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Dr. Goldman

Why Carboplatin, Pemetrexed and Pembrolizumab Have Become My New Go-to Regimen for First-Line Non-Squamous NSCLC Treatment

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Why carboplatin, pemetrexed and pembrolizumab have become my new go-to regimen for first-line non-squamous NSCLC treatment.

By Jonathan W. Goldman, MD


Metastatic non-small cell lung cancer (NSCLC) treatment has generally improved by optimizing care for “slices of the pie”—pieces of a pie chart representing all of lung cancer patients. Initially, mutation-based treatment led the way; 10% of lung cancers were identified as EGFR-mutant and treated with appropriate tyrosine kinase inhibitors. Subsequently, thinner and thinner slices of the population, each 1-7% of NSCLC patients, have been described and their cancers targeted. More recently, immunotherapy entered the picture, but again the greatest benefit of this therapy was limited to the 20-25% of patients that were PD-L1 positive. Despite all of these advances, we still had at least half of patients receiving more than 10-year-old chemotherapy as their initial treatment.

We now have preliminary evidence that this may be changing. Langer, et al reported in November 2016 (Lancet Oncology) the phase 2 KEYNOTE-021-G1 cohort of non-squamous NSCLC patients treated with the standard, carboplatin and Alimta (pemetrexed), alone or with the PD-1 inhibitor, Keytruda (pembrolizumab). Previous attempts to add to a platinum-doublet had generally provided marginal benefits at best (for example, with Avastin [bevacizumab] or Erbitux [cetuximab]). In contrast, the 021G trial suggested massive benefits, at least as far as response rate (RR) and progression free survival (PFS).

The 021G trial was a moderate-sized phase 2 trial with 123 patients split between the two arms. With Keytruda added to chemotherapy, the response rate increased from 29 to 55%, and importantly this benefit was irrespective of PD-L1 status (above or below a 1% PD-L1 cutoff). PFS was also significantly improved from 8.9 to 13.0 months with a hazard ratio of 0.53, which represents a decrease in the risk of cancer progression by almost half. Many of the trials leading to new drug approvals especially in an unselected cohort report hazard ratios of 0.75 or 0.80, so the benefit in 021G is staggering. The overall survival curves were overlapping at the time of the initial report, and if they suggested a possible survival benefit when updated at the 2017 ASCO Annual Meeting, there was still no statistically significant difference. This lack of a clear survival benefit is certainly at least in part due to crossover at the time of progression from the chemotherapy alone arm to get Keytruda or another immunotherapy (32% within the study and 74% if you count receiving an immunotherapy agent at any point, on or off the trial).

Furthermore, the toxicity associated with the addition of Keytruda was generally manageable, although moderate to severe toxicity (grade 3 or higher) was increased from 28 to 41%. Primarily, these were hematologic toxicities, including anemia and low blood counts, which oncologists are very comfortable managing. Stereotypical immunotherapy toxicities (such as pneumonitis, colitis or hepatitis) were reported at rates similar to previous experience with single-agent PD1 or PDL1 inhibitor therapy. Nevertheless, Keytruda was discontinued due to toxicities in 10% of patients, including in 1 patient with grade 3 pneumonitis, and doctors and patients will need to be on the lookout for such complications.

Many investigators and thought leaders were surprised when the FDA granted priority review for the front-line Keytruda-chemotherapy combination in January 2017. While lung cancer drug approvals had come from phase 2 or even phase 1 data before, that had consistently been for targeted therapy in areas of unmet need. However, just a few months later, on May 10, 2017 the FDA provided accelerated approval based on the RR and PFS benefits reported from KEYNOTE-021-G1. This does require verification in confirmatory trials including the KEYNOTE-189 trial, which mirrors the 021G trial but in a larger, phase 3 format.

This approval further shocked the lung cancer community. It certainly put standard treatment pathways and clinical trials, both open and in planning, in to disarray. However, from the FDA standpoint, how could you say no to a doubling in the response rate and a 50% decrease in the risk of progression? From the patient standpoint, there is now a novel treatment option that applies to the majority of patients. This is an event to celebrate.

There have been several lines of criticism of this combined treatment modality. The clearest is that if the overall survival curves remain overlapping, it may be advantageous to use chemotherapy and immunotherapy sequentially instead of concurrently. However, it seems likely that if the impressive RR and PFS advantages of concurrent therapy are real, they will translate into a survival advantage. It is also important to remember that patients can worsen rapidly during front-line therapy and never have the opportunity to benefit from a second-line treatment. If a survival advantage is not seen in the small phase 2 trial, it seems likely to be demonstrated in the larger phase 3 trial.

Another criticism of the concurrent approach is the associated medical and financial toxicity. Some presume that most patients will be benefiting from either the chemotherapy or the immunotherapy, and that by giving everything together, we are exposing patients to needless drug toxicity and society to unsustainable costs. One could respond, firstly, we do not know exactly how chemotherapy and immunotherapy may be interacting and there may be synergism beyond the efficacy of the individual parts. (Some hypothesize that tumor cell death via chemotherapy releases antigens that prime an immune response, which is then amplified into an immune effector response by immunotherapy.) Secondly, the toxicity profile as seen in the 021G trial shows that concurrent administration of chemotherapy and PD-1 blockade is tolerable for most patients. Thirdly, we have used expensive triplet regimens before (the best example being carboplatin, Alimta and Avastin) but at least with the 021G triplet there is evidence for major benefit.

In the end, we are all awaiting the confirmatory phase 3 trials of chemoimmunotherapy across many of the PD1 and PDL1 inhibitor drug-development pipelines. In the meantime, I applaud the FDA’s provisional approval and I am happy to be able to provide this as an option for my patients. I have heard some doctors state that they will reserve the triplet for patients that “need a response.” I have never met a patient who did not feel that he or she needed a response, and therefore the 021G triplet is my new go-to first-line regimen for non-squamous NSCLC patients without targetable mutations.


Dr. Goldman joins GRACE from UCLA Medical Center in Santa Monica, where he specializes in Hematology and Oncology.  He serves as Assistant Professor of UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology.  


 

 

 

 


GRACE Video

Immunotherapy Combinations

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Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

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The class of agents known as immune checkpoint inhibitors have really invigorated our study of lung cancer, and many other cancers over the last few years. Agents like Opdivo, also known as nivolumab, and Keytruda, known as pembrolizumab, are now commercially available, FDA approved as a second line therapy for patients who have progressed on first line standard chemotherapy. We are now actively asking the question of whether we might be able to move these immunotherapies into the first line setting and also asking whether we might do well by giving a combination of immune therapies, rather then just one treatment at a time.

So these agents, immune checkpoint inhibitors, are largely categorized into PD-1 or PD-L1 inhibitors, and those are just targeting two separate sides of an interaction between two receptors. The PD-L1 is on the tumor cells, PD-1 is on the immune T cells, and so blocking either side of this can lead to a beneficial effect because this effect leads to a braking mechanism on the immune system — you take away that braking system and you turn off the brakes and lead things to move forward, and that’s what we often see.

There are other agents that can also lead to braking mechanisms and that have been studied in other cancers. An agent such as Yervoy, which is known as ipilimumab is a CTLA-4 inhibitor and this is an agent that’s been approved in melanoma. In fact, the combination of Opdivo (nivolumab) and Yervoy (ipilimumab), as two different ways of blocking the immune system, have been shown to be beneficial as a combination in melanoma compared with either one on its own. Because of that, we’re looking at combinations of immunotherapies compared with single immunotherapy approaches, or standard chemotherapies.

One interesting study being done right now is called CheckMate 227 and it is looking at first line treatment of patients with advanced lung cancer that is either squamous or non-squamous histology. It does not require any level of PD-L1 expression on the tumors, the protein associated with tendency toward better efficacy of immunotherapies, partly with the thought that the combination of two immunotherapies may make even the cancers that don’t express PD-L1 respond well. This trial is looking at first line therapy with either standard chemotherapy of cisplatin or carboplatin with Alimta for non-squamous cancers, or Gemzar (gemcitabine) for squamous cancers, compared with either Opdivo alone or a combination of Opdivo and Yervoy — Opdivo being a PD-1 inhibitor, Yervoy being a CTLA-4 inhibitor — and asking the question of whether immunotherapy is as good, better, or worse than standard chemotherapy as a first line treatment, and whether the combination of two immunotherapies is better than first line therapy. 

I should mention that there are other trials looking at very similar versions of this question using different combinations of immunotherapies. There are many companies looking at several different immunotherapies in development and they are overall really very comparable and all quite exciting.

You can learn more about this specific trial from the link on the screen,

CheckMate 227 Clinical Trial

but I would encourage you, if you talk to your doctor and they recommend a trial with an immunotherapy in the first line setting, potentially comparing it to chemotherapy, to carefully consider it — it does not have to be this specific trial to be of interest.

We’re going to learn more about this in the coming years and we’re going to figure out the best way to integrate immunotherapies with our standard treatment approaches today.


GRACE Video

Immunotherapy as First-Line Treatment

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Dr. Jack West, Swedish Cancer Institute, raises the question of whether to use immune checkpoint inhibitors as first-line treatment of lung cancer, alone or in combination with chemotherapy.

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A class of agents known as immune checkpoint inhibitors has really incredibly invigorated the field of lung cancer and many other cancers over the last year or two. These agents are given intravenously and essentially take off a braking mechanism for the immune system and by doing that, can stimulate it to recognize and attack your own cancer. These agents, at least a couple of them, have been approved by the FDA as of now, in late 2015, and the question is whether they should be used earlier than the second line setting where they’ve already been approved.

Two agents, one known as Opdivo or nivolumab, and another known as Keytruda or pembrolizumab, are approved in patients who have already demonstrated progression after receiving a first line chemotherapy. So the question is: should these treatments be given earlier in therapy? There are two leading considerations in how we might do this. One is that we might give an immunotherapy in combination with standard chemotherapy. There are other ways to do this that might give the immunotherapy instead of standard chemotherapy. There are studies looking at various combinations being done with any of the many immune checkpoint inhibitors that are in development right now.

An interesting trial that is being done now is with pembrolizumab, or Keytruda — this is the KEYNOTE-189 trial that is looking at whether the addition of Keytruda to standard chemotherapy improves outcomes for patients when they get it first line. Specifically this trial is for patients with a non-squamous cancer and these patients can have any level of PD-L1 expression, the protein that tends to be associated with better activity of the immune checkpoint inhibitors — there’s no restriction on PD-L1 expression and patients just have to have not received prior therapy for advanced lung cancer. These patients are then randomized to receive the two drug chemotherapy combination of cisplatin or carboplatin with Alimta, or that same chemotherapy combination with Keytruda (pembrolizumab). That study is being done now and we hope to learn more about it in the next year or two, to learn whether it is beneficial to give these immunotherapy agents in combination with chemotherapy, compared to giving them sequentially.

Another very similar study, though looking at squamous lung cancer, is called EMPOWER 131 — this is with an immune checkpoint inhibitor known as atezolizumab. This agent is being looked at in combination with either carboplatin and Taxol, or carboplatin and Abraxane, a very similar agent. There are two arms of this study where a patient gets a combination of chemotherapy and the immune therapy, and the third arm is just carboplatin and Abraxane alone. We should learn more about the potential benefits of combining immune checkpoint inhibitors with chemotherapy in the first line setting from this, looking at both patients with squamous and non-squamous histology in different trials.


GRACE Video

Maintenance Therapy for Advanced NSCLC

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Dr. Jack West, Swedish Cancer Institute, defines maintenance therapy in advanced NSCLC and discusses maintenance treatment strategies.

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For patients with advanced non-small cell lung cancer, our typical approach, if we have someone who does not have a driver mutation that we typically treat with a pill-based targeted therapy, is to give chemotherapy. That chemotherapy is typically given in a cycle of three weeks or sometimes a four week period of time where the blood counts go down and then recover. That treatment is typically given once every three weeks, sometimes once or twice on a weekly basis in that three week interval, but we typically give that therapy for about four to six cycles of therapy — that’s about three to five months of treatment. By that time, by four to six cycles in, the two drug combination that includes a drug called platinum is usually creating some cumulative side effects: fatigue, low blood counts, and other complicating issues that make it increasingly challenging to administer more of the same potentially intensive therapy, and by four to six cycles you really tend to reach a point of diminishing returns.

At that point we often favor a maintenance therapy approach. That is, dropping the carboplatin or stopping all of the agents that have been given previously and either continuing one or more of the agents from the first line setting, or using what’s called switch maintenance to give a completely different treatment. These maintenance therapies are designed to do what their name suggests — to maintain a response after we’ve seen the most shrinkage that we’re likely to get from the more intensive first line therapy.

When we do a continuous maintenance approach, it’s typically taking a drug like cisplatin or carboplatin in combination with one or two partner drugs, usually a second chemotherapy agent and sometimes Avastin which blocks a tumor’s blood supply, and then after four to six cycles we drop the platinum and we will typically continue a drug like Alimta if that’s been given in the first line setting, and if a drug like Avastin has also been given we might continue that and give Alimta and Avastin together until the cancer progresses.

If a combination like carboplatin and Taxol were given with Avastin, the maintenance therapy is often just the Avastin because Taxol tends to have some cumulative neuropathy issues — numbness and tingling that can lead to a real limitation in how much of that therapy you can give. We might also consider a switch maintenance approach — instead of continuing some of the agents, come in with Alimta as a single agent if a patient has non-squamous histology. Another agent that is approved as a switch maintenance therapy is Tarceva (erlotinib) — this doesn’t tend to be as favored as a switch maintenance because the efficacy of Tarceva in patients who don’t have an EGFR mutation tends to be on the lower side.

What do these maintenance therapies have in common? Well they’re all agents that can be given on a longitudinal basis without a lot of cumulative side effects and they tend to be the agents that have good activity in patients who have already been on prior therapy. So any of these is a reasonable choice, the most common being a continuation maintenance of dropping the platinum and continuing one or two partner drugs that were given with it, or sometimes switching to an agent like Alimta (pemetrexed) or Tarceva (erlotinib). It’s also reasonable to not pursue maintenance therapy if a patient has cumulative side effects and really needs a break from therapy. That is certainly something to discuss with the patient; it’s not as if maintenance therapy is a mandate for all patients, but it is something that is a strong consideration if a patient is motivated and can continue to tolerate ongoing therapy after four to six cycles.


GRACE Video

Histology-Specific Recommendations – Large-Cell Neuroendocrine

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GRACE Cancer Video Library - Lung

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Dr. Jack West, Swedish Cancer Institute, identifies the best choice for first-line chemotherapy for large-cell neuroendocrine histology.

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One of the less common subtypes of non-small cell lung cancer is known as large cell neuroendocrine, and it is in the same family as small cell lung cancer — these are all known as neuroendocrine cancers. They originate from cells that are in the middle of the body, in the middle of the chest, that have evolved to have hormone-secreting abilities. Because of that, large cell neuroendocrine and small cell lung cancer really share enough features that they are treated in a very similar way.

The standard approach for most patients with advanced non-small cell lung cancer for metastatic lung cancer, if you do not have a driver mutation like EGFR or ALK, is a two drug combination, a so-called platinum-based doublet with cisplatin or carboplatin in combination with a partner drug. For many subtypes of lung cancer, what that partner is doesn’t matter too much — the various combinations all produce very similar results. However we tend to make a very specific recommendation for patients with a large cell neuroendocrine cancer and in fact we treat it very much like we would a small cell lung cancer.

For decades we’ve known that cisplatin or carboplatin in combination with a drug known as etoposide is a very effective treatment approach for small cell lung cancer and because large cell neuroendocrine is in the same family and has so many similar features, the most common recommended approach in terms of the chemotherapy that we would favor is cisplatin or carboplatin in combination with etoposide. Other options are certainly reasonable, but they are not as commonly recommended.

Unfortunately we don’t have a lot of actual research yet on the best approaches for patients with advanced large cell neuroendocrine cancers, but we’re starting to look into that for the first time in a very meaningful way. Until we have those results, we really do tend to favor a platinum and etoposide approach.


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