Targeted Oncology Staff Writer

 Case Based Peer Perspective event, Corey J. Langer, MD, director, Thoracic Oncology, Abramson Cancer Center, professor of Medicine, Hospital of the University of Pennsylvania in Philadelphia, PA, discussed options for a 63-year-old patient with stage III non–small cell lung cancer.

™: Can you discuss the presentation of this patient with stage III non–small cell lung cancer? 

: This is a classic case of stage III, or apparent stage III [locally advanced lung adenocarcinoma]; we don’t have the biopsy results yet. Transbronchial lung biopsy of the left upper lobe mass and node sampling showed adenocarcinoma at the primary site and in 4L and level 7 nodes. Level 7 subcarinal and level 4R contralateral were negative, so this patient is T2aN2M0 stage IIIA. Based on the bulk and extent of mediastinal disease, active emphysema, and borderline PFTs [pulmonary function tests], the patient’s cancer was deemed unresectable. Even if it had been resectable, he might have been deemed medically inoperable. He was referred for consideration of concurrent chemotherapy and radiation [cCRT].

The rule of thumb [with cCRT] is, preexisting interstitial lung disease [ILD] is at least a relative contraindication, as is any preexisting inflammatory disease above and beyond random episodes of pneumonia. Patients with progressive disease will often have a fair amount of interstitial markings, so you have to be careful. My other rule of thumb is, if they’ve got lousy PFTs, FEV1 [forced expiratory volume in 1 second] less than 1, I’m not sure that’s somebody you’re going to treat concurrently. That may be someone you treat sequentially and use different forms of radiation.

What are the recommended cCRT options from the National Comprehensive Cancer Network (NCCN) guidelines?

The current NCCN guidelines for cCRT include cisplatin plus etoposide and weekly paclitaxel plus carboplatin. In this COVID-19 [coronavirus disease 2019] era, when I’m trying to cut down on the number of institutional contacts, I’ve [increasingly] been giving [2 other NCCN guideline-recommended regimens], carboplatin/pemetrexed [Alimta] and cisplatin/pemetrexed, in stage III disease.1 We have data from the PROCLAIM trial [NCT00686959] showing cisplatin/pemetrexed is at least equivalent to older etoposide/platinum regimens.2 As far as I’m concerned, these are the standard regimens, and I’m hardpressed to show any major differences in outcome using any of these regimens. There’s always been this prejudice against carboplatin-based regimens that somehow they’re inferior. But we have data…that refute that supposition.

When is it best to initiate immunotherapy following radiation in a patient such as this?

I think 6 months is beyond the window of opportunity. I’ve done it at 2 months. I have to say that’s outside of the window of PACIFIC [NCT02125461]. It should be noted the Hoosier Oncology Group trial, which used pembrolizumab in the same setting, did extend the interval. They didn’t mandate a 2- to 6-week window, and they did go up to 8 weeks.

Which data support durvalumab in a patient with a partial response (PR) to cisplatin/pemetrexed and cCRT?

The PACIFIC trial was started before we had much data for durvalumab [Imfinzi] in stage IV recurrent disease. Randomization was 2:1, durvalumab versus placebo, for up to a year, every 2 weeks, [with randomization occurring] up to 6 weeks after cCRT. To be enrolled, patients had to have performance status 0 or 1. If patients’ status was 2 or 3 they weren’t eligible. Many patients are 1.5 or 2 and I’m sure some sneaked on, but by definition patients should have had a decent performance status. We don’t know the extent of their tumors or their PET status prechemoradiation. Those data were not tracked. Primary end points were overall survival [OS] and progression-free survival [PFS], and the key secondary end points [were overall response rate, duration of response, safety and tolerability, and patientreported outcomes].

The PFS curves were unprecedented. The hazard ratio was 0.51 [95% CI, 0.41-0.63]; [the durvalumab arm PFS of 17.2 months was] essentially triple the PFS of the placebo arm of 5.6 months and far better than we’ve seen historically. The benefit was persistent over time, which was reported in the supplement to Scott Antonia’s first paper.

 Updates have shown that this benefit persists. There was a plateau at 2 to 3 years in the durvalumab arm. There was a plateau, as well, in the placebo arm, but far lower than for durvalumab. There was about a 23%\ [difference in] improvement in 18- to 24-month PFS [between the 2 arms].

PFS benefits were seen across the board. They were independent of histology, although a bit more pronounced in the nonsquamous group. The HR [in the nonsquamous group] was 0.45 [95% CI, 0.33-0.59] versus 0.68 [95% CI, 0.50-0.92] for the squamous group. [PFS benefit was independent of] age group, gender, smoking status, and stage IIIA or IIIB. Even the PD-L1 less than 25% and PD-L1 unknown subgroups had a PFS benefit [HR, 0.59; 95% CI, 0.43-0.82 and HR, 0.59; 95% CI, 0.42-0.83, respectively]. Only 43 patients [across both arms] had EGFRmutant tumors, about 5% of all enrollees. The corresponding confidence interval was wide but overlapping unity [HR, 0.76; 95% CI, 0.35-1.64].

In the subgroup analysis of about a quarter of all those enrolled who were able to complete radiation and be randomized within 14 days, the HR was relatively superior, 0.39 [95% CI, 0.26-0.58], compared with 0.63 [95% CI, 0.49-0.80] for those who were randomized between 14 and 42 days, which is the more typical HR. Patients in the first category probably had lower volume tumors, fewer complications, no overt [adverse] effects, and were ready and motivated to go. There may have been other variables that conspired to result in this superior PFS benefit… but these results have been used to argue for more rapid institution of durvalumab.

The updated survival benefit was presented by Jhanelle Gray, MD, last year at ASCO [American Society of Clinical Society].

 I don’t think there’s a more recent curve, but I was a skeptic until the OS results came out. Once they came out, I embraced this approach wholeheartedly. There was [nearly] a 14% [difference in] improvement [between the 2 arms] at 3 years…and, again, a plateau in the OS curves. The median OS in [the durvalumab arm]—patients who completed cCRT without progression and went on to durvalumab—had not been reached. More than 50% of patients in that arm were alive at 3 years. The placebo group, compared to historic controls, was doing fairly well, with OS of about 43%, which was inferior to durvalumab. The durvalumab arm benefit was not just a statistically significant but [also] a clinically meaningful improvement.

For patients who had PD-L1 less than 1% in the post hoc analysis, the HR at the time of the second paper was 1.36 [95% CI, 0.79-2.34]. In the other PD-L1 groups, there was a survival benefit [greater than or equal to 1% (HR, 0.53; 95% CI, 0.36-0.77); less than 25% (HR, 0.92; 95% CI, 0.63-1.34); greater than or equal to 25% (HR, 0.46; 95% CI, 0.27-0.78)]. For patients with 

-mutant tumors, so few events occurred [durvalumab, 10 events in 29 patients; placebo, 6 events in 14 patients] that there were no survival data for the 5% or so of patients with 

Less than 60% of patients enrolled had adequate tissue for PD-L1 assessment. Only about 20% of patients enrolled had a PD-L1 status of 0.4 An update on survival at 3 years [showed] the HR had dropped from 1.36 [95% CI, 0.79-2.34] to 1.14 [95% CI, 0.71-1.84] and the confidence intervals were clearly overlapping unity.

 The EU [European Union] has taken this seriously. In an effort to limit cost, their approval for durvalumab is restricted to patients with tumors that are PD-L1 positive, 1% or higher.

 In the US, the approval is a blanket approval, independent of PD-L1 status.

Should durvalumab be started in a patient with PD-L1 less than 1% or patients with known 

There may be priming by radiation that can actually induce PD-L1. PD-L1 status was tested for on the original diagnostic specimen; it was not tested postchemoradiation…so we don’t know the [PD-L1 tumor status of patients] at the time durvalumab was started in PACIFIC.

In the dark ages, it was radiation alone and, until 2017, it was just cCRT. Every attempt to improve upon that with rituximab [Rituxan], with expanding the dose of radiation to 74 Gy, with empiric use of TKIs [tyrosine kinase inhibitors] independent of 

 status, all of those—or more chemo, 3 cycles of docetaxel— all those studies were consistently negative. There wasn’t a hint of PFS or OS benefit.

We know a lot in metastatic disease…but we don’t have a lot of data for this scenario for people who received cCRT in stage III and then went on to a TKI. How can the dose of durvalumab be adjusted for those who are concerned about reducing potential exposure to coronavirus disease 2019 (COVID-19)? 

Standard dosing is every 2 weeks; that’s the FDA approval. However, the current PACIFIC trials are looking at dosing every 4 weeks. I think many are moving to [this] regimen. It’s not the standard, but in light of COVID-19 it can make sense.

What are some of the relevant safety data from PACIFIC?

In PACIFIC, any-grade pneumonitis occurred in about a third of patients [in the durvalumab arm] compared with a quarter of patients in the placebo group; rates of grade 3 and 4 [pneumonitis] were low…3.4% [for the durvalumab arm] versus 2.6% [for the placebo arm]. There was no major difference in grade 5 [pneumonitis, 1.1% for durvalumab vs 1.7% for placebo]. The discontinuation rates were a bit higher for the durvalumab group [15.4%] compared with the placebo group [9.8%]. Any-grade pneumonia, and this didn’t include just pneumonitis but infectious pneumonia, was double [the rate] in the durvalumab arm [13.1% compared with 3.8% in the placebo arm]. For immune-mediated adverse events [imAEs], there was a 3-fold difference, 24% versus 8% [for durvalumab vs placebo], but they were mostly grade 1 or 2. The grade 3 and 4 [imAE] rates were 3.4% [for durvalumab] vs 2.6% [for placebo].

The NCCN Guidelines now include consolidated durvalumab: every 2 weeks for up to 12 months; it’s a category 1 designation.

The NCCN deleted its earlier recommendation for an additional 2 cycles of full-dose chemotherapy if patients have not received full-dose cCRT, based on concerns that the risk of pneumonitis will go up if they subsequently receive durvalumab.

 This was not included in the PACIFIC study and, in that setting, durvalumab was substituting for and probably doing better than chemotherapy. I still give 2 cycles to patients who are not candidates for durvalumab, but if they’re going to get durvalumab, I do not give it.

Are there patients who should not receive durvalumab? 

Patients with immune-mediated diseases, collagen and vascular diseases, inflammatory bowel disease, and organ recipients [are not good candidates for durvalumab]. I’ve given it to a patient who had renal transplant, figuring that if things got bad, they could go on dialysis. I have not been brave enough to give it to people who had heart or liver transplants. It really depends on the circumstances. In patients with preexisting ILD or poor PFTs, I usually hold off.

This patient received durvalumab after cycle 8. He developed fatigue, mild shortness of breath, and cough, but…no chest pain. He had no fever, no recent sick contacts, or flu. His vaccines were up-to-date, and his chest CT showed reticular nodular interstitial markings on both sides, but particularly the left.

How should immune-related pneumonitis be managed in patients on durvalumab?

Patients with grade 3 or 4 pneumonitis, I will not rechallenge. For patients with grade 1, I will. I start right off the bat with milligrams per kilogram if it’s severe enough to cause an interruption in therapy. Depending on how quickly they improve, I’ll taper accordingly. In some cases, I rechallenge with steroids on board. Many studies now will allow up to 10 mg of prednisone baseline, figuring that they may have needed this for COPD [chronic obstructive pulmonary disease] or other issues. If I do rechallenge, I don’t do it without at least some steroid. I’ll give the patient 5 or 10 mg. You really have to be very selective about the patient. If they develop pneumonitis on rechallenge, they’re done.

ASCO guidelines for management of immune-related pneumonitis state that…for grade 1, hold the [immune] checkpoint inhibitor [ICI]. Repeat scans in 3 to 4 weeks…and consider PFTs. If there’s radiographic evidence of improvement, you can rechallenge. Even in this group, I might give some steroids. Monitor these patients closely, with exams and pulse oximetry. For grade 2, the ASCO guidelines say to hold the ICI…and start prednisone, 1 to 2 mg/kg per day. I don’t do 2 mg/kg unless the patient is very sick, and if that’s the case, they’re usually in the hospital. There can be other conditions causing the pneumonitis…so consider bronchoscopy with BAL [bronchoalveolar lavage] and, if they’ve got fever, empiric antibiotics. If there’s no improvement after 2 to 3 days [on steroids], treat as grade 3.

In this age of COVID[-19], the work-up would include a COVID-19 test, as well as sputum cultures, blood cultures if they’re febrile, and bronchoscopy if you have the suspicion that there’s some other agent involved.

Per the ASCO guidelines, with grade 3 or 4 pneumonitis, stop the ICI permanently. The patient doesn’t need oxygen if they’re that sick. Use a higher dose of steroids, and if steroids

aren’t working, there are some other options, including infliximab and mycophenolate. I’ve used both. I’ve also used IVIG [intravenous immunoglobulin] as the ASCO guidelines suggest. I’ve not used cyclophosphamide or cyclosporine. Taper steroids slowly over 4 to 6 to 8 weeks.

Frequently, you have a devil of a time getting these patients below 10 to 20 mg. In this sort of situation, it’s absolutely essential there be multidisciplinary management. Pulmonologists are an integral part of the team. If these patients end up in the hospital, the infusion team are an integral part of the team. There are 4 players: medical oncologists, radiation oncologists, pulmonologists, and [the infusion team].

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 6.2020. Accessed September 26, 2020. https://bit.ly/2EAH60w

2. Senan S, Brade A, Wang L-H, et al. PROCLAIM: randomized phase III trial of pemetrexed- cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. 

l. 2016;34(9):953-962. doi:10.1200/JCO.2015.64.8824

3. 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.

l. 2017;28(suppl 5):v634. doi:10.1093/annonc/mdx440.049

4. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. 

. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697

5. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. 

. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937

6. Grey JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. 

l. 2019;37(suppl 15):8526. doi:10.1200/JCO.2019.37.15_suppl.8526

7. Summary of product characteristics. European Medicines Agency. Accessed October 5, 2020. https://bit.ly/2SxKahO

8. Imfinzi. Prescribing information. AstraZeneca; 2017. Accessed October 5, 2020. https://bit.ly/3jANBAa

9. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. 

. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385

Articles

During a Targeted Oncology Case Based Peer Perspective event, Corey J. Langer, MD, discussed options for a 63-year-old patient with stage III non–small cell lung cancer.

Consolidation Immunotherapy Following Chemoradiation for Stage III NSCLC Is Standard of Care for Most Oncologists

Laura M. Kulik, MD, professor of Medicine (Gastroenterology and Hepatology), Radiology and Surgery (Organ Transplantation) at the Feinberg School of Medicine at Northwestern University in Chicago, IL, talked through diagnosing a 77-year-old female patients with hepatocellular carcinoma as well as the treatment options for her disease during a Targeted Oncology Case Based Peer Perspectives event. 

™: What is your initial impression of this case?

Looking at this patient, she has metastatic disease and her age—as a hepatologist, the first things that I’m always running through in my mind are: Is this a surgical patient, [is there] the option for resection, and is this a transplant candidate? In this patient, the answer to these is clearly no.

Would you recommend a biopsy for this patient?

We are seeing a rise in cholangiocarcinoma, particularly among people who are older, and this patient is 77. She has risk factors for cholangiocarcinoma with scar tissue, including excessive alcohol use, hepatitis C virus [HCV], and hepatitis B [HBV].

We don’t do biopsies…in hepatology like we used to. We’re using noninvasive ways to assess whether someone has fibrosis. They may not be cirrhotic. We use things [such as] the Aspartate Aminotransferase [AST] to Platelet Ratio Index score, which looks at the AST and platelet ratio, the size of the spleen, the size of the portal vein, whether there’s presence of varices, et cetera. But it’s not always 100%, and about 25% of people who have a normal-appearing liver on an ultrasound may have underlying cirrhosis. And if someone does not have underlying cirrhosis—LI-RADS [Liver Reporting & Data System] is based on the presence of having cirrhosis—then a biopsy is required to make sure that this is indeed hepatocellular carcinoma [HCC].

LI-RADS keeps changing; it is a living document. If a patient’s reading on LI-RADS is 5, which meets the criteria of HCC, it is a 

96% chance that [the] patient does indeed have HCC. But many people do feel strongly about proceeding with a biopsy; [it] may be helpful not only for the diagnosis but potentially prognosis and potentially treatment strategies.

There’s always been the fear of bleeding. This patient is on apixaban, so I would not biopsy without the risk-benefit ratio of being able to stop her anticoagulant. Then there’s the fear of seeding; this patient already has metastatic disease. In my practice, if this was a transplant candidate, we would not allow biopsies because [our past transplant surgeon] was fearful of needle track seeding, based on [more than] 25 years of [experience] and seeing a handful [of occurrences].

Would your use of a biopsy be different if the patient did not have cirrhosis? And would it be different if this were a LI-RADS 4?

If this patient didn’t have cirrhosis, there’s a potential that this could be another type of a lesion because the risk of HCC is not as high without underlying cirrhosis; about 90% of people with HCC will have advanced fibrosis. Some of the guidelines have changed. European guidelines recommend in people with advanced fibrosis, which is stage 3 and stage 4, to do screening. Whereas the American guidelines have stuck with having underlying cirrhosis.

We know that this carries about an 80% chance that this will be HCC. But, as we’ve spoken about, if it is cholangiocarcinoma, there would be differences in how we would approach this patient. Some will undergo locoregional therapy if this wasn’t metastatic disease. If it is a mixed tumor, I’ve generally seen the oncologist do systemic therapy with gemcitabine and cisplatin before using something like a tyrosine kinase inhibitor [TKI].

Assuming that the biopsy was obtained, and it does confirm that this is a diagnosis of HCC, would you suggest further genetic analysis of the biopsy tissue?

Next-generation sequencing has become, on most tumors, standard of care. This is not something, as a hepatologist, that we’re 

generally sending. We send this to oncology to deal with. I haven’t seen a ton in HCC because there [have] not been a lot of actionable mutations.

There have been some data from Harding et al that looked at that, where they did a prospective trial and they did genetic analysis of tumors.

 They were able to differentiate people who were more likely to have an [improved] overall survival [OS] when you looked at TKI versus immunotherapy, based on the type of mutation, if it was an PI3K-mTOR versus WNT/β-catenin pathway present. But, when they looked at the number of people who had an actionable mutation, which we know in HCC is low, it was consistent with what we see in the literature.

I think that patients like when there’s more information, when you tell them you’re going to be doing this to see whether there is something that can be done that is outside what we normally would do. There [have] been a lot of genetic analyses and publications that have looked at this on an RNA level, all different types, and there’s a percentage of patients with HCC who would respond to an IDO inhibitor. So I think it is worth doing it, even though the number of patients that we find that we can do something on is not as high as what we would like.

What do the National Comprehensive Cancer Network (NCCN) guidelines suggest for patients in this setting?

For first-line therapy, there is no wrong answer.

 People can start with sorafenib [Nexavar], lenvatinib [Lenvima], or the combination therapy. There’s also a suggestion for nivolumab [Opdivo] monotherapy, or folinic acid, fluorouracil, and oxaliplatin in certain clinical circumstances.

Are there adverse effects that affect your choice of lenvatinib or sorafenib in a patient?

[With lenvatinib], appetite, fatigue, and weight loss are what I have seen [most] in these patients because they are already sarcopenic, which has been found to be a risk factor for cirrhotic patients and in many chronic diseases. I found [appetite] is more [of a problem] with lenvatinib, but I have been using it more and more as opposed to sorafenib, also in combination with locoregional therapy.

In terms of using locoregional therapy, if the patient has new lesions develop within the liver or after a number of treatments, when would you switch to systemic therapy?

I’ve been at meetings where the interventional radiologists are overdoing transcatheter arterial chemoembolization or overdoing radioembolization, to the point that the patients are no longer Child-Pugh A, which is the context that all these registrations were in. Once they [progress to] Child-Pugh B or C, they have potentially lost the opportunity for an improvement in OS associated with systemic agents. Every patient needs to be looked at as an individual in terms of making those decisions.

All these trials [that we discussed] were in patients who were Child-Pugh A. We have some evidence from GIDEON, and there’s also been a recent meta-analysis looking at sorafenib, but for some of these newer drugs, we don’t have extended real-world experiences yet, in terms of using them in patients with more advanced disease.

How does the patient’s Child-Pugh classification affect your treatment?

Patients are always going to want to try something because we finally have some drugs that have [shown] activity, so they’re willing to try. But one of the things I always point out to patients when we first start talking about this is the unfortunate situation that there are 2 things working against them: their chances of dying of liver failure, if they’re not a transplant candidate, say in this patient due to age and advanced disease, versus dying of their liver cancer. The liver cancer may be causing the liver failure because of the amount of tumor burden that they have.

In someone who is Child-Pugh B, they have a 30% chance, without cancer, that they will die in the next year without a transplant. It is difficult to temper that with patients and say, “I can make your cancer look better, but you may die as a result of your liver disease first.”

Albumin-bilirubin [ALBI] is the newer classification that is gaining use as opposed to the Child-Pugh classification. It’s simple to use. You look at the bilirubin and the albumin levels. There’s a calculator; you put the 2 points together, and it tells you whether the patient is a 1, 2A, 2B, or 3. There’s been a lot of work that’s looked at this in systemic options as well as in locoregional therapy and resection to help guide how these patients are going to do. I think there’s going to be more real-world data that will come, particularly in combination therapy because of the risk of varices. I would be more afraid of using something with a combination such as bevacizumab [Avastin] in someone whose Child-Pugh classification is worsening because we know that their chances of bleeding increase as their Child-Pugh increases.

Do you use TKI as a monotherapy in the first line for your patients with advanced HCC?

I think that with the excitement of the checkpoint inhibitors and now with the combination therapy, people are using this more. Personally, if we see a patient who has a portal vein thrombus— not within the main portal vein or not involving both the right and the left—and they’re otherwise a good transplant candidate, I would [suggest] radioembolization for them and then likely start lenvatinib.

I choose lenvatinib over sorafenib because of the increase of response rates, which is what we need to see in order…for this person to potentially [be eligible for] transplant.

What do you consider to be the most important end points in selecting systemic therapy for patients?

I would say that of the many [advisory] boards that I’ve gone 

to say that survival is [most important], and safety and tolerability are [right behind that]. Response rate, I think, is important, depending on what your goal is for that patient. If you’re never going to get this patient to transplant or even resection, some centers will be aggressive and will resect if they treat and they have an increase in their [future liver remnant] and a response in the portal vein, as long as it’s not main portal vein, then they will consider doing a resection on that person. Response rate is important if that is one of the goals or potentials.

Does the etiology of the patient’s disease of HCV versus HBV make a difference in terms of treatment?

In both of these diseases, we have good antiretroviral therapies, so we can apply that to hopefully keep the liver function sustained, so that they can receive anticancer therapy for a longer period of time. There was a meta-analysis conducted that had shown a trend. It wasn’t significant, but there was a high trend in patients with HBV doing better with lenvatinib compared with sorafenib, but no difference in patients with HCV in terms of outcomes.

This patient is not someone that [I would ever] downstage. I think it’s hard to not give patients a false sense that this could be something that could happen. At Northwestern Medicine, we’ve transplanted 5 people who have had nonmain portal vein thrombosis who have had a great response. There was a recent publication from Canada, as well as centers throughout the United States, that found the AFP level was a strong predictor. So, if it was less than 10 ng/mL and they had response in the portal vein, that these patients had OS of 5 years, I believe it was 60%.

If you had a patient who may potentially receive a transplant, what are your thoughts on using a checkpoint inhibitor?

In these patients, I have shied away from the use of a checkpoint inhibitor until we have more information. Patients who have been on immune checkpoint inhibitors will get a transplant with a great response. The question will be: Could you have not transplanted them, and they would have done fine because of the response that they had? Are they going to be at higher risk of graft loss as a result of rejection? It’s great that we have all these different treatments, but it also brings up additional questions.

What are the relevant data in this setting?

The SHARP trial [NCT00105443] was the first clinical trial that showed efficacy of a drug in HCC.4 These patients had no previous systemic treatment. They were randomized to sorafenib or placebo, with a primary outcome being OS and time to progression. This pivotal trial showed a significant improvement in OS, as well as an improvement in time to radiographic progression.

This led to the REFLECT study [NCT01761266], which was a head-to-head study looking at sorafenib versus lenvatinib.5 Lenvatinib was dosed according to patients’ weight, and sorafenib was the standard. Patients who had portal vein invasion that was main portal vein, or bile duct invasion, or greater than 50% of the liver were excluded from this study. OS was the primary end point.

This was designed as a noninferiority study. Lenvatinib numerically had better OS, at 13.6 months compared [with] 12.3 months [HR, 0.92; 95% CI, 0.79-1.06]. This was not significant, but it did meet the preassigned confidence interval of coming under 1.08 and therefore met its primary end point of noninferiority.

When you looked at things such as progression-free survival [PFS] and time to progression, as well as response rates, all of these were significantly improved in patients who received lenvatinib over sorafenib.

Lenvatinib is not inferior and had significant improvements and parameters such as time to progression and PFS.

1. Harding JJ, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. 

. 2019;25(7):2116-2126. doi:10.1158/1078-0432.CCR-18-2293

2. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 5.2020. August 4, 2020. Accessed September 16, 2020. https://bit.ly/2YGXWlA

3. Casadei Gardini A, Puzzoni M, Montagnani F, et al. Profile of lenvatinib in the treatment of hepatocellular carcinoma: design, development, potential place in therapy and network meta-analysis of hepatitis B and hepatitis C in all phase III trials. 

. 2019;12:2981-2988. doi:10.2147/OTT. S192572

4. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. 

. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857

5. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. 

2018;391(10126):1163-1173. doi:10.1016/ S0140-6736(18)30207-1

Laura M. Kulik, MD, talked through diagnosing a 77-year-old female patients with hepatocellular carcinoma as well as the treatment options for her disease during a Targeted Oncology Case Based Peer Perspectives event.

Kulik Addresses Transplant and Therapy in HCC

The use of chemoimmunotherapy as treatment of patients with treatment-naive stage IIIB or IV nonsquamous non–small cell lung cancer (NSCLC) was the topic of a 

 Case Based Peer Perspective discussion led by Charu Aggarwal, MD, MPH

Leslye M. Heisler associate professor for Lung Cancer Excellence at Penn Medicine in Philadelphia, PA. 

™: What’s the rationale for using a triplet chemoimmunotherapy regimen in untreated stage IIIB or IV nonsquamous NSCLC?

I would point to the KEYNOTE-189 [NCT02578680] clinical trial, which was a large randomized clinical trial evaluating the use of triplet chemoimmunotherapy in patients with stage IIIB or IV nonsquamous NSCLC.

translocation, and patients were randomized in a 2:1 fashion to receive the triplet [carboplatin or cisplatin plus pemetrexed (Alimta) and pembrolizumab (Keytruda)] every 3 weeks for 4 cycles followed by pemetrexed plus pembrolizumab maintenance or just the chemotherapy for 4 cycles followed by pemetrexed plus placebo maintenance followed by pembrolizumab every 3 weeks upon progression.

At a median follow-up of close to 2 years, the median overall survival [OS] was 22 months for the triplet, near doubling compared with chemotherapy alone with a hazard ratio of 0.56, and there was a tail to the [Kaplan-Meier] curve.

 There are some patients that are maintaining that benefit even at the almost 30-month mark.

The OS by different PD-L1 expressions, even for patients that had less than 1%, [showed] benefit with a hazard ratio of 0.52, and the benefit was clearly for all subsets, including for PD-L1 categories from 1% to 49% or greater than 50%. The patients who had tumors with PD-L1 expression greater than 50% seemed to 

be just hitting their median OS. It’s almost not reached with a hazard ratio of 0.59, so quite significant benefit with the use of triplet, even for this population.

If you look at progression-free survival data, I think it’s not as impressive for the PD-L1 less than 1% population, but overall in the total population, median progression-free survival has a hazard ratio of 0.48, and then there was an improvement seen across the other PD-L1–positive subgroups, 1% to 49% as well as the greater than or equal to 50%.

For the best overall responses, the response rates are much higher in patients who received the triplet. There are even some complete responders with triplet with an overall response rate that’s partial responses of about 48% with the triplet.

How do the findings from the KEYNOTE-042 trial affect your decision for treatment?

The data for using pembrolizumab in greater than 1% as monotherapy comes from KEYNOTE-042 [NCT02220894], which was presented in 2018 and 2019 at the American Society of Clinical Oncology Annual Meeting.

 This trial randomized patients with squamous and nonsquamous histology with metastatic NSCLC with a TPS [tumor proportion score] of greater than 1% to receive pembrolizumab monotherapy versus standard-of-care chemotherapy, which could be carboplatin plus paclitaxel for squamous disease or carboplatin and pemetrexed for nonsquamous disease. These patients had no history of untreated or unstable CNS [central nervous system] metastases. OS in patients with PD-L1 greater than 50%, greater than 20%, greater than 1% was the primary end point.

Patients who had a TPS of 1% to 19% [made up] about a third [of the cohort], and a majority of the patients were greater than 50%, so almost half of the patients had a high TPS 50% or greater score.

When we review the median progression-free survival [PFS], it doesn’t seem to be that significantly different from what we are seeing for chemotherapy alone with the exception of maybe the PD-L1 greater than 50%.

The median OS is 16.7 months with a hazard ratio of 0.81 compared with chemotherapy. I think the greatest benefit and the majority of the benefit was being derived from patients who had PD-L1 greater than 50% where we saw a hazard ratio that was close to 0.69 and then the PD-L1 greater than 20% were in the middle at 0.77 hazard ratio.

Looking at patients with PD-L1 to 49%, the hazard ratio was 0.92, so that demonstrates minimal advantage over chemotherapy alone. Some may argue that giving pembrolizumab monotherapy may be just as fine as giving chemotherapy in terms of efficacy for this population, but may avoid the toxicities, although I think if there is somebody who is able to receive triplet therapy should be able to receive it. On the other hand, I also hear the argument that there are some patients who just cannot receive chemotherapy, so this may be certainly a reasonable choice.

What are the implications of the IMpower150 [NCT02366143] trial?

I think the study has been dubbed as the 

of immunotherapy study. Basically, this was the atezolizumab [Tecentriq] version of KEYNOTE-189 building upon the success of the initial carboplatin, paclitaxel, and bevacizumab [Avastin] backbone.

Patients with stage IV metastatic NSCLC that were treatment naïve were randomized into 3 arms. Arm A was atezolizumab plus carboplatin and paclitaxel. Arm B was the main interventional arm, which was the quadruplet, and arm C was the control arm [of] carboplatin, paclitaxel, and bevacizumab. Maintenance therapy was different. Patients taking the quadruplet [regimen] received atezolizumab and bevacizumab maintenance and they received atezolizumab maintenance alone for arm A, and bevacizumab maintenance alone for arm C. This trial allowed for up to 6 cycles 

of induction and patients were treated with atezolizumab as well as bevacizumab until disease progression.

In the quadruplet arm there was a significant improvement with a 

value of .002, and there was an improvement, 19.2 months median OS for the quadruplet versus 14.7 months.

The OS for the intention-to-treat population, arm A versus arm C, shows that the addition of atezolizumab to carboplatin and paclitaxel did have somewhat of a benefit with a hazard ratio of 0.88. This was a trend. The efficacy boundary was not crossed, and this was not something that received approval, at least not from this trial.

The triplet for atezolizumab that led to its approval was IMpower130 [NCT02367781]. This evaluated patients with nonsquamous stage IV NSCLC randomized to receive atezolizumab plus carboplatin plus nab-paclitaxel [Abraxane] versus carboplatin plus nab-paclitaxel alone. Atezolizumab was the maintenance arm, and in this trial, patients could receive pemetrexed maintenance as a switch maintenance because they were starting with carboplatin and nab-paclitaxel. Patients were treated until progressive disease.

value was significant, and the use of carboplatin plus nab-paclitaxel plus atezolizumab was published in 

It led to an improvement in PFS as well as OS.

What are the treatment options for patients with stage IV NSCLC with no 

 This was a complicated study, in patients with stage IV NSCLC who were treatment naïve and did not have an 

alteration. Patients were analyzed and stratified by 2 groups; greater than 1% PD-L1 or less than 1% PD-L1. The data that we saw most recently looked at the combination of nivolumab [Opdivo] plus ipilimumab [Yervoy] versus histology-specific chemotherapy in both PD-L1–positive and –negative subgroups.

Patients had PD-L1 greater than 1%. Median OS was 17.1 months for nivolumab plus ipilimumab, and chemotherapy was 14.9 months. This was a positive trial. This was one of the primary end points with a hazard ratio of 0.79.

Overall, if you include the PD-L1–negative patients, this trial was still positive with a hazard ratio of 0.73. The OS came in at about 17.1 months. This has a long follow-up with curves out to 42 months, and even with that long follow-up, we are seeing a median OS of about 17.1 months. For patients with PD-L1 less than 1%, median OS was about 17.2 months.

Regarding safety, the data for grade 3/4 diarrhea was about 1.7%, and then the other toxicities don’t seem that significant. Overall, 33% rate of all-event AEs does not seem that bothersome, at least at this point in time. I think some of this may be related to the slightly modified dose 

Is there benefit to using a quadruplet regimen up front?

CheckMate 9LA [NCT03215706] is using the approach of quadruplet up front, giving a limited bolus of combination chemoimmunotherapy up front and then maintaining patients on nivolumab and ipilimumab later.

 Patients who were treatment naïve with NSCLC, no 

, were stratified by PD-L1, sex, and histology. Patients received nivolumab at 316 mg every 3 weeks, and ipilimumab was administered every 6 weeks. Chemotherapy was administered every 3 weeks for 2 cycles versus chemotherapy, which was every 3 weeks for 4 cycles. The primary end point was OS.

The median OS was 15.6 months versus 10.9 months for chemotherapy with a hazard ratio of 0.66. This has achieved approval based on the trial having met its primary end point. It does look like a positive trial, but I will point out that the chemotherapy arm, at 10.9 months, does seem to do quite as well as we would have expected it to do. Maybe 11 to 12 months may have been a better historical control.

Patients with PD-L1 less than 1% seemed to have a hazard ratio of 0.62. PD-L1 greater than 50% doesn’t seem to maintain that much of a differentiation in the long run, however. The curves look similar to each other, but there’s separation at 4 months or 6 months.

The disease control rate with the quadruplets was about 84% and 76% with chemotherapy. Overall response rate was about 38% with quadruplet versus 25% with chemotherapy. The duration of response was much longer with quadruplet at 11.3 months.

I think some of us have been concerned about using the quadruplet. About 358 patients on this trial were treated with the quadruplet and any treatment-related adverse event [TRAE], which was grade 3 or 4, was seen in about 47% of patients. However, serious TRAEs were in a quarter. Most common any-grade AEs were nausea, anemia, asthenia, and diarrhea.

The most common toxicities were skin, and there were some chemotherapy-related toxicities like anemia, neutropenia, alopecia, and thrombocytopenia. We didn’t see a lot of toxicity in terms of pneumonitis or colitis, but there was significant, as we would expect, endocrine 

abnormalities that were seen, which we are all well versed with in managing.

Based on this trial, FDA approved nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC and again, this is not based on PD-L1 expression. Patients received 2 cycles of chemotherapy, and then they received nivolumab and ipilimumab maintenance after that.

1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer

. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005

2. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from keynote- 189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. 

. 2020;38(14):1505- 1517. doi:10.1200/JCO.19.03136

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. 

. 2018;36(suppl 18):LBA4. doi:10.1200/ JCO.2018.36.18_suppl.LBA4 36

4. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. 

2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7

5. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. 

2018;14;378(24):2288-2301. doi:10.1056/NEJMoa1716948

6. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. 

2019 Jul;20(7):924- 937. doi:10.1016/S1470-2045(19)30167-6.

7. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. 

. 2018 May 31;378(22):2093- 2104. doi:10.1056/NEJMoa1801946.

8. Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. 

. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501

The use of chemoimmunotherapy as treatment of patients with treatment-naive stage IIIB or IV nonsquamous non–small cell lung cancer was the topic of a Targeted Oncology Case Based Peer Perspective discussion led by Charu Aggarwal, MD, MPH.

Aggarwal Examines Nivolumab Plus Ipilimumab in First-Line NSCLC

 Case Based Peer Perspective event, Anna C. Pavlick, DO, MS, MBA, assistant professor of Medicine (Interim), Weill Cornell Medical College, Cornell University, Weill Cornell Medicine in New York, NY, discussed the case of a 69-year-old patient with cutaneous squamous cell carcinoma. 

™: What are some of the tests you would recommend to treat this patient?

You could consider an MRI to rule out perineural invasion, especially with the numbness. Because most of these [lesions] are usually locally invasive, I don’t think it is necessary to scan for distant disease without any palpable adenopathy. However, I would certainly want to get an MRI to look at perineural [invasion].

How do you define locally advanced squamous cell cancer?

For me, when I first started looking at and being referred patients with advanced squamous cell, I had a melanoma mind-set. So to me, locally advanced melanoma means that I have a deep melanoma that also has positive lymph nodes. [Those] criteria [do] not hold true when it comes to squamous cell carcinoma. If you have lymph node involvement in squamous cell carcinoma, it’s considered metastatic disease. That was something I had to get my head wrapped around, because I always wanted to make them stage III, when in fact, they’re stage IV. I would probably define it as a lesion [that] cannot be resected safely by the surgeons with adequate margins.

Most surgeons are going to say that they can resect pretty much anything. But the question is, do you have multifocal disease? Are you going to be able to get clean margins? It is the clean margins that are important. Many of these patients will have multifocal disease, as well.

I know I’m fortunate that I have a cutaneous oncology team, which incorporates a medical oncologist, a surgical oncologist, head and neck, pathology, radiation oncology, and dermatology. Sometimes, patients like this will come to oncology, and [other times] patients like this will go to the surgeons. I’m fortunate enough to have my surgeons call me and say that we need to talk about the case. They sometimes ask, “Can you downsize this for me before I take the patient to the [operating room]?”

I have the luxury of having radiation oncologists in the same building who can discuss radiating this lesion, maybe because the patient doesn’t want systemic therapy.


What kind of follow-up data do we have for cemiplimab?

The phase 2 EMPOWER trial [NCT02760498] essentially 

evaluated cemiplimab in patients over a 3-year follow-up.1 The first cemiplimab trial [NCT02383212] evaluated patients who were all comers, locally advanced, as well as metastatic.2 Then there was an additional expansion cohort that looked at patients with just distant disease or just localized disease, as opposed to just clumping them together.

In the Rischin study, these patients had a 15-month follow-up.1 Looking at the data, 193 patients were enrolled. Group 1 was a mixture of 59 patients with locally advanced and metastatic disease. Then group 2 was 75 patients [with] locally advanced disease. And group 3 was 56 patients, and that was metastatic patients. The average age was 72, which I don’t think anybody is surprised about, with a higher percentage of those patients being men. About 70% of patients had the primary presentation site of the head and neck. About 40% of patients had locally advanced disease, whereas 60% had metastatic disease.

Whether patients had locally advanced or metastatic disease, the study demonstrated that the responses were essentially equal across all comers, demonstrating roughly a 50% response rate.

What did the clinical activity in this trial demonstrate?

Looking at clinical activity at 1-year follow-up and 2-year follow-up, patients have prompt responses. Usually, the time it takes for patients to respond to immunotherapy is about 2 cycles. The data in this study suggest that over time, you can develop more durable responses. You might have a partial response, which can then lead into a complete response.

Keep in mind, however, that response rates are only 50%. If you don’t see a patient responding by the second or the third cycle, and their tumor is growing, just cut your losses, move on, and accept the fact that this is a nonresponder.

Also, there is a plateau associated with progression-free survival and overall survival. In patients who do have responses, about 40% of those responders will have long-term durable responses. If you look at overall survival, 73% of patients are alive, which is exciting compared with the chemotherapy data. If you look at the chemotherapy data of 5FU [fluorouracil]/platinum or 5FU/platinum with cetuximab, you have about an 8-month average response. But there is no durability to that. These were exciting data.

During a Targeted Oncology Case Based Peer Perspective event, Anna C. Pavlick, DO, MS, MBA, discussed the case of a 69-year-old patient with cutaneous squamous cell carcinoma. 

Targeted Oncology Staff Writer | Authors

Articles

Consolidation Immunotherapy Following Chemoradiation for Stage III NSCLC Is Standard of Care for Most Oncologists

Kulik Addresses Transplant and Therapy in HCC

Aggarwal Examines Nivolumab Plus Ipilimumab in First-Line NSCLC

Pavlick Explores Role of Immunotherapy in Cutaneous Squamous Cell Carcinoma