GRACE :: Lung Cancer

Expert Round Table with Drs. Hensing & Jackman: Molecular Markers & Sequence of Therapy for Stage IV Lung Adenocarcinoma

Dr West — Tue, 31 Aug 2010 02:12:02 +0000

The second part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a case of a relatively young, generally healthy woman diagnosed with a lung adenocarcinoma that turned out to be stage IV.

Here, we discuss our priorities for molecular testing and how the results of EGFR, KRAS, and EML4-ALK testing would alter our clinical recommendations. We then discuss the options for this patient, with special focus on how long to continue first line therapy and when and how to transition off of first line treatment into either observation or maintenance therapy.

Here’s the audio and video podcasts of the discussion, along with the transcript and figures.

drs-hensing-and-jackman-molec-testing-sequence-of-rx-case-2-audio-podcast

drs-hensing-and-jackman-molec-testing-sequence-of-rx-case-2-transcript

drs-hensing-and-jackman-molec-testing-sequence-of-rx-case-2-figures

This program was sponsored by OSI Pharmaceuticals, who had no input in its content. We appreciate their support in making this activity possible.

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Can An Early PET Scan Predict Response to Tarceva?

Dr West — Fri, 27 Aug 2010 04:48:27 +0000

Over three and a half years ago, I wrote a post about about early work looking at the possibility that a PET scan done anywhere from three days to a month out from the start of a new systemic therapy (chemo or EGFR inhibitor) for advanced NSCLC could be predictive of a good outcome or not. Despite the increasing use of PET scans not only for staging but also for follow-up to assess response in patients with NSCLC, there hasn’t been a lot of new information since then. However, a study presented at ASCO 2010, coming from several Australian hospitals in collaboration with a couple in southern California, compared PET scans done after two weeks and then two months of Tarceva (erlotinib) therapy with the more established standard measure of response assessment, CT scans after two months of therapy.

The study enrolled 74 patients with advanced NSCLC who had not received Tarceva in the preceding 14 days and hadn’t previously received an EGFR inhibitor. This population was pretty typical for a non-Asian lun cancer population, with only about 10% never-smokers, 58% male. They all received three baseline scans in the 14 days leading up to starting Tarceva: a standard chest CT, an [18]- fluorodeoxyglucose (FDG)-PET scan that measures cellular metabolism (see this post or this podcast for general review of metabolic imaging with PET), and a newer and less commonly available form of PET scan with a different tracer called [18]-fluorodeoxythymidine [FLT] that measures cell proliferation. Then, in addition to standard CT assessments 56 days later (a “cycle” of Tarceva on a study is typically 28 days, so 56 days would be the usual interval for a follow up assessment after two cycles), the enrolled patients were supposed to undergo a repeat FDG-PET and FLT-PET at both 14 and 56 days into treatment:

(click on image to enlarge)

Of the 74 enrolled, 51 completed all of their scans as planned and were eligible to be analyzed. The study compared response rates as assessed by these methods and how well these modalities predicted progression-free survival (PFS) and overal survival (OS), including reviewing how they did in different clinical groups by molecular factors like EGFR and KRAS mutation status.

While the criteria for response assessment by CT are pretty well established and based on measurements of the diameters of target lesions being followed (see this summary of the RECIST criteria), there aren’t as well established for PET scans. In this study, the investigators defined a PET response as a 15% or greater reduction in the maximum standard uptake value (SUV), the pivotal measurement of PET imaging, in up to five identified target areas on PET.

Below is the “waterfall plot” of responses as measured by a standard FDG-PET at 14 days, with the downward bars showing reduction of PET uptake, and the upward bars noting increasing PET uptake indicative of progression. Below the bars, and definitely only visible if you click to see the expanded version, are codes for the CT-defined response later seen at day 56, patient sex, tumor histology, and various molecular markers they collected:

In the trial as a whole, only 4 of the 51 patients (8%) had a CT response, but 13 (26%) had a response as measured by an FDG-PET at 14 days. FLT-PET showed similar trends, though the response rates were a little lower. Progression numbers were pretty similar with all three imaging techniques.

It’s also interesting to note that PET responses were seen not only in three of the four patients with an EGFR mutation, but in several who didn’t have an EGFR mutation, and some degree of decreased PET uptake was seen in some patients with a KRAS mutation. This strongly suggests that patients with a KRAS mutation may still benefit from an EGFR mutation, as some limited other evidence has also suggested.

The authors also found that day 14 FDG-PET scan results predicted both PFS and OS, and that the FLT-PET didn’t do a better job. Here’s the curves for these endpoints, with groups separated by whether they demonstrated a an FDG-PET response at 14 days:

Overall, this work suggests that PET scans within just a few weeks after starting Taceva can do a pretty good job discriminating who’s likely to benefit. While there’s little mystery about the minority of patients with an EGFR mutation who have a dramatic improvement within days and will show a response by just about any measure, this study is most interesting in demonstrating that there are subtle hints of who is showing some degree of benefit or not in the much larger population of patients who don’t have an EGFR mutation and may even have a KRAS mutation. It also underscores that you don’t need to have an EGFR mutation to actually derive benefit from Tarceva.

One big question, though, is whether a 14 day assessment would actually lead people to change what they’re doing. If you see a response or stable disease, that’s reassuring, but it’s not clear to me that someone who is showing increasing PET uptake two weeks into Tarceva will then decide to stop it and either move on to something else or abandon treatment. We generally follow the edict that a test is only worth obtaining if you’ll use the information to change what you do. But if an early PET leads some people to continue it when they might otherwise drop it if they don’t feel clearly better, or to stop it if the scan is moving in the wrong direction, then it may be a worthwhile approach to pursue.

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Introduction to Locally Advanced, Unresectable Stage III NSCLC

Dr. Pinder — Sun, 22 Aug 2010 20:11:21 +0000

When I was a medical student, the question about lung cancer that was always asked on “the Boards” had to do with the difference between stage IIIA and stage IIIB non-small cell lung cancer (NSCLC). The reason this question was always asked is because patients with stage IIIA NSCLC might be considered for surgery, whereas patients with stage IIIB NSCLC would not be considered for surgery and instead would be treated with chemotherapy and radiation. The idea is that young doctors should be able to make that distinction and to direct patients to the appropriate specialist/treatment. While I guess it makes a good test question, this distinction is too simplistic and doesn’t really give anyone a good understanding of the complexities of managing stage III lung cancer. And, in reality, all patients with suspected stage III lung cancer should be evaluated by a multidisciplinary team that includes thoracic surgeons, radiation oncologists, pulmonologists and medical oncologists. If the Medical Board would write a test question aimed at getting across this important principle, I’d breathe a big sigh of relief for lung cancer patients.

First, what makes a lung cancer stage III (as opposed to I, II or IV)? Let’s start with a lesson in anatomy and staging. The staging of lung cancer is determined by the size and invasiveness of the primary tumor (T), the location of any lymph nodes involved (N) and whether there is any evidence of metastasis to other organs, including the lining of the lung (pleura) or the opposite lung (M). The hilum is the highway into the lung - it contains the airways and blood vessels that enter the lung and branch off into the various lobes and segments of the lung. The trachea (windpipe) branches off into the right and left mainstem bronchi and these enter each lung through the hilum. The blood vessels that supply the lung also enter at the hilum, as do the lymphatic channels. Lymph nodes at the hilum can be involved with a lung cancer. These are considered N1 nodes, and most cases of lung cancer with just N1 involvement are stage II.

Most commonly, patients are classified as stage III because of involvement of lymph nodes in the mediastinum (a space in the middle of the chest between the two lungs). If the involved mediastinal lymph nodes are on the same side of the chest as the lung tumor (ipsilateral nodes), this is classified as N2 and is considered stage IIIA disease. If the involved lymph nodes are on the opposite side of the mediastinum (contralateral nodes), these are considered N3 nodes, and the cancer is stage IIIB. If a patient has involvement of supraclavicular lymph nodes (just above the collar bone, or clavicle) on either side, these are considered N3 lymph nodes, and the stage is likewise IIIB.

The assignment of lymph nodes to N1, N2 or N3 based on location is not arbitrary: the prognosis changes depending on the site of lymph node involvement. In general, lung cancers with the best prognosis are N0 (no lymph node involvement). As we go from N1 to N3, the risk of recurrence of the cancer increases. A patient may also be classified as having stage III lung cancer even if no lymph nodes are involved, if the tumor invades another organ in the chest such as the heart, large blood vessels, esophagus or bones of the spine (T4).

(click on image to enlarge)

There are a variety of ways to establish the diagnosis of locally advanced NSCLC. Most patients with lung cancer have a CT of the chest and we may see enlarged lymph nodes on the CT. Alternatively, lymph nodes in the chest may not be particularly enlarged but may light up on a PET scan. Although abnormal lymph nodes on PET are suspicious, other processes such as infection or inflammation can cause lymph nodes to light up on a scan and most experts recommend that suspicious mediastinal lymph nodes on PET get biopsied to confirm that the patient has stage III disease. This is usually accomplished through a mediastinoscopy, EBUS or EUS.

So let’s say that a mediastinoscopy is performed for PET-positive lymph nodes in the mediastinum, and multiple lymph nodes come back with cancer in them. This patient has stage IIIA NSCLC. Most lung cancer experts would recommend radiation and chemotherapy given at the same time (concurrent therapy) for a patient with multiple mediastinal lymph nodes involved. Why? Patients with stage III NSCLC have a high risk of recurrence, both locally in the chest and at distant sites, such as bone, liver, etc. Although radiation can address the tumor in the chest, it cannot kill off micrometastases that are already floating around.

Several clinical trials have examined whether chemotherapy improves survival when added to radiotherapy for stage III NSCLC - the answer is yes! So why not do chemotherapy and radiation sequentially rather than concurrently? Again, the answer comes from clinical trials: giving therapy concurrently results in better outcomes for patients. Chemotherapy acts as a radiosensitizer so in addition to its potential benefit in reducing metastases at distant sites, it also helps radiation to work better. The downside of concurrent therapy is that it is definitely more toxic than giving chemo and radiation sequentially, particularly with respect to inflammation of the esophagus (esophagitis), which is associated with difficulty swallowing.

If you are uncertain about which chemotherapy regimen should be given with radiation for stage III NSCLC, you are not alone. Why not just give the same drugs we use in stage IV NSCLC with radiation? First, chemotherapy drugs differ in how much they sensitize cancer cells (and normal tissues) to radiation. Some drugs, like cisplatin and etoposide, can be given at full doses and provide the right amount of radiosensitization. Taxol (paclitaxel) and Taxotere (docetaxel) can be given with radiation, but the doses must be reduced substantially, to a level that would not be considered as effective at fighting micrometastases as full doses. Gemcitabine is an incredibly potent radiosensitizer and is not considered safe in combination with radiation for lung cancer.

The most commonly used regimens are cisplatin and etoposide at full dose, or carboplatin and Taxol given weekly at low doses with radiation. These two regimens have never been compared head to head, but if we look at different studies that have used the two regimens, we see that the studies which used cisplatin typically have longer median survival (approaching the two year mark) compared to the studies that used weekly carbo/taxol. Toxicity is typically greater with full dose cisplatin compared to low-dose carboplatin, and so a patient who is weaker or has significant medical problems (such as kidney dysfunction) may not tolerate a full-dose cisplatin combination. There are certainly many oncologists who favor carbo/taxol weekly with concurrent radiation, but many experts favor cisplatin-based chemo for the subset of stage III NSCLC patients who can tolerate it.

A recent trial reported results incorporating not one but two newer drugs with radiotherapy. CALGB 30407 was a randomized phase II trial looking at two new combinations: carboplatin and Alimta (pemetrexed) plus radiation, with or without the EGFR monoclonal antibody Erbitux (cetuximab). The goal was not to compare these two regimens (the numbers are too small in a randomized phase II study to draw firm comparisons), but rather to explore promising combinations. Both regimens showed a median survival of about 22 months, which compares favorably with historic controls. It is important to note that this trial included patients with squamous cell cancers, a group who we now know does NOT appear to benefit from Alimta. Currently, a randomized phase III study comparing cisplatin/Alimta/radiation to the old standard cisplatin/etoposide/radiation is underway - only patients with non-squamous cancers are being included.

Another area of significant controversy involves what to do after completion of radiation. Patients who have had surgery for NSCLC typically get 4 cycles of chemotherapy as adjuvant treatment. Patients with stage IV NSCLC are typically given 4-6 cycles of a platinum-based combination. We have good data for giving chemotherapy with radiation in stage III disease (typically two cycles are given with radiation) but we are always tempted by the prospect that more is better. Unfortunately, available studies do not support the role of “consolidation” chemotherapy or targeted therapy after completion of concurrent chemoradiation. The Hoosier Oncology Group (HOG) trial randomized patients to either observation or 3 cycles of Taxotere after patients had completed standard cisplatin and etoposide (2 cycles) with radiation. The patients who got Taxotere did not live longer, and they had more treatment-related complications compared to the patients who were observed.

Many made the argument that perhaps Taxotere was just too toxic and that a less toxic consolidation therapy such as one of the oral epidermal groth factor receptor EGFR) inhibitors, Iressa (gefitinib)or Tarceva (erlotinib), would let the glory of consolidation therapy shine through. Unfortunately, we were wrong again.

SWOG S0023 randomized patients with stage III NSCLC to either Iressa or placebo following a challenging regimen of cisplatin/etoposide/radiation, followed by consolidation Taxotere. The trial unexpectedly showed that survival was significantly worse for patients who received Iressa compared to placebo.

Even more surprising was the finding that excess deaths in the Iressa arm were not due to toxicity but rather apparently to lung cancer progression.

A more recent trial comparing placebo to Tarceva after concurrent chemoradiotherapy was more encouraging, with a trend towards improved survival for patients who received consolidation Tarceva.

This difference did not reach statistical significance, and I would say that most lung cancer researchers are not advocating Tarceva after chemoradiation at this time.

Am I forgetting something? Oh, yes - the radiation component. Although medical oncologists would like to take all of the credit for the gradual gains we have made in survival for patients with locally advanced NSCLC, we must acknowledge that tremendous improvement in radiation techniques has occurred over the last 30 years. Most of the trials that established the benefit of concurrent chemoradiation delivered radiation doses of around 60 Gy. With better techniques that can mitigate damage to normal tissues, radiation oncologists are looking to push the envelope by escalating the dose of radiation. A large, multicenter clinical trial is hoping to answer the question of whether higher doses of radiotherapy result in improved outcomes by comparing 60 Gy to 74 Gy concurrent with chemotherapy.

One final issue bears mentioning: relapse in the brain is common for patients with locally advanced NSCLC, occurring in up to 30% of patients. In up to 20%, the brain may be the only site of relapse. Chemotherapy is generally felt to do a poor job of penetrating the blood-brain barrier, so even our most effective regimens are not going to kill off micrometastases in the brain. In small cell lung cancer (SCLC), prophylactic brain radiation for limited stage patients, and more recently even patients with extensive SCLC has been shown to lower rates of brain relapse and improve survival. We sought to answer the question of whether this would hold true for NSCLC but unfortunately the clinical trial aimed at answering this question was closed early because of low accrual. Although brain metastases were reduced in the group who got brain radiation, we could not show any improvement in survival. We will never know if this was because it doesn’t improve survival or because we just didn’t have enough patients. I think that if this trial had accrued enough patients we would have shown a benefit for those who receive radiation. Nevertheless, brain radiation does come with the risk of neurologic side effects and ideally, a new systemic therapy that crosses the blood brain barrier and works elsewhere in the body would be the way to go. I can dream…

So finally, in summary:

1. Locally advanced, unresectable NSCLC is a common problem, accounting for approximately 1/3 of new lung cancer diagnoses.

2. The optimal way to treat locally advanced NSCLC remains in question though most would advocate chemo and radiation concurrently (without surgery) for patients with bulky lymph nodes or multiple sites of lymph node involvement.

3. The optimal chemotherapy regimen remains in question. Strategies to incorporate more effective therapies are being explored.

4. Concurrent chemoradiation is toxic: strategies to reduce toxicity are needed.

5. We think higher doses of radiation will be better (within reason) and hope to answer this question through an ongoing clinical trials.

6. Relapses in the brain are common and we need better ways of addressing this problem.

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Expert Case Discussion with Drs. Hensing and Jackman, Molecular Markers and Sequencing Therapy for Advanced Squamous Cell NSCLC

Dr West — Fri, 20 Aug 2010 21:47:06 +0000

Several weeks ago, my colleagues Dr. Tom Hensing from North Shore Health System in Chicago, affiliated with the University of Chicago, and Dr. David Jackman from Dana Farber Cancer Institute in Boston, were kind enough to take the time to go over a series of cases in a webinar format. We reviewed the time line of several patients with advanced NSCLC, focusing on two central questions:

1) For various clinical situations, which molecular markers would you be inclined to recommend?

2) How would you be most inclined to have a patient approach an end to first line therapy and either continue ongoing maintenance therapy (continuation maintenance), transition to a new maintenance therapy (switch maintenance), or just hold off on treatment until there is evidence of progression and a clear reason to restart treatment.

The first case we covered is an elderly gentleman with a good performance status and an advanced squamous cell NSCLC. Here is the audio and video versions of the podcast, as well as the accompanying transcript and figures.

drs-hensing-and-jackman-molec-testing-sequence-of-rx-case-1-audio-podcast

drs-hensing-and-jackman-molec-testing-sequence-of-rx-case-1-transcript

drs-hensing-and-jackman-molec-testing-sequence-of-rx-case-1-figures

This program was sponsored by OSI Pharmaceuticals, who had no input in its content. We appreciate their support in making this activity possible.

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Zactima (Vandetanib) Trial vs. Placebo Negative (for Survival): Details from ASCO

Dr West — Wed, 18 Aug 2010 00:28:37 +0000

The negative trials don’t get a lot of discussion, but the ZEPHYR trial, a phase III study that directly compared Zactima (vandetanib), an oral inhibitor of EGFR and angiogenesis, vs. placebo, was one that merits some follow-up after my reporting that it failed to show a survival benefit, which was essentially the only thing we learned about the trial prior to ASCO this year. A more complete report of the ZEPHYR trial was presented at ASCO, and though it suffered the indignity of being the rare phase III trial that didn’t get presented during an oral session, I think the results are important enough in trying to assess the real value of Zactima that the results merit being reviewed.

ZEPHYR was the last of four major lung cancer trials with Zactima to be completed and reported. The others are summarized in a prior post, and they showed at best equivocal results. The others are discussed in a point-counterpoint fashion by GRACE member and moderator Neil Berch (arguing that the Zactima glass is half full) and me (taking the less beloved view that the benefits are extremely marginal and probably not enough) — let the record show that, at the present time, his post has been more favored by the people who have added a rating.

But with the overall results of these Zactima trials being so… debatable, I guess you could say… the results of a trial that compares Zactima to placebo alone is especially important. The ZEPHYR trial did that, enrolling 924 patients who had received 1-2 prior lines of chemotherapy, possibly with Avastin (bevacizumab) as well, and had also received and eventually progressed on an oral EGFR inhibitor such as Tarceva (erlotinib) or Iressa (gefitinib); patients were randomized 2:1 to receive Zactima (300 mg by mouth daily, a dose that is believed to have both anti-angiogenic activity and block EGFR), or placebo. What was especially notable is that this was a very unusual NSCLC population, comprised of 53% never-smokers, 53% women, with 80% of patients having an adenocarcinoma, and a median duration of prior EGFR inhibitors of 5 months. These results strongly suggest that the patients who went on this trials were heavily over-representing patients with an EGFR mutation and/or other demographic characteristics associated with unusually long survival with NSCLC.

As shown in the figures below, the trial showed while Zactima improved progression-free survival by nearly 40% (though essentially identical at the median, where half of the patients have progressed), it showed only the slightest hint of a more favorable overall survival with Zactima.

(click on image to enlarge)

Overall survival was the primary endpoint of the study, so this was considered a negative trial.

Importantly, the study looked at many clinical and molecular biomarkers to see if it was possible to identify one or more subgroups likely to benefit more with Zactima, but none of these analyses yielded any results to support the idea that we could focus our efforts with Zactima on a particular population.

Zactima was also associated with several side effects that were far greater than seen in the placebo arm. As in prior studies with Zactima, diarrhea, rash, high blood pressure, and EKG changes associated with altering the heart’s electrical system were seen with it far more than with placebo.

Taken together, the results indicate that Zactima has some activity in this population, but with an improvement in progression-free survival but not overall survival, and with several associated side effects, this agent has lost momentum. I think with several other more encouraging leads out there for new agents, our attention, as well as opportunities for patients are better focused on agents that show the promise of doing far better.

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PF299804 vs. Tarceva: Added Benefit Over a Current Standard?

Dr West — Fri, 13 Aug 2010 21:33:00 +0000

In my last post, I described the novel oral agent PF299804 (PF299), an irreversible “pan-HER” inhibitor not only of the epidermal growth factor receptor but of other members of the human epithelial growth factor receptor (HER) family. We covered some small studies in patients previously treated with chemotherapy and an EGFR inhibitor, with these studies demonstrating that this new agent clearly has activity, shrinking a minority of tumors, with many other patients demonstrating prolonged stable disease even after several lines of prior therapy. This suggests that this agent can provide some additional benefit beyond that conferred by a reversible EGFR inhibitor that we already have available, namely Tarceva (erlotinib) or Iressa (gefitinib).

But another way to ask about how much PF299 offers over a currently available standard oral EGFR inhibitor is to compare them directly in patients who have never received prior therapy against EGFR. That study has been done and was presented at ASCO 2010.

Michael Boyer, out of Sydney, Australia led a randomized phase II trial that was conducted at a handful of centers around the world. The study enrolled 188 patients with advanced NSCLC and tissue available for molecular marker studies, who had previously received one or two prior lines of chemotherapy but hadn’t received EGFR inhibitor therapy. Patients were randomized to receive either daily Tarceva at the standard 150 mg daily dose, or PF299 at 45 mg by mouth daily. The primary endpoint was progression-free survival (PFS), and the investigators also looked at tumor response rate, side effects, and several other measures. They planned subset analyses of PFS results based on clinical and molecular variables as well. It’s worth noting that while the two arms were well balanced for many variables, it just happened to work out that the PF299 arm had a higher proportion of patients with an EGFR mutation (20% vs. 12%). On the other hand, more patients on the PF299 arm had a marginal performance status of 2 (19% vs. 3%), which would be expected to disfavor the PF299 arm.

The trial demonstrated a significantly higher response rate with PF299 vs. Tarceva (17% vs. 4%, p = 0.009) as well as a significantly improved PFS in recipients of PF299 in the overall trial population (p - 0.019).

(click on image to enlarge)

What was especially interesting was that there didn’t seem to be any isolated subgroup that received a much greater benefit with PF299 vs. Tarceva, or vice versa. Instead, just about all subgroups had similar degree of modestly superior PFS in the recipients of PF299. In the figure below, the blue boxes situated to the left of the vertical line on the right side represent improvement with PF299 over erlotinib (and the more to the left, the stronger the benefit). There are no blue boxes that fall to the right of the bar to signify better results with Tarceva.

In these plots, the width of the various boxes is proportional to the size of the group, and the horizontal lines extending from it represent the degree of variability in the results. So we see that whether patients have an EGFR mutation or wild type, KRAS mutation or wild type, adenocarcinoma or non-adenocarcinoma, men or women, never-smoker or ever-smoker, and Asian or another race, the trend favored PF299 to a similar degree of about 30-40%. The only subset that didn’t show that trend was comprised of patients 65 or older, which was a small group, and in whom the results were remarkably similar between PF299 and Tarceva.

This study also provided an opportunity to directly compare PF299 in terms of side effects to an agent we’ve become very familiar with. These results showed that side effects may well be a concern and potential limitation for PF299, at least at the dose studied. ”Dermatitis acneiform”, as opposed to “rash”, was more common with PF299 (though I think it may be splitting hairs to try to understand how they categorized dermatitis acneiform compared to rash). Also, nailbed infections, mouth sores, and diarrhea were all more common and tended to be more severe with PF299 vs. Tarceva. Since there are certainly patients for whom side effects of Tarceva can be a real challenge, it sounds to me like PF299 may be more difficult for many patients to navigate, even if side effects were most often in the mild to moderate range.

The authors concluded that this work is promising enough to warrant a larger, randomized phase III trial with the same design, and I certainly agree. Other studies with PF299, both in EGFR inhibitor-treated and naive patients are likely to be pursued in the next few years, and I certainly would be eager to have my patients participate. It may well prove to be an agent that not only can provide additional benefit to the minority of patients who have an initial response to an EGFR inhibitor and then become resistant, but also appears likely to provide a meaningfully greater efficacy than Tarceva in a much broader population of patients, in various clinically and molecularly defined subgroups. It will be important for future trials and overall clinical experience to better define that advantage and explore the potentially increased toxicity challenges that may be a real limitation for some patients.

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PF299804: Irreversible Pan-HER Tyrosine Kinase Inhibitor Showing Great Promise in Advanced NSCLC

Dr West — Thu, 12 Aug 2010 04:04:42 +0000

We’ve received several questions about agents that might be helpful for patients who have already responded to inhibitors of the epidermal growth factor receptor (EGFR) like Tarceva (erlotinib) and Iressa (gefitinib) and then demonstrate progression. These latter agents are reversible inhibitors of of the tyrosine kinase domain (signalling portion inside the cell) of the EGFR molecule, meaning that they attach to and periodically detach from the receptor. Other inhibitors, like the novel Pfizer agent PF299804, bind to EGFR irreversibly, never coming off of the receptor, and requiring the cell to make new EGFR molecules without an inhibitor on them. Such agents can kill many kinds of cancer cells in a lab-based model, and appear that they may do so more effectively than currently agents like Tarceva and Iressa, but how well they work in real patients has remained an open question.

Another unresolved issue is whether PF299804, an inhibitor of not only EGFR but of other members of the human epidermal growth factor receptor (HER) family, of which EGFR (also known as HER1) is just one type, are more effective in patients than agents that inhibit EGFR alone. Such agents that block multiple members of the HER family are sometimes referred to as “pan-HER” inhibitors (as in “across the HER family“), but they’re still in clinical studies to determine whether such agents provide incremental benefit beyond what we see with the EGFR-specific agents we already use.

Though results with the orally available irreversible pan-HER inhibitor PF299804 weren’t a lead story at ASCO 2010, I think several of these trials were quite encouraging, both for patients with an EGFR mutation who might seek something after they become resistant to an EGFR inhibitor that previously was very beneficial, and also for people who don’t have an EGFR mutation and hope to do better than they might expect to do with an agent like Tarceva or Iressa.

A pair of studies were done on patients with advanced NSCLC who had previously been pretty treated with both chemotherapy and an EGFR inhibitor. First, one done in Asia by Park and colleagues enrolled 12 patients in an initial phase I portion, followed by an additional 42 patients in the subsequent phase II study after a dose of 45 mg by mouth daily had been identified as the appropriate target dose. The analysis focused on the patients in the phase II portion at the 45 mg daily dose, of whom 40 had response data available.

Overall, these results were quite encouraging, with 48% of patients still without progression 4 months after starting treatment, 15% showing a partial response (PR), and another 52.5% demonstrating stable disease (SD) as their best response. The duration of treatment is shown in the figure below, with the length of the horizontal line extending to the right proportional to the duration of time on the drug and without progression:

(click on image to enlarge)

The waterfall plot below shows the distribution of tumor shrinkage (proportional to the length of the lines going down from the horizontal line, clustered to the right), progression (upward lines clustered to the left), and stable disease (short lines not going much down or up):

Of course, the other important factor is tolerability, which was pretty good. The leading side effects were diarrhea, rash, and mouth sores, all typically in the mild to moderate range.

A very similar trial of American patients was reported by Campbell and colleagues. This study enrolled 66 patients with advanced NSCLC, previously treated with both chemotherapy and erlotinib, and over 80% had tumor tissue available for molecular marker studies. They divided their population into the 50 with an adenocarcinoma, of whom more than half were never-smokers and the majority had an EGFR mutation, and the other 16 with a non-adenocarcinoma, who were much less likely to be never-smokers or have an EGFR mutation.

They saw a wide range in duration of treatment, with 13 patients (23%) demonstrating prolonged clinical benefit (either a complete response (CR), PR, or SD lasting at least 24 weeks). Not all of these patients had an EGFR mutation (7 did, 4 were EGFR wild type (no mutation), and 2 were unknown). Overall, though, progression-free survival was longer in patients who had an EGFR mutation:

The side effect profile was remarkably similar to the Asian experience, though the investigators noted that the side effects seemed to gradually decrease with ongoing treatment.

Overall, then, these studies both demonstrate that an encouraging fraction of pretty extensively treated patients with advanced NSCLC show tumor shrinkage or at least prolonged stable disease with this oral agent, and that the results, while perhaps most encouraging in patients with an EGFR mutation or the demographic features where it is prevalent, convincingly reveal activity in patients who don’t have an EGFR mutation.

How does PF-299 stack up against erlotinib in patients who haven’t received an EGFR inhibitor previously? I’ll cover that next.

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Jack West, TV Personality?

Dr West — Mon, 09 Aug 2010 20:13:58 +0000

People have said to me that a name like Jack West sounds like a good TV name, so I suppose it was only a matter of time before I found my way to the small screen. Yikes!

(click on image to enlarge)

This coming Saturday (August 14th), I’ll be part of a team of three on an expert panel covering many aspects of lung cancer on a program on Discovery Channel called Discovery Channel CME: Individualized Therapy for Non-Small Cell Lung Cancer. It airs at 8 AM and repeats again at 8 AM on August 21st and 28th.

Though it’s continuing medical education (CME) and is ostensibly targeted for physicians, we provide a very broad coverage of the field that many people here may find helpful, if not even a bit basic. My co-panelists are Dr. Mark Socinski (Univ. of North Carolina at Chapel Hill), who recently did a terrific webinar program on maintenance therapy for advanced NSCLC, and Dr. Jyoti Patel (Northwestern Univ.), who is a longtime friend and now leads the very important POINT BREAK Phase III trial.

My suggestion was to have the experts voted off of the panel one by one as the program progressed, just to spice things up and add some suspense a la Survivor. Surprisingly, they didn’t go for that.

So, hey — it’s a start. It’s 8 AM, so if you’re interested, you can always TiVo it…

Be glad I spared you the photo of me with the make-up artist.

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Treatment of Small Cell Lung Cancer

Dr Gadgeel — Sat, 07 Aug 2010 16:22:20 +0000

This is the second of two parts in the Reference Library by Dr. Gadgeel on small cell lung cancer.

Patients with Limited Stage Small Cell Lung Cancer

As stated in the prior chapter from the reference library on basic principles and workup of small cell lung cancer (SCLC), in patients with limited disease (LD)-SCLC, the cancer is only detected in the lung, or the lung and the lymph nodes. But even if it is only detected in these sites it is known, based on prior studies, we remain concerned that the cancer has spread to other parts of the body but that it has not yet grown in these other sites for it to be seen on the scans.

It is for this reason chemotherapy is always included in the treatment of LD-SCLC . Chemotherapy goes throughout the body and therefore will not only attack the cancer visible in the primary lung tumor and the lymph nodes, but also the SCLC cells in the other parts of the body that may exist but remain invisible on the scans.

Chemotherapy by itself can eradicate SCLC in areas where it is not big enough to be seen on the scans. As far as the SCLC that is big enough to be seen, chemotherapy can shrink the cancer but cannot be expected to eradicate it completely. Therefore for the SCLC in the lungs and lymph nodes, radiation therapy is utilized, combined with chemotherapy. Thus limited SCLC is routinely treated with both chemotherapy and radiation therapy directed to disease in the chest. This chemotherapy and radiation is generally given concurrently, since the chemotherapy makes the radiation therapy stronger against the cancer than what it would be by itself (called radiosensitization). There is also evidence that giving the radiation earlier rather than later is most beneficial.

Specifics of Treatment for LD-SCLC

Cisplatin or Carboplatin, with Etoposide

The chemotherapy typically consists of 2 drugs — cisplatin or carboplatin — combined with etoposide. This combination is given most commonly over three days with cisplatin or carboplatin given on the first day with etoposide, and then etoposide alone given on 2^nd and 3^rd days. All drugs are given intravenously. The chemotherapy is repeated every 3 weeks for a total of 4 or sometimes 6 cycles.

Radiation therapy is targeted to the small cell lung cancer in the chest that can be seen on the scans. Radiation therapy generally is given daily Monday-Friday for about 6-7 weeks.

Some doctors also give radiation therapy twice daily Monday-Friday, based on a clinical trial that demonstrated particularly favorable survival with this approach. If given twice daily, the duration of radiation is for 3 weeks. There has to be a minimum of 6 hours between the two sessions if given on the same day.

Common side-effects of this treatment

Nausea/Vomiting - Usually can be well controlled with appropriate anti-nausea medications

Fatigue - A general sense of tiredness is experienced by many patients about 1 or 2 days after the chemotherapy. The extent of the tiredness varies from patient to patient. This symptom generally lasts for 2-4 days with the intensity of the tiredness reducing with every passing day. It is possible that the extent of the tiredness may be worse with each subsequent round of chemotherapy

Lowering of blood counts, particularly whiteblood cell count - The lowering of white blood count is usually for only few days, which is less worrisome than a situation in which the white blood cell count is very low for a week or longer, as is typical in treating leukemia or some other cancers. However during this typically brief time of low blood cell counts, the patient is at higher risk for getting an infection. If a patient during this period gets an infection, then the infection could spread in the body very rapidly, since the number of white blood cells is not adequate to fight it, so intravenous antibiotics are needed. It is therefore very important that a patient on chemotherapy go to the emergency room right away if they get a fever of 101°F or more at anytime during the treatment period. The probability of this happening is very low, less than 5%.

Esophagitis (inflammation and swelling of the esophagus) - The esophagus connects the mouth to the stomach. It runs at the back of the middle of the chest. Even though radiation doctors have become very good at targeting the radiation only to the cancer, there is some extension of the radiation treatment to the surrounding structures, including the esophagus. This can cause inflammation and swelling in the esophagus, which makes swallowing food painful. Usually this starts about 2-3 weeks into treatment. In most patients this can be managed readily with proper instructions on food intake, hydration with fluids and medications. However, in < 10% of the patients, it may be severe enough that the patient has a difficult time swallowing food or water and may need to be admitted to the hospital for intravenous fluids and other support.

Pneumonitis (inflammation and swelling of the lung) - Some patients may develop inflammation in the lungs, usually in the area of radiation. This can cause coughing, shortness of breath, and fever. This usually happens about 2-6 months after radiation and is felt to be a reaction in the lung to the treatment. In about 10% of the patients, it could be severe enough to require admission to the hospital. Though it can resolve on its own with time, it is severe enough, treatment with steroids may be needed, with oxygen support also sometimes added as well. Most patients recover from this condition significantly or even completely.

Since this side effect may occur even several months after completion of treatment, it is important for the patient to inform their doctors if they develop new cough or shortness of breath and not assume it is an unrelated minor issue such as a cold.

Prophylactic Cranial Radiation (PCI) - Almost 50% of SCLC patients can develop brain metastases. Chemotherapy can go to all different parts of the body but one area it does not reach in sufficient amount is the brain. This is because the brain is covered by something known as the blood-brain barrier that limits the amount of chemotherapy that can get through.

Thus, if any SCLC cells have travelled to the brain, they likely would not be adequately treated with chemotherapy alone. Therefore patients with limited stage SCLC who have completed chemotherapy are treated with radiation to the brain. This radiation is given from Monday-Friday for about 3 weeks.

There is a small chance that this radiation treatment may affect the cognitive function of the brain in the future, but this risk is felt to be quite low compared with the benefits of markedly reducing the risk of brain metastases in patients otherwise highly likely to develop them.

Outcome of Chemotherapy+Radiation Therapy in LD-SCLC Patients

Data to date suggest that with chemotherapy and radiation, about 20% of the patients with LD-SCLC can have their cancer eradicated and therefore cured.

Unfortunately, this also means that 80% of the patients are not cured. In these patients, the cancer may shrink and may even become small enough that it cannot be seen on the scans, but it has not been completely eliminated. The cancer in these patients will eventually recur, generally within the first 2-3 years, though patients can have late (after the first 3 years) recurrences. Even in patients in whom the cancer is not cured, the treatment rendered does provide benefit, since survival is far longe rwith treatment than without; quality of life is also significantly improved with treatment.

PCI improves the survival by 5%. Thus, the cure rate is improved from about 20% with chemotherapy and radiation therapy to about 25% with the addition of PCI.

It isn’t possible to predict which patients can be cured before starting therapy. Instead, only gradual follow-up after treatment will the greatest beneficiaries of treatment be clarified.

Generally, physical exam and scans are done every 3-6 months for the first 2-3 years and yearly scans thereafter. There are no data that shows that these scans help find the recurrence of cancer sooner than if scans are done only at the time of patient developing symptoms. However, it is generally accepted practice to obtain the scans on the schedule described above.

Treatment of Extensive Stage Small Cell Lung Cancer Patients

The primary treatment of SCLC with extensive disease (ED-SCLC) is chemotherapy. The chemotherapy used in ED-SCLC patients is generally the same as discussed for patients with LD-SCLC.

Cisplatin or Carboplatin, with Etoposide

The treatment is repeated every 3 weeks, with cisplatin or carboplatin given on the first day and etoposide typically given over about 3 days.

Scans to assess the response of the cancer to this treatment are done after every 2-3 rounds (or about 6-9 weeks). This chemotherapy is able to shrink the cancer or stabilize the cancer in about 60-70% of patients with ED-SCLC. In addition, relief of cancer-related symptoms can be fairly quick with this chemotherapy. Assuming that the cancer is shrinking or stable and the patient is tolerating the treatment without significant side-effects, the treatment is extended for 4 or perhaps up to 6 cycles. There are no data to suggest that extending treatment with this chemotherapy beyond this point has any benefit.

After this fixed duration of treatment, patients are monitored with physical examination and scans to assess if the cancer is remaining stable. This assessment is usually done every 6-8 weeks. Unfortunately, it is expected in ED-SCLC that the cancer will show evidence of growth again, at which point the next chemotherapy treatment is started or consideration of a focus exclusively on symptom management.

Adverse Effects of this Treatment

Nausea and vomiting, fatigue, and reduced blood cell counts are all seen as described in the section on LD-SCLC above. However, both esophagitis and pneumonitis described in the treatment of LD-SCLC are rarely seen in the absence of chest radiation.

Cisplatin or Carboplatin, with Irinotecan

In a trial conducted in Japan, the combination of cisplatin and irinotecan was found to be better than cisplatin and etoposide. Two separate trials were conducted in the United States to confirm the results of this trial. Both the trials failed to show that the combination of cisplatin and irinotecan is better than cisplatin and etoposide. The results with the two treatments were very similar. The reasons for the disparity in results between the Japanese and US trials are unclear, but it is thought that genetic differences in how different chemotherapy agents are metabolized by different racial groups may be a major factor. In Japan, the combination of cisplatin and irinotecan is used for the treatment of patients with ED-SCLC. In the US, however, this is not as commonly used as a combination of a platinum agent with etoposide.

If cisplatin and irinotecan is given, the treatment is most commonly administered as follows-

Cisplatin is given once every 3 or 4 weeks. Irinotecan is given on a weekly basis for 2 weeks out of 3, or 3 weeks out of 4. The schedule of the 2 drugs is repeated every 3 or 4 weeks. This treatment is also given for 4 cycles.

Adverse Effects of this Treatment

Nausea and vomiting, fatigue, and reduced blood cell counts are all seen as described above.

Diarrhea - Irinotecan is known to cause diarrhea, which can be severe. The diarrhea usually starts about 1 or 2 days after treatment. It is very important for the patient to start taking an anti-diarrheal medication immediately with the onset of diarrhea to control it effectively. In a small percentage of patients, the diarrhea can be severe despite taking an anti-diarrheal and may even require hospitalization for management that includes intravenous fluid support.

Management of Brain Metastases

Small cell lung cancer patients with evidence of brain metastases require whole brain radiation to treat the brain metastases. Because brain metastases in SCLC are so commonly a multifocal process, stereotactic brain radiation is not an accepted alternative in this setting.

The timing of the brain radiation could vary. If the patient has evidence of brain metastases on the scans but has no symptoms from the brain metastases, chemotherapy can be initiated first with close monitoring of the brain metastases on the scans, and the brain radiation can be done following the completion of some initial chemotherapy. However, if the patient has any symptoms that are related to the brain metastases, these patients should be first treated with whole brain radiation and then treated with chemotherapy. Depending upon the patient’s condition the doctors may decide to start with chemotherapy and the whole brain radiation together.

Prophylactic Cranial Radiation-

Because the potential for spread to the brain in small cell lung cancer patients is very high, as noted above, PCI has also been evaluated for patients with ED-SCLC. A recent European study demonstrated that patients with ED-SCLC, no evidence of brain metastases, and who have responded to first line chemotherapy benefit from receiving brain radiation following the completion of front line chemotherapy. The benefit is in the form of extending survival and markedly reducing the chance of the patient developing subsequent brain metastases.

Based on these results small cell lung cancer patients are considered for brain radiation following the completion of chemotherapy. However it is important to mention that due to certain reservations regarding this trial, the strategy of brain radiation following chemotherapy is not applied to all patients.

Second Line Treatment

As mentioned above, it is expected that cancer will eventually progress in a patient with ED-SCLC at some time point following the completion of first line therapy, usually in the range of months. At the time of progression, patients are most commonly treated with a drug called topotecan (Hycamtin). This drug is FDA approved for the treatment of patients with ED-SCLC whose cancer has progressed following treatment with prior chemotherapy and has been shown to improve qualify of life and also survival in this setting.

Topotecan is usually administered over 5 days every 3 weeks. Because this schedule typically leads to a very significant drop in blood counts and is also inconvenient for many patients who may be symptomatic from their relapsed cancer, some doctors also treat patients with weekly administration of topotecan. Topoecan can be administered intravenously or orally.

As in the first line setting, scans are usually done after 2 rounds (about 6 weeks) of chemotherapy to assess the status of the cancer. When treating recurrent SCLC patients, the treatment with topotecan is usually continued until there is evidence that the treatment is not working or the patient does not tolerate the side-effects from the treatment.

Topotecan is able to keep the cancer controlled on an average for about 3 months. Again the duration for which the cancer is controlled varies from patient to patient. The probability of topotecan working is higher in a patient whose cancer was controlled for longer than 3 months after completing the first chemotherapy.

Adverse effects of Topotecan

Lowering of blood counts, particularly white blood cell count and platelets - The probability of the white blood cell count dropping significantly is high enough for some doctors to consider giving an injection called neulasta, which can reduce the extent and duration of the drop in white blood cells ,even with the very first round of topotecan.

Nausea/Vomiting - Not very common with this chemotherapy but could occur.

Diarrhea- May occur, though not common

Fatigue- Also possible but not very common.

Retreatment with Cisplatin (or Carboplatin) and Etoposide

In a small proportion of patients with ED-SCLC, the cancer may remain controlled for longer than 6 months after the initial treatment. In these patients, re-treatment with the original treatment is often considered, and the cancer could be controlled with the same chemotherapy again. Usually the control of the cancer with re-treatment does not last as long as the first time, and in some patients re-treatment with the same chemotherapy may not work at all.

Subsequent Chemotherapy

If topotecan does not control or shrink the cancer or does so for a period of time before the cancer starts growing again, it is feasible to treat with other chemotherapy drugs, but we don’t have good evidence to support the use of other chemotherapy drugs following the use of a platinum agent with etoposide in first line therapy followed by topotecan as second line therapy. The lack of data does not mean there is no benefit from such therapy, but rather that we don’t know if doing more chemotherapy is valuable or not.

If the general condition of the patient is relatively good, many oncologist may consider offering these patients other chemotherapy drugs such as Taxol (paclitaxel) or Gemzar (gemcitabine). It is important to remember that these patients could be considered for clinical trials evaluating investigational drugs. However, many patients in this setting are struggling with increasing cancer-related side effects and cumulative toxicity issues with chemotherapy. For such patients, supportive care rather than further anti-cancer treatment may be most advisablee.

The GRACE Lung Cancer Reference Library is made possible by an unrestricted educational grant from Pfizer Oncology.

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ARQ197: Encouraging Results from ASCO 2010

Dr West — Thu, 05 Aug 2010 21:54:13 +0000

Continuing with the webinar discussion I had with Dr. Pennell, here is a summary I did of a randomized phase II trial of the novel agent ARQ-197 combined with the EGFR inhibitor Tarceva (erlotinib):

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Dr. West: We’re going to shift gears and move into the metastatic setting, and this is a new agent called ARQ197 that is orally available, which was tested in combination with erlotinib(Tarceva) compared with Tarceva alone. And this was actually in the patients who had received one or more prior lines of chemo and could not have received prior Tarceva or another EGFR inhibitor, directly comparing these two groups that randomized one-to-one. Also, patients who had been assigned to placebo could actually go on the combination at the time of progression, and we did get some interesting information from that.

(click on image to enlarge)

The study enrolled very quickly: it was a randomized Phase II trial, and I’ll show you the numbers very shortly. My center was one that was planning to be involved, but it actually enrolled so quickly at a few centers that we didn’t even get the chance.

So what is this ARQ197? It’s a MET inhibitor, and MET stands for mesenchymal-epithelial transition factor, and this is involved in the cascades of EGFR and KRAS and others.

And it’s actually one of the potential mechanisms for resistance to EGFR-inhibition and in itself is associated with cell proliferation, motility, migration, angiogenesis, this transition from epithelial to mesenchymal that is associated with resistance to EGFR-inhibitors and promotes invasion and metastasis and it’s associated with worse outcomes when it’s over-expressed in patients with lung cancer tumors.

The study involved 167 patients randomized between the two arms and showed an improvement in progression-free survival, which was the primary endpoint of the study.

It was statistically significant and a really clear difference between the two arms as you can see that its hazard ratio of 0.81 corresponds to a 19% improvement, although it was especially concentrated at the median point which is here at 0.5, you could see a very significant difference.

The overall survival was in favor of the combination, though it was not statistically significant and that’s shown here, a difference of about seven weeks or so.

The study also included a breakdown looking at a few different variables, and one was by histology. When they looked at patients with non-squamous tumors, which were the majority — about two thirds — they found that overall survival actually was significantly better with ARQ197.

This was unplanned, but nowadays we know that histology can be extremely relevant and the differences are even more robust if we concentrated the evaluation at patients with non-squamous histology.

They also looked at a few molecular variables, and what was interesting to see was that there was even more of a pronounced benefit in the patients who were EGFR wild type who we generally think of as not getting as profound a benefit with EGFR-inhibitors like Tarceva.

But here there was a really differential effect, admittedly in not incredibly large numbers, but it was still nearly a hundred patients. And also in patients with KRAS mutations, again small, small numbers, but this is a group of patients for whom we have not seen, had very difficult time making gains. Certainly, if this holds up in larger studies, it would represent a major benefit to be able to find something that could actually improve outcomes for the patients who we haven’t been able to serve extremely well with Tarceva alone.

What’s also instructive is to see an improvement in some patients who were assigned to Tarceva alone and then crossed over to the combination, because there were actually two out of 23 evaluable who actually demonstrated significant tumor shrinkage and another nine who had stable disease. So you actually saw some improvement in people who had already been exposed to the same EGFR-inhibitor without the novel agent.

This is going to be moving forward in a larger study that I’m very much hoping to be involved with, and the final design of that is still in the works at this point.

Dr. Pennell: Hopefully, that one will not accrue so quickly that you won’t be able to participate.

Dr. West: Yeah, right — well, it will be a larger study. Overall, I would say this is certainly an encouraging avenue. I’d welcome your thoughts, Nate.

Dr. Pennell: I completely agree. I think this is an exciting avenue. We tend to get caught up with these targeted drugs, looking at the relatively small subpopulation of patients who have really the driving molecular changes like an EGFR mutation or the ALK translocation. We have to remember that the vast majority of patients with non-small cell lung cancer don’t have a single genetic change that’s driving it, but rather a number of different pathways that are active in their cancer cells. And MET is a pathways that is one of the highest of all the tyrosine kinases, and the activities of the MET receptor are among the most important pathways activated in lung cancer – at least in lung cancer cell lines — and probably that’s true in actual lung cancer as well.

It’s probably not a single molecular change causing this, and so inhibition of MET by itself is unlikely to have a whole lot of benefit. But in combination with other drugs such as EGFR inhibitors, I think this is a very promising approach, especially for people who don’t have an EGFR mutation.

The KRAS data is intriguing. We’d caution everyone that there were only 15 patients with KRAS mutation for this analysis, so it’s very hard to say comparing five patients to 10 patients is meaningful, but certainly, it should be looked at in larger studies of similar benefit. So I’m excited, I agree.

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