Immunotherapy Paradigm Continues to Evolve in NSCLC

Mark A. Socinski, MD

Recent approval of immunotherapy in the first-line setting for treatment of patients with locally advanced and metastatic non—small cell lung cancer (NSCLC) without driver mutations represents “a fundamental change in care,” according to Mark G. Kris, MD. However, he and other experts who participated in an OncLive Peer Exchange^® panel agreed that integrating the recently approved agents into clinical practice will be the next challenge moving forward.

The panelists discussed the importance of testing for PD-L1 expression and managing immune-related toxicities early, as well as the ongoing trials of immunotherapy/chemotherapy and immuno/immuno (I/O) combinations. They agreed that combinations with immunotherapy may allow for effective chemotherapy-free regimens and introduce the possibility of longterm survival in settings with poor prognosis, such as unresectable NSCLC, but that clinicians need to be aware of the unique immune-related adverse events (AEs).

Testing for PD-L1 Expression

“Obviously, we need to be very [vigilant] in these patients,” said Kris. “But I do think that the chance of a cure justifies more risk.”PD-1/PD-L1 inhibitors have changed the therapeutic paradigm for lung and other types of cancer since they demonstrated durable clinical activity in a subset of patients with treatment-refractory disease.1 In NSCLC, patients with EGFR mutations or rearrangements in ALK or ROS1 remain candidates for first-line targeted therapies but the role of immunotherapy is rapidly changing. The KEYNOTE-0012 and KEYNOTE-0103 trials showed that patients with high PD-L1 expression (≥50% of tumor cells) had a higher response rate to pembrolizumab (Keytruda) in the first-line setting than those with lower or absent PD-L1 expression, which supports inclusion of PD-L1 immunohistochemistry in the standard testing panel, according to Kris. “You have to meet with your pathologist and make sure that it’s clearly explained why you need this test.”

Immune-Related Toxicities

Although some experts have indicated concern about variability among the PD-L1 testing platforms, a recent analysis4 showed greater than 90% agreement among 3 validated, commercially available PD-L1 immunohistochemistry assays at multiple expression cutoffs ranging from 1% to 50%. D. Ross Camidge, MD, PhD, stated that this high level of agreement is reassuring for widespread implementation of affordable assays in community practices (although he noted that the assay associated with atezolizumab [Tecentriq] may not correspond as well with the others). However, he also emphasized the importance of looking at PD-L1 expression as a continuous variable when analyzing the results of clinical trials or considering treatment options for patients. “By setting something that says, ‘we’re including people in our trial who are above this,’ they don’t suddenly all become homogeneous above that level.”The panelists also commented that toxicities associated with PD-1/PD-L1 inhibitors, such as pneumonitis and inflammation of the pancreas, liver, or thyroid, are distinct from chemotherapyrelated AEs and may not be apparent immediately. David R. Spigel, MD, pointed out that colitis that may occur with immunotherapy often resembles the diarrhea associated with other therapies and appears minor at first, but can lead to hospitalization if not addressed early with a course of steroids or temporary withdrawal of the immunotherapy drug.

Immune-Related Toxicities

Although some oncologists are concerned that steroids may reduce the efficacy of immunotherapy, Spigel stated that steroids may allow patients to continue receiving the PD-1 inhibitors and have not been shown to reduce efficacy with melanoma. Additionally, he stated that many participants were taking steroids in the pivotal trials that showed positive outcomes with PD-1 inhibitors. Mark A. Socinski, MD, moderator of the panel, also noted that erring on the side of early, aggressive management of toxicities is of primary importance, particularly with the lack of convincing data showing an interaction between steroids and PD-1 inhibitors. Kris also added that infliximab is a less toxic, often overlooked option that should be considered before steroids, particularly in patients who cannot tolerate steroids.Immunotherapeutic Agents

Unlike nivolumab (Opdivo) and pembrolizumab, which bind to the PD-1 receptor on lymphocytes, atezolizumab targets the PD-L1 on the tumor cells. Some experts have hypothesized that targeting PD-L1 may reduce the autoimmune effects that occur from direct inhibition of PD-1, but the results from the phase II POPLAR trial5 and phase III OAK trials6 , while showing that atezolizumab improved survival over docetaxel in the second-line setting, did not suggest differences in efficacy or toxicity between atezolizumab and pembrolizumab or nivolumab. “In terms of single-agent use, atezolizumab looks more similar than different [to pembrolizumab and nivolumab],” said Jared Weiss, MD.

Even if clinical efficacy and toxicity are nearly identical, the different settings in which the drugs were approved may be a deciding factor when choosing a PD-l/PD-L1 inhibitor. Nivolumab and atezolizumab are approved in the second-line setting regardless of PD-L1 status, whereas pembrolizumab was initially approved in the first- or second-line setting for patients with tumors expressing PD-L1 on ≥50% or ≥1% of their cancer cells, respectively.

In May 2017, the FDA granted accelerated approval for pembrolizumab to be used in combination with pemetrexed and carboplatin for first-line treatment of metastatic nonsquamous NSCLC regardless of PD-L1 status. This decision surprised the panelists, who noted that the cohort G of the KEYNOTE-021 trial7 did not show an increase in overall survival (OS) with the pembrolizumab-containing regimen, although the objective response rate was higher (55% vs 29% with pemetrexed and carboplatin alone). However, Spigel was optimistic that the ongoing phase III trial would further demonstrate the benefits of the pembrolizumabcontaining combination and that the accelerated approval will allow more patients to benefit.

The panelists also discussed the issues of patient convenience with each of the immunotherapies. Atezolizumab and pembrolizumab are dosed once every 3 weeks whereas nivolumab is dosed every 2 weeks, although the FDA recently accepted supplemental Biologics License Applications to add a dosing schedule of 480 mg every 4 weeks. Although these differences in frequency may seem minor, they may make a difference to patients who travel long distances to the clinic, according to Weiss. “I hand out a lot of gas cards by our local advocacy organization because people have trouble affording the gas to come into my cancer center,” he said. “In that context with that kind of population…it matters a lot.”

Immunotherapy Combinations

The rapidly evolving landscape of combination treatments for NSCLC, including immunotherapy/ chemotherapy and I/O combinations, has introduced the possibility of multiple combination options for first-line treatment within the next several years. However, the panelists noted that the disappointing outcome of the CheckMate-026 study,8 which failed to show improvement in progression-free survival (PFS) with nivolumab versus chemotherapy for first-line treatment of patients with metastatic NSCLC and tumors with PD-L1 expression on ≥5% of tumor cells, has increased emphasis on trial design and multiple primary endpoints in current trials to ensure that they obtain at least 1 positive outcome.

A prime example of this multiple endpoint approach is the phase III MYSTIC trial,9 which randomized patients with treatment-naïve advanced or metastatic NSCLC to receive durvalumab (Imfinzi; a PD-L1 inhibitor), durvalumab plus tremelimumab (a CTLA-4 inhibitor), or standard-of-care chemotherapy. In February 2017, the investigators added OS as a co-primary endpoint with PFS, included patients with PD-L1—expressing or PD-L1–negative tumors, and expanded their direction to look at durvalumab monotherapy and durvalumab plus tremelimumab. Although the durvalumab/tremelimumab combination10 showed antitumor activity in patients with PD-L1-positive and PD-L1-negative NSCLC, an interim analysis11 of the MYSTIC trial published on July 27 showed that neither the combination nor single-agent durvalumab improved PFS for any level of PD-L1 expression. The investigators will continue evaluating data on OS, which will be available in early 2018.

However, the panelists stated that the interim results of the phase III PACIFIC trial12 suggest that durvalumab following radiation and platinum-based chemotherapy may have a promising role for treatment of unresectable NSCLC, which has had poor outcomes that have not improved for decades. In the trial, patients with unresectable stage III NSCLC who received durvalumab after radiation and platinum-based chemotherapy had a significantly longer PFS than those who received placebo. After a median follow-up of 14.5 months, patients who received durvalumab had a median PFS of 16.8 months compared with 5.6 months for placebo (stratified HR, 0.52; 95% CI, 0.42-0.65; P <.0001), according to findings presented at the ESMO 2017 Congress, which was held September 8-12 in Madrid, Spain.13 According to the panelists, who commented based on an earlier announcement about the trial,12 these findings suggest that longterm survival is possible for unresectable disease. “It gives us at least some hint of hope that…for the first time in a very long time we might move the needle on cure,” said Weiss.

However, figuring out which combinations to use in clinical practice will be the biggest challenge for oncologists, according to the panelists. The negative results of CheckMate-026 have made Spigel hesitant to predict the outcomes of the ongoing trials, and he noted that the I/O combinations, such as durvalumab/tremelimumab and nivolumab/ipilimumab (Yervoy), may have delayed toxicities that are different from those with single-agent checkpoints and may play a factor in choosing a regimen.

Camidge predicted that pembrolizumab plus chemotherapy will be adopted first in clinical practice, regardless of PD-L1 immunohistochemistry. “I’m betting on the path of least resistance…I’m not saying scientifically that’s valid, but I think that’s what most people will do,” he said.

The other panelists noted that the immunotherapy combinations will likely be an attractive option for many physicians simply because they do not contain chemotherapy. “I think there’s such a push away from chemo…it’s like the win [is that] you can do something without chemo,” said Kris.

Weiss also noted a strong “cultural tidal wave” in favor of immunotherapy without chemotherapy in the oncology community, and the potential to increase the cure rate with immunotherapy combinations may justify a greater risk for developing toxicities among some oncologists and patients. “People don’t want their cancer coming back,” said Spigel. “They’re going to take that risk that’ll probably be manageable for most patients.” Antiangiogenic Therapy

The vascular endothelial growth factor-A (VEGF-A) inhibitor bevacizumab (Avastin) has fallen out of favor among many oncologists, possibly due to the shift away from maintenance therapies coupled with the groundbreaking data with immunotherapy, according to Socinski. The ECOG 5508 trial14 showed no significant improvement in the rate of 1-year OS with addition of bevacizumab to pemetrexed for maintenance therapy, and the panelists agreed that the rapidly evolving landscape of immunotherapy has made maintenance therapy an outdated concept. “It’s a 2013 question answered in 2018,” said Kris.

Multiple Possibilities on the Horizon

Ramucirumab (Cyramza), another anti-VEGF monoclonal antibody, is approved for use with docetaxel in the second-line setting for patients with metastatic NSCLC. However, the panelists noted that fewer oncologists are using docetaxel (with or without ramucirumab) for second-line treatment of NSCLC due to its toxicity and relatively low efficacy. Kris stated that he may consider docetaxel plus ramucirumab for patients with tumors that do not express PD-L1, have a low mutational burden, and do not demonstrate microsatellite instability in the second-line setting, whereas Socinski may consider it for patients with a history of autoimmune disease who may not tolerate immunotherapy.The panelists concluded the session by stating that the rapidly evolving field of treatment for lung cancer, including immunotherapy combinations, radiation therapy, and surgical approaches, is complex but promising for improving patient outcomes. According to Kris, the abundance of new options in the pipeline will require oncologists to carefully review the choices to determine the most appropriate course of treatment for each patient. “Even things that are outside the box like radiation, surgery—things that we would never have done 10 years ago, we’re doing now, and they can help individual patients,” he said. “So just make sure you think of everything.”

References

1. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454. doi: 10.1056/NEJMoa1200690.
2. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non—small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028. doi: 10.1056/NEJMoa1501824.
3. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7.
4. Ratcliffe MJ, Sharpe A, Midha A, et al. Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cutoffs in non-small cell lung cancer. Clin Cancer Res. 2017;23(14):3585-3591. doi: 10.1158/1078-0432.CCR-16-2375.
5. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-1846. doi: 10.1016/S0140-6736(16)00587-0.
6. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial [ Correction published in Lancet. 2017;289)10077):e5]. Lancet. 2017;389(10066):255-265. doi: 10.1016/S0140-6736(16)32517-X.
7. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3.
8. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426. doi: 10.1056/NEJMoa1613493.
9. Peters S, Antonia S, Goldberg SB, et al. 191TiP: MYSTIC: a global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy or durvalumab monotherapy versus platinum-based chemotherapy (CT) in the first-line treatment of patients (pts) with advanced stage IV NSCLC. J Thorac Oncol. 2016;11(suppl 4):S139-40. doi: 10.1016/S1556-0864(16)30300-8.
10. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299-308. doi: 10.1016/S1470-2045(15)00544-6.
11. AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer [news release]. Cambridge, UK: AstraZeneca; July 27, 2017. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2017/astrazeneca-reports-initial-results-from-the-ongoing-mystic-trial-in-stage-ivlung-cancer-27072017.html. Accessed July 28, 2017.
12. Imfinzi significantly reduces the risk of disease worsening or death in the phase III PACIFIC trial for stage III unresectable lung cancer [news release]. Cambridge, UK: AstraZeneca; May 12, 2017. https://www.astrazeneca. com/media-centre/press-releases/2017/imfinzi-significantly-reduces-the-risk-of-disease-worsening-or-deathin-the-phase-iii-pacific-trial-for-stage-iii-unresectable-lung-cancer-12052017.html. Accessed July 28, 2017.
13. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled Phase III study of durvalumab after chemoradiation therapy (CRT) in patients with Stage III, locally advanced, unresectable NSCLC. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA1.
14. Karayama M, Inui N, Fujisawa T, et al. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer. Eur J Cancer. 2016;58:30-37. doi: 10.1016/j.ejca.2016.01.013.