “How are we going to do it?”
“Nuclear weapons states don’t want to be part of that. They see nuclear weapons have a role. And many of the nuclear weapons states allies don’t want to be part of it. They say we still need to rely on nuclear weapons.”
COULD INDIVIDUAL COUNTRIES DECIDE TO GIVE UP THEIR NUCLEAR WEAPONS ONE BY ONE?
“Under the current circumstances I don’t think so. There was a window after the end of the Cold War where countries such as Britain were—[although] not officially planning to get rid of it— were taking steps where they were seriously appearing to go in that direction.”
“They had a real tough political debate about whether they should extend their ballistic missile submarine force and build a replacement for it. They’ve now decided to do that.”
“There was a period there when it seemed potentially likely that had improvements in East-West relations between NATO and Russia continued you might have had a situation where Britain would have been willing to be the first one to give up nuclear weapons.”
“I don’t think that’s going to happen now. Europe is certainly in a very different place—not just in nuclear issues but in general stability issues and security people are beginning to see more fear in the overall—not only military but also political—development. And that it’s not as stable and predictable as they might have thought.”
AS AN EXPERT WHO’S LOOKED AT THIS IN DEPTH WHAT ARE YOUR RECOMMENDATIONS FOR AVOIDING CATASTROPHE IN THE FUTURE?
“The tasks at hand are certainly two-fold. One is to reduce the arsenals in a responsible way. We are still way beyond what is reasonably needed for basic deterrence.”
Ninety Three Percent
“You can see the United States and Russia are completely “out of whack” with the rest of the countries in the world that have nuclear weapons. There’s no other nation that believes you need to have more than a couple of hundred weapons for a nuclear deterrent yet these two countries alone have 93 per cent of the world’s arsenals.”
“So these two countries have, foremost, a responsibility to freeze their arsenals and reduce them—continue to reduce them drastically.”
“Once you go down that path, that raises some other new questions you have to think about. The dynamic, then, between the countries that are left will be different, because they have similar arsenals, similar sizes. And so there might be a new dynamic that you have to think carefully about.”
“So there’s something about reducing arsenals in and of itself that can contribute to the right direction, I think, but the other one is to reduce the way you operate and posture those forces so you reduce the likelihood that they can come into use.”
“And that involves, for example, eliminating pathways to accidental launch—the technical “glitches” or misinterpretations of—or radar signals and what have you—that can lead to launch of nuclear weapons because of an accident or mistake.”
“You also want to think about how to reduce the alert level of nuclear weapons so that nuclear weapons are not as threatening on a day-to-day basis. We don’t foresee nuclear weapons being used any time so you might want to ask: ”So why do we want to be able to launch nuclear weapons at a short moment’s notice?”
“On all of these levels there are things you can do to reduce nuclear dangers.”
WHAT WOULD YOU RECOMMEND ABOUT WHAT PEOPLE SHOULD BE DONING AND BE THINKING ABOUT RIGHT NOW?
“They should definitely be thinking about how to continue reductions both in numbers and also the role of nuclear weapons. But foremost: Don’t get caught up in this temptation that we see right now to respond to East-West crisis in sort of a “Cold War” fashion.”
Dangerous Cycle of Threats
“There is a worrisome degree of willingness among some people both in Russia and also in NATO countries to, sort of, say: “We now have a crisis. Therefore we need to do the appropriate things. Therefore we need to posture more offensively …….”
“That is an enormously dangerous cycle to get into, and it’s really hard to get out of.”Hans Kristensen INTERVIEW edited
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.)
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.
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.
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 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 briefing on the KEYNOTE-024 study at ESMO noted this was the first time that an immune-oncology strategy had been demonstrated in the first-line setting. “Until now we’ve seen a lot in second and third line or further lines of therapy,” said.
ESMO officer Solange Peters, MD PhD, Médecin Cheffe of Thoracic Malignancies, at the Centre Hospitalier Universitaire Vaudois (CHUV) at Lausanne University in Switzerland told OT the KEYNOTE-024 study had demonstrated that even though chemotherapy was already quite good this form of immunotherapy had made a further improvement.
“It’s an amazing set of data because for the first time our classical standard of care—platinum-based chemotherapy—is questioned. It was very improbable until now that new combinations or new agents would dramatically change the course of the disease by replacing platinum-based chemotherapy,” she said.
The KEYNOTE-024 study authors concluded that pembrolizumab had superior PFS and OS over platinum-based chemotherapy in patients with advanced NSCLC and PD-L1 expression (TPS) of at least 50 per cent, and that these findings—together with the lower rate of treatment-related AEs—implied that the drug may be the new standard of care for first-line therapy for this group of patients.
Reck said there was a clear message for clinicians. “Management of first-line therapy of patients with advanced non-small cell lung cancer has changed. We have to add the assessment of PD-L1 in our first-line diagnosis. We have a new group of patients identified that has a substantial benefit by a mono-therapy by an anti-immune treatment—the patients with high PD-L1 expression. We have to identify the patients up-front because we have to treat them up-front.”
161209 Audio Journal of Oncology RECK PRODUCTION MASTER
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
“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.
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 optimistic. “Having many treatment options is much better than to have only one treatment option,” he said, adding that ceritinib was now the preferred option for patients who had already been exposed to crizotinib.
While ceritinib was the only second generation ALK inhibitor so far licensed in Switzerland, giving it an advantage there for treating patients who had failed crizotinib, there were some outstanding issues, said Stefan Zimmerman—including gastrointestinal toxicity—which distinguished ceritinib from other second generation ALK inhibitors such as alectinib.
“This data has to be put in the context of the ALEX trial (http://meetinglibrary.asco.org/content/167434-176) which is going to change what we’ve seen from the data at ASCO [about] the way we treat these ALK-rearranged patients—meaning that we’ll most certainly be starting with second generation inhibitors up front in the hope that at least we can overcome this extremely high rate of cerebral progression which is a major issue with crizotinib and one of the major reasons why we do not like to use it and we—absolutely—are desperate for better agents,” he told the AJO.
Solange Peters said the ASCEND 5 study had successfully answered an important question. “Once you have given crizotinib and platinum-based chemotherapy what should you do? Should you go to the usual docetaxel or second-line chemotherapy or should you switch to a targeted therapy? And the answer is very clear. Targeted therapies are better than chemotherapy—very clear,” she said.
Also commenting on the ASCEND 5 findings, Alice Tsang Shaw, MD, PhD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center in Boston, MA, welcomed this first randomized study to examine how a second generation ALK inhibitor compared to standard second line chemotherapy in ALK positive patients who failed the standard first line therapy.
“Single arm studies have suggested that ceritinib and alectinib could be standard options in the second line setting after crizotinib has failed,” said Shaw. “The positive effect on progression-free survival in this phase 3 study confirms that there is greater benefit using a second ALK inhibitor over standard chemotherapy. This will establish sequential crizotinib followed by a second generation ALK inhibitor as the standard treatment for patients with metastatic ALK positive lung cancer.”
She added that they were all awaiting the outcome of studies testing the second generation ALK inhibitors ceritinib (versus chemotherapy) and alectinib (versus crizotinib) in the first-line setting. “The latter trial addresses one of the most fundamental questions in the field, which is what should be the first ALK inhibitor that patients receive?”
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 were no deaths related to atezolizumab and one death was related to docetaxel.
“Atezolizumab offers a new second-line therapeutic strategy for patients with non-small-cell lung cancer, regardless of the PD-L1 status of the tumor,” Barlesi said.
Martin Reck MD PhD, from the Department of Thoracic Oncology at Lung Clinic Grosshansdorf in Germany, commented that the OAK study had provided “a very important piece of information” on the role of PD-L1/PD-1 antibodies in treatment of NSCLC and that it confirmed the overall survival benefits shown in the earlier POPLAR and CHECKMATE trials.
But he said the results show that it would not be possible to use PD-L1 testing negativity as an exclusion factor for treatment since the drug benefited all subgroups.
“My suggestion would be that PD-L1 is perhaps one imperfect surrogate marker to describe the activity. It’s a good “enrichment” factor but we need additional markers for the characterization of patients who might not benefit from this treatment or who might really benefit.”
Stefan Zimmermann MD from Hôpital Fribourgeois, HFR Hôpital Cantonal, Fribourg, Switzerland, who chaired a briefing on the OAK findings at ESMO told the Audio Journal the new data on atezolizumab needed to be viewed in the context of other studies with other checkpoint inhibitors.
“It reinforces the message that in second and further lines of therapy there is benefit even in patients who have low or no expression of PD-L1,” he said, and his interpretation of the data was that “you don’t need an assay”, since most—if not all—subgroups benefit from an immune-oncology approach rather than standard chemotherapy.
“I can imagine that atezolizumab will get regulatory approval so we’ll now have a wealth of choices in second and further lines. We [already] have nivolumab that has regulatory approval, we have pembrolizumab in second line for PD-L1-espressing patients and we might [soon] have atezolizumab,” he said.
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