#LCSM Chat Topic 6/15: Patient Reported Outcomes (PROs)—more effective than some approved cancer drugs for advanced disease
With the proliferation of smartphones and personal tracking devices (such as Fitbits), technology has the means for cancer patients to provide feedback to their healthcare providers about their symptoms and side effects of treatment. Such feedback is called “patient reported outcomes,” or PROs. However, PROs are difficult to measure in a consistent manner, and thus far have not been incorporated into many cancer center clinics or clinical trials.
But times are changing. One of the big news items to come out of the huge American Society of Clinical Oncology (ASCO) Annual Meeting this month was a study of a web-based system that enabled cancer patients to self-report their symptoms. In this study, patients who used the tool reported weekly on 12 common symptoms experienced during chemotherapy (among them appetite loss, difficulty breathing, fatigue, hot flashes, nausea, and pain), and graded them on a five-point scale. This web-based tool actually helped patients live longer. The increased survival benefit (five months) was better than the survival benefits offered by many new cancer drugs submitted to the FDA for approval.
Patient reported outcomes as quality measures are of interest to major cancer organizations. The US Food and Drug Administration had issued guidance for industry regarding patient-reported outcome measures, and the National Cancer Institute has developed a standardized measurement system for patient reported outcomes. ASCO has a PRO committee that is developing and testing PRO measures.
On June 15 at 8 pm Eastern Daylight Time (5 pm Pacific), #LCSM Chat will discuss patient reported outcomes and how they might help improve treatment outcomes as well as clinical trials. Moderator Janet Freeman-Daily @JFreemanDaily will lead our chat using the following topic questions:
- T1: What patient-reported outcome measures would be most valuable to patients during treatment?
- T2: What technologies would be most effective for communicating and capturing patient reported outcomes in cancer?
- T3: What patient-reported outcomes would be meaningful to patients when evaluating treatment options and related quality of life?
- T4: How can we make patient-reported outcomes measurable–how to measure level of nausea? Neuropathy? Breathing difficulty?
- T5: What patient-reported outcomes be valuable in studies of cancer care and survivorship?
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- Web-Based System for Self-Reporting Symptoms Helps Patients Live Longer (ASCO 2017 abstract)
- Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (US Food and Drug Administration)
- Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) (National Cancer Institute)
- The Rise of Patient-Reported Outcomes in Oncology (ASCO)
- Implementing Patient-Reported Outcome Measures (Partners HealthCare)
For our chat on 5/18/17, starting at 8 PM Eastern, 5 PM Pacific, we’ll cover several key trial results and the potential implications of them. While each has the potential to be practice changing, all three have the primary endpoint of progression-free survival (PFS) but, to our knowledge, don’t necessarily improve overall survival (OS). It is interesting that the differences between the settings and trial designs have led many lung cancer experts to favor adoption of some of these results but not necessarily others. But what do patients and caregivers think of PFS, and does it matter whether there is a cost of worse side effects and loss of subsequent treatment options?
The first trial we’ll consider is one we’re likely to hear more about in a few weeks, at the ASCO annual conference in Chicago. Known as the ALEX trial, it is a global randomized trial of ALK-positive patients who hadn’t received a prior ALK inhibitor and received either first line crizotinib, as a current standard of care, or alectinib, a second generation ALK inhibitor currently approved for patients who have progressed on prior crizotinib. We know from a press release about the ALEX trial that the trial is positive for a significant PFS benefit, but pursuing this approach will likely effectively remove a treatment option from the sequence of options over time. Specifically, if the PFS with crizotinib (Xalkori) is about 9 months, and we get another 9 months from alectinib (Alecensa) as a second line treatment after crizotinib, what happens if we get a PFS of 17 months with alectinib after moving it to first line, assuming we get little or no benefit from crizotinib if we bypass it and try to come back to it (unproven, but very likely)? How much does the relative tolerability of the two treatments matter? Importantly, alectinib and other second generation ALK inhibitors also protect against brain metastases far more effectively than crizotinib, so should that lead us to lean more toward using it over crizotinib? And how valuable is it to know you’ve got another very good treatment to switch to once your first line treatment stops working well?
Another critical study that has proven to have major implications is KEYNOTE-021g, a randomized phase II trial of standard chemo with carboplatin/pemetrexed (Alimta) with or without the immunotherapy pembrolizumab (Keytruda) – half receiving chemotherapy alone, and half receiving chemo/immunotherapy concurrently. There was no restriction by expression of PD-L1, and the study showed a higher rate of tumor shrinkage and longer PFS with chemo/immunotherapy together, but the early data showed no improvement in OS. Despite these limitations, the US FDA just approved the combination of chemotherapy with pembrolizumab for first line treatment of patients with non-squamous non-small cell lung cancer (NSCLC), with no need for PD-L1 testing. While this sounds like a significant victory, many lung cancer specialists think this was a poor decision by the FDA: the study was very small, with larger and more definitive studies coming very soon, and many are concerned about the approval of an extremely expensive combination that hasn’t been shown to improve OS significantly. With immunotherapy already approved as second line treatment for the vast majority of advanced NSCLC patients who don’t have high level PD-L1 expression that would lead to it being used first line, we’re left asking whether there’s a value in combining multiple treatments up front rather than spreading them over time, especially if this combination leads to combined side effects? How valuable is it to avoid chemotherapy in patients who could potentially do just as well without chemotherapy? Is it helpful to have a better idea of which agent(s) are leading to tumor shrinkage and which are less active (or non-active) bystanders, especially if some of the very high cost of a combination of maintenance chemotherapy and immunotherapy gets passed to the patient?
The final study we’ll consider, called PACIFIC, randomized patients with stage 3, locally advanced NSCLC to receive either immunotherapy with durvalamab (Infinzi) or placebo (2:1 toward immunotherapy) for 12 months after completing the concurrent chemo/radiation that is the current best standard of care for patients. We expect to cure about 20-25% of patients with stage 3 NSCLC who receive chemo/radiation, so the real goal is to improve true cures of patients. This trial, however, also focused on PFS as the primary endpoint and is positive for a significant PFS benefit, as reported after a scheduled interim analysis of the data, though we have yet to learn about whether this will translate into more cures and a significantly higher OS rate in recipients of immunotherapy. While a positive trial like this is extremely welcome news in a setting where real advances have been very slow in coming, does a year of immunotherapy in patients who may otherwise already be cured require there to be a significant improvement in the cure rate before it should be adopted? Does the cost of immunotherapy require there to be a survival benefit?
We’ll therefore consider the various pros and cons of focusing on PFS as an endpoint and whether that should be enough to change our practices. In some settings, PFS may merely be an early proxy signal for a later survival benefit, but that isn’t necessarily the case.
Our moderator @JackWestMD (Dr. Jack West) will lead our discussion of the following questions:
- T1 How does Progression Free Survival (PFS) differ from Overall Survival (OS) for measuring drug effectiveness in a clinical trial?
- T2 If 2 approved targeted therapies have same OS, how do you choose best treatment? Do fewer side effects and treating brain mets count?
- T3 Is it better to use targeted therapy with longest PFS first, or use it later in hopes of getting longer total PFS?
- T4 If patient is eligible for 2+ therapies, how do patient & doctor prioritize OS/PFS/side effect/cost info to choose Rx?
- T5 Should patients take chemo-immunotherapy combination up front in hopes of longer PFS, even if some patients will be overtreated?
- T6 If drug cost >$10K/mo, should FDA set stricter approval requirements, such as OS >6 mo compared to existing approved drug?
- T7 Should FDA expedite approval to improve patient access for drug if OS is no better than other approved drugs for that disease?
- T8 For cancer stages in which cure is possible, is improved PFS enough to change standard of care, or should we expect better OS/cure?
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