Top Immuno-Oncology Takeaways

ACCC Immuno-Oncology Institute Executive Committee Chair Lee Schwartzberg, MD, FACP, highlights his top picks for compelling, potentially practice-changing immunotherapy abstracts presented during the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Dr. Schwartzberg is Chief, Division of Hematology Oncology; Professor of Medicine, University of Tennessee; and Executive Director, West Cancer Center, Memphis, TN.

What were the standout sessions on immunotherapy at ASCO?

Important Messages About Combination Therapy in Non-Small Cell Lung Cancer

Lee Schwartzberg MD, FACP: There were many immuno-oncology presentations, but the ones that stood out focused on lung cancer. These studies continue to demonstrate the value of immune checkpoint inhibitors in first-line and second-line treatment of non-small cell lung cancer NSCLC). If we couple the data that was released just a few weeks before ASCO at the American Association for Cancer Research (AACR) meeting,¹ the ASCO presentations clearly cement a new paradigm for the treatment of first-line NSCLC.

We now know from several studies that were presented, (e.g., KEYNOTE-407 study) that the combination of chemotherapy with carboplatin and paclitaxel or nab-paclitaxel, and pembrolizumab is an option for patients with squamous cell carcinoma.² I think it’s fair to say that with the data that came out from ASCO and AACR, that all patients with NSCLC benefit from the addition of an immuno-oncology agent, whether or not they express PD-L1.

There does appear to be a differential benefit for higher expressions of PD-L1, but even the patients who had no expression seem to have at least some benefit. So, I think many people have interpreted this as practice changing to the extent that patients who are unselected by PD-L1 status are potential candidates for pembrolizumab added to platinum doublet chemotherapy, with pemetrexed the partner for non-squamous and paclitaxel the partner for squamous histology.

The one possible exception to that, which we only have cross-trial comparisons on, is for patients who have high PD-L1 (> 50%). As was shown in KEYNOTE-042, patients who have over 50% PD-L1 have excellent outcomes with pembrolizumab monotherapy.³ Of course, you’re always making decisions based on the individual patient in front of you, and for a high PD-L1 expressing patient that needed a rapid response, you might use a combination.

But clearly, there are now a couple of different options. For non-squamous patients, the standard of care in terms of chemotherapy would be carboplatin and pemetrexed with pembrolizumab where we have survival data. And we have that from KEYNOTE-189.⁴ We also have data that was presented at ASCO from the IMpower 131 trial that looked at carboplatin nab-paclitaxel, bevacizumab with or without atezolizumab in all histologies.⁵ IMpower 131 showed a progression-free survival (PFS) benefit, but we don’t yet have the overall survival with this regimen.

Other biomarkers may also define a subset candidates for alternative therapy. For instance, patients who have high tumor mutational burden (TMB) and are PD-L1 negative show PFS benefit from the combination of ipilimumab plus nivolumab. This combination would be particularly attractive because the benefit from chemotherapy plus pembrolizumab in this subset is more modest, and ipilimumab plus nivolumab may be a less toxic regimen in that case, although it’s more toxic than monotherapy.⁶

Still Work to Be Done in Other Cancers

Dr. Schwartzberg: We heard about some additional studies in breast cancer. I would say monotherapy in breast cancer is not a very effective approach, so the thrust in breast cancer has been a combination of chemotherapy, plus a checkpoint inhibitor. We saw some additional data in the neoadjuvant setting in triple negative breast cancer which showed some modest benefit,⁷ somewhat less than we saw in the I-SPY study.⁸ 

So, we’re anxiously awaiting the phase 3 trials that have been completed with checkpoint inhibitors – either pembrolizumab or atezolizumab in combination with chemotherapy in triple negative breast cancer. We expect those to report out at the end of this year or early in 2019, and I think we’ll have a clear idea of whether there’s a group of patients that should receive an immune checkpoint inhibitor in first-line metastatic breast cancer by next year.

There was some interesting data with prostate cancer.⁹ Monotherapy is not particularly effective in prostate cancer, so the strategies here will either be chemotherapy plus immunotherapy, like in NSCLC, or combination therapy that makes prostate cancer so-called “hotter” and more immune responsive. We know that if these tumors turn out to be “hot” or have lots of neoantigens, a high TMB, and the cancers that do have those characteristics – high PD-L1, high tumor mutational burden, high mutations in general – like melanoma and squamous cancers tend to be the ones that respond best to single-agent PD-1s or PD-L1 antibodies.

There was also interesting data with breast and ovarian cancer, looking at combining checkpoint inhibitors with PARP inhibitors.¹⁰ There’s a fairly strong preclinical rationale for this approach, because DNA-damaging agents like PARP inhibitors appear to increase neoantigens and, therefore, potentially make immune checkpoint inhibitors more potent. They may stimulate gamma interferon production, which is known now to be a central component of improving the effect of cytotoxic T-cells.

So, there are a couple of different mechanistic reasons that PARP inhibitors could work in diseases where they have some activity. We’ve seen phase-2 data now with niraparib and pembrolizumab from the TOPACIO trials in both breast cancer and ovarian cancer that were presented, where patients both with BRCA mutations and those without BRCA mutations had good responses in heavily pre-treated patients.¹¹ So that’s an interesting signal.

We saw a number of other combination treatments, but I would say none of them were so effective that they got our attention as a particular path that’s going to go forward, with the exception of ipilimumab and nivolumab. This combination is continuing to mature in several areas. It’s already approved, obviously, in renal cancer and also has activities we talked about in NSCLC and it’s being evaluated in other cancers.

What are the key clinical issues stemming from research presented on checkpoint inhibitors in patients taking antibiotics?

Antibiotic Use and Checkpoint Inhibitors

Dr. Schwartzberg: We have now an evolving body of data around antibiotic use with checkpoint inhibitors and that relates to a couple of things that the ACCC Immuno-Oncology Institute is really focusing on. First, how do we translate the clinical trial data into real-world usage? In many cases, clinical trials are proscriptive on the medications that patients can be taking to get into the trial. That’s not true in the real world where patients may be on all kinds of medications.

Many patients take antibiotics for many reasons, and we all know that when you go to a primary care doctor with a fever, you’re going to get an antibiotic whether it’s viral or bacterial. In most cases, those don’t have any negative effects. But the study presented at ASCO was a retrospective review of patients who were getting antibiotics within two weeks of starting their immunotherapy.¹² They did seem to have worse outcomes in terms of both response rates and progression-free survival, and even overall survival.

And that came on the heels of another trial that was published in the Annals of Oncology in June which showed very similar results, in that the outcomes were worse for patients who got antibiotics.¹³ Now, this is not so far-fetched at all, because we’re just beginning to understand the interaction of the microbiome of the gut with cancer and with treatment of cancer, and there are many different studies now that are looking at the importance of the microbiome in the overall ecology of a person. We haven’t really focused on this before, but we know that the gut microbiome has an essential role in immunity and possibly autoimmunity.

So, it makes a lot of sense that altering the ecology of a gut microbiome could impact the response to immune therapy. This early retrospective data provides a note of caution about keeping patients on antibiotics at the same time they’re starting immune therapy.

Steroid Use and Checkpoint Inhibitors

The second issue is around steroid use. There were early concerns about steroid use with checkpoint inhibitors: that they could be deleterious to patients or blunt the effect of checkpoint inhibitors. That turned out, for the most part, to not be correct. We now strongly recommend steroids whenever there’s a severe immune-related adverse event (irAE). And the impact on efficacy downstream for steroids that are used to treat the irAE don’t seem to impact on the long-term outcome of patients that stay on checkpoint inhibitors.

We also know that there doesn’t seem to be really any detriment of using pulse steroids in conjunction with chemotherapy as antiemetics, or as anti-allergic medications as are typically used when you give a platinum doublet with paclitaxel. One could argue that a benefit of using nab-paclitaxel in the treatment of NSCLC is no requirement even for pulse steroids with this agent.

However, a study from Sloan Kettering presented at ASCO looked at a large number of patients and found that patients who were on chronic steroids at doses that would still even be modest – at least 10 mg of prednisone a day – did not do as well on checkpoint inhibitors.¹⁴ The lesson is, don’t be afraid of steroids to treat adverse events. Don’t be afraid of intermittent pulse steroids in conjunction with chemotherapy. But unless there’s a good reason for patients to be on long-term steroids, try to get them off.

However, these findings could be a surrogate for some of these patients having other diseases (e.g., autoimmune diseases) that might increase toxicity of checkpoint inhibitors or decrease activity in a different way.

In the last 18 months, there’s been a lot of activity concerning the management of irAEs and there are now several clinical practice guidelines. What needs to happen to keep these recommendations moving into community cancer settings?

Evolving irAE Management

Dr. Schwartzberg: There were a number of abstracts on symptom management of irAEs from different viewpoints. Immune-related adverse events tend to happen late, and not necessarily in the first couple of months of treatment. So clinicians have to be highly attuned to considering adverse events later in the course of therapy.

The most common events are usually thyroid and skin reactions, and monitoring is paramount. Skin is fairly easy to monitor, obviously, because you’re looking at the patient every time they come in. Most centers have instituted routine monitoring of thyroid function, which is very simple to do, and intervene when signs and symptoms of hypo- or hyperthyroidism are recognized. The same goes for skin reactions.

We do see that the scope of irAEs has increased over time. The Food and Drug Administration presented an analysis of adverse events related to reports that they’ve received in the cardiovascular space,¹⁵ which is not something that we’ve particularly been focusing on. Cardiovascular irAEs are not very common. But I thought it was interesting that hypertension was one of the adverse events that stood out. More common irAEs for patients receiving checkpoint inhibitors than in a matched normal population are vasculitis, pericarditis, and even ischemia.

So, it’s possible you’re getting some inflammation there, and reaction. We have to be vigilant about patients potentially having cardiovascular events – if they were high risk before treatment, they could get worse after immunotherapy.

A couple of abstracts focused on the economic aspects and the organizational aspects of irAEs, and we do find that the number of patients getting admitted for immune-related adverse events has gone up over the years.¹⁶ We need to be careful about the number of patients being admitted. Early recognition of an irAE when a patient is sick enough to go to the hospital is really key to keep the economic cost down.

These events not only cover a wide spectrum, but they can also occur late, and not unusually occur even after a year of therapy. Unlike chemotherapy toxicities which tend to occur early, these can occur late. So, again, vigilance throughout the course of these patients’ treatment is really important.

Toxicity Teams

There was an interesting study from Johns Hopkins that created an interdisciplinary team within the institution to handle irAEs. This team is almost like a specific palliative care team that’s focused only on patients getting immunotherapy and included multidisciplinary experts from not only oncology, but also other specialties.

Although that’s not something that could easily be done in the community, per se, I think it’s important for community oncologists to have their “go-to” pulmonologists, cardiologists, dermatologists, and gastroenterologists and endocrinologists who they communicate with on a regular basis specifically around patients getting I-O therapy. These subspecialties can provide attention, opinions, and expertise early on in the irAE trajectory. And that’s my learning from that. If you have that expertise in-house, even better.

[Learn more about how the team at Johns Hopkins was created.]

CAR T-Cell Therapy

Cellular therapy is continuing to gain traction, and we’re now seeing exciting results not only in lymphoma and leukemia, but also in multiple myeloma, which is likely to be the next area where cellular therapies using CAR-T becomes an approved therapy. It’s much more difficult in the solid tumors, and it will be several years before we start to see strong results in that area, but the work in hematologic malignancies is moving very quickly.

The next big hurdle for CAR-T therapy will be reimbursement. ACCC is working on this, but I think patient access and reimbursement for cellular therapy is going to be a dominant theme over the next year or two. This will be very difficult to solve, given the cost of these therapies, the need for tremendous resources and supportive care, and the ability of institutions to pay for this and for patients to have access to these potentially life-saving therapies.

[Read the ACCC comment letter to CMS’ NCA on CAR T therapy.]

References

1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.
2. Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). Presented at the American Society of Clinical Oncology Annual Meeting June 3, 2018 (Abstract 105).
3. Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Presented at the American Society of Clinical Oncology Annual Meeting June 3, 2018 (Abstract LBA4).
4. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.N Engl J Med. 2018;378(22):2078-2092.
5. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol.2018;36 (suppl; abstr LBA9000).
6. Borghaei H, Hellmann MD, Paz-Ares LG, Ramalingam SS, Reck M, et al. J Clin Oncol. 3018;36(suppl; abstr 9001).
7. Loibl S, Untch M, Burchardi N, et al. Randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC). J Clin Oncol. 2018;36(15_suppl):104-104.
8. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol. 2017;35(Suppl 15) abstract 506.
9. Stein MN, Fong L, Tutrone RF, et al. KEYNOTE-046: ADXS-PSA plus pembrolizumab (pembro) in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2018;36(15_suppl):5019-5019.
10. Vinayak S, Tolaney SM, Schwartzberg LS, et al. TOPACIO/Keynote-162: niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. J Clin Oncol. 2018;36(suppl; abstr 1011).
11. Vinayak S, Tolaney SM, Schwartzberg LS, et al. TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. J Clin Oncol. 2018;36 (suppl; abstr 1011)
12. Tinsley N, Zhou C, Villa S, et al. Cumulative antibiotic use and efficacy of immune checkpoint inhibitors in patients with advanced cancer. J Clin Oncol. 2018;36 (suppl; abstr 3010).
13. Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018;29(6):1437-1444.
14. Arbour KC, Mezquita L, Long N, et al. Deleterious effect of baseline steroids on efficacy of PD-(L)1 blockade in patients with NSCLC. J Clin Oncol. 2018;36(15_suppl):9003-9003.
15. Amiri-Kordestani L, Moslehi J, Cheng J, et al. Cardiovascular adverse events in immune checkpoint inhibitor clinical trials: A U.S. Food and Drug Administration pooled analysis. J Clin Oncol. 2018;36; (suppl; abstr 3009).
16. Reynolds KL, Cohen JV, Durbin S, et al. Inpatient admissions related to immune-related adverse effects (irAE) among patients treated with immune checkpoint inhibitors for advanced malignancy: A tsunami is coming, but are we ready? J Clin Oncol. 2018;36(5_suppl):127-127.