Alexander Spira, MD, PhD

Alexander Spira, MD, PhD, FACP, director of the Virginia Cancer Specialists Research Institute, discusses the rationale for combining amivantamab-vmjw (Rybrevant) and lazertinib (Leclaza) for the treatment of relapsed or refractory 

-mutant non–small cell lung cancer (NSCLC).


There are currently very few treatment options for patients with relapsed/refractory NSCLC harboring 

 mutations. Because of this, investigators are asssesing the combination of amivantamab, lazertinib, carboplatin, and pemetrexed (Alimta) in patients who have progressed after treatment with osimertinib (Tagrisso) and chemotherapy.

findings of the phase 1 CHRYSALIS-2 trial 

(NCT04077463) which evaluated the combination, encouraging responses were observed in patients who were pretreated with 

-mutant NSCLC. These data were presented at the 2022 IASLC World Conference on Lung Cancer.

 The goal of this is a couple fold. Number 1 is amivantamab is an antibody, so it works in a different mechanism of action than osimertinib. In theory, it should be able to overcome resistance. It binds 

 at the cell surface, so it can overcome any intracellular mechanisms of resistance.


The addition of osertinib has a couple of rationales. Number 1, it is is pretty well tolerated. Number 2 is not all cancer cells become resistant at the same time, so you're attacking it in a couple of different ways. The other real advantages that we hope and we know is that lazertinib has central nervous system penetration, so can help maintain central nervous system, ie brain responses, in this patient population, where amivantamab by itself does not do such a good job. One of the big things about osimertinib is that it has central nervous system penetration, so we'd like to keep that.

Videos

Alexander Spira, MD, PhD, FACP, discusses the rationale for combining amivantamab-vmjw and lazertinib for the treatment of relapsed or refractory EGFR-mutant non–small cell lung cancer.


Evaluating Amivantamab/Lazertinib Combo in EGFR-Mutant NSCLC

Alexander Spira, MD, PhD, FACP, director of the Virginia Cancer Specialists Research Institute, discusses the safety profile of amivantamab and lazertinib in 

mutated non-small cell lung cancer (NSCLC), based on 

 (NCT02609776) presented at the 2021 American Society of Clinical Oncology Annual Meeting.

According to Spira, the safety profile of the combination is very different from chemotherapy. The major adverse events include rash and diarrhea. Additionally, amivantamab may cause infusion-related toxicities. However, according to Spira, the combination in well tolerated.

Changes in patients’ nails and hair are also common with the combination. Most infusion-related reactions occur in the first day, according to Spira, and generally do not continue for much longer.

Alexander Spira, MD, PhD, FACP, director of the Virginia Cancer Specialists Research Institute, discusses the safety profile of amivantamab and lazertinib in EGFR-mutated non-small cell lung cancer, based on data from the CHRYSALIS tria.

The Safety Profile of Amivantamab and Lazertinib in EGFR-Mutant NSCLC

 Case-Based Roundtable event, Alexander Spira, MD, PhD, discusses when the use of durvalumab (Imfinzi) followed by chemoradiotherapy is appropriate for patients with unresectable stage III non–small cell lung cancer (NSCLC).

: What regimen would you choose for this patient for concurrent chemotherapy and radiation?

: The National Comprehensive Cancer Network [NCCN] guidelines recommend cisplatin/etoposide—I remember when that was the one that everybody used; sadly, I’m getting old—and carboplatin/pemetrexed [Alimta], cisplatin/pemetrexed, and weekly carboplatin/paclitaxel.

I think most oncologists use weekly carboplatin/paclitaxel in a case like this. There’s a plus-minus on the adjuvant carboplatin/paclitaxel. I always find it somewhat ironic; when you’re doing definitive chemoradiotherapy for a bad stage III disease, you are giving an equivalent of 2 cycles of chemotherapy, sometimes even a bit less if you look at the doses, but if they have adjuvant therapy, you give them 4 cycles of a higher dose. This just shows the inconsistency in terms of what we know and how we really treat patients.

This patient got cisplatin/pemetrexed with concurrent radiation, and follow-up imaging showed a partial response with shrinkage and no evidence of metastatic disease.

[Many patients do not complete chemoradiotherapy.] I think the biggest reason, for me at least, is toxicity—esophagitis—especially in an older population.

Would you give this patient durvalumab (Imfinzi) after the completion of chemoradiotherapy? What does the PACIFIC study reveal about this?

The PACIFIC study [NCT02125461] was a phase 3, randomized, placebo-controlled study of patients with stage III [locally advanced, unresectable non–small cell lung cancer] who did not progress after definitive chemo-radiotherapy and were 18 or older, performance status 1, life expectancy 12 weeks or more, all-comers population, 1 to 42 days post chemoradiation.

 The patients were randomized 2:1 durvalumab versus placebo, and the end points were progression-free survival [PFS] by blind review, overall survival [OS], and standard secondary end points.

This [trial] was well before we really understood immunotherapy and targeted therapy, so there was no mandate that the patients have 

 [testing]. Many did not, and some we did not have PD-L1 status on as well.

We are now up to a 4-year update, which is great. Both the 12-month and 18-month PFS were significantly better [with durvalumab]. I call it the 2-finger rule: If I can fit 2 fingers between the Kaplan-Meier curves, it is a home run. It’s not as good as the [coronavirus disease 2019] COVID-19 Pfizer vaccine, but it’s a really good result. [The PFS was] 55.7% versus 34.4% at 12 months, and 49.5% versus 26.7% [at 18 months], with a nice tailing off of the curve as well. [Median] PFS was 17.2 versus 5.6 months [stratified HR, 0.51; 95% CI, 0.41-0.63].

What is an appropriate time interval between the completion of chemoradiotherapy and the initiation of durvalumab?

The subgroup analyses [of the PACIFIC trial favor durvalumab], which is great.5 But patients who were randomized less than 14 days after the last radiation did better [unstratified HR, 0.39; 95% CI, 0.26-0.58] than those who were randomized after 14 days [unstratified HR, 0.63; 95% CI, 0.49-0.80]. I believe that they started the durvalumab just a day or 2 after randomization.

There are 2 ways of looking at this. One is that the patients who were randomized in less than 14 days were able to get on the durvalumab sooner because they had less burden of stage III disease or were feeling better, which is a very important thing; they may have had less esophagitis, or they just did better.

I believe that [initiating durvalumab] sooner is probably better. [But] people do need a bit of break, so I want to be realistic as well. Patients are tired, patients are beaten up, they get their scan, you’re on vacation for 2 weeks because it’s summer. They’ve been going every day for a while. They just want to go out to dinner for a few nights or at least not come to the doctor’s office for a week or 2. But again, getting closer to that time point in my mind is a little bit better. So I just tell them I try and do it sooner rather than later. But usually it is within 6 weeks, and remember the PACIFIC study wanted everybody on [durvalumab] within 6 weeks.

In the old days, patients would come and get a CT scan 4 to 6 weeks after. I’m not going to go back and discuss whether or not you should be giving people consolidation chemotherapy. That is something many oncologists did a long time ago, and we should have and have gotten away from it. But my take-home message is just to [initiate durvalumab] as soon as possible, within reason. Whether it’s 14 days or 21 days probably doesn’t matter. Really look at the patient and figure out whether they are ready for it. Many patients just need a break.

What else can we learn from the PACIFIC trial?

The 4-year OS rate is pretty good: 49.6% with durvalumab versus 36.3% [with placebo (stratified HR, 0.71; 95% CI, 0.57-0.88)].

 I’ll call this the almost-2-finger rule. I’m sure there’ll be a 5-year update and, for those who are still practicing, probably even a 10-year update as well.

[Subgroup analyses of PFS and OS generally favor durvalumab over placebo.] For patients with stage IIIB disease, the error bars did cross the median [toward favoring placebo], so I have a little bit of concern for higher-stage disease. It’s a pretty unimpressive curve for the 

 mutation: Both OS and PFS scores cross the median [favoring placebo]. There were only 43 patients in the entire study with 

Another interesting thing is that the nonsmoking patients did even better [with durvalumab] than the smoking patients. It is a small number but it’s a pretty impressive number there, for what that’s worth.

Does the PACIFIC trial shed light on the relationship between durvalumab effectiveness and PD-L1 status?

The prespecified [PD-L1] analysis was for 25% or more, or less than 25%. Then the post hoc [analysis] was 1% to less than 25%, 1% or more, and less than 1%.

Patients with PD-L1 less than 1% fell on the wrong side of the curve [favoring placebo]. The approval for the PACIFIC trial in the United States was for all-comers, so it was done regardless of [PD-L1] status. PD-L1 testing was not required, and over one-third of participants had unknown [PD-L1 status]. [The testing] was all done from prebiopsy; postbiopsy was not possible. The PD-L1 cutoff of 1% was a post hoc analysis that was unplanned, requested by the European Medicines Agency.

I think it is an interesting thing; it’s very hypothesis-generating. Whether patients with PD-L1 less than 1%really don’t need durvalumab, we don’t know because the study did not look at them specifically. But I think it does raise some important questions. I would give it to people. The reason I check PD-L1 status is that people start to have some adverse effects [AEs]. And let’s face it, you hit month 6 and month 7, you have an older patient—my biggest issue in patients who have been on durvalumab for a while—they develop myalgias and arthralgias. To me, that’s the biggest dose-limiting toxicity over time. I might have more of a threshold to stop a little bit early if the patient starts to have some of those AEs, which can go on for a while and affect their activities of daily life significantly. So that’s one of the reasons I check PD-L1. Admittedly, there are no good data, but I put that in my toolbox and just think about it as well.

In the safety summary, grade 3/4 and grade 5 AEs were pretty similar in the durvalumab and placebo arms [grade 3/4 AEs, 96.8% vs 94.9%; grade 5 AEs, 4.4% vs 5.6%, respectively].

 There were a few more treatment-related AEs in the durvalumab arm [67.8% vs 53.4%], and a few more serious AEs [28.6% vs 22.6%].5The placebo arm had 8.1% immune-related AEs.5 So that’s the power of placebos, I like to say. There was more pneumonitis and pneumonia [in the durvalumab arm (any grade pneumonitis, 33.9% vs 24.8%; any grade pneumonia, 13.1% vs 7.7%)].

 We always have a tough time in clinical studies distinguishing and quantifying pneumonia versus pneumonitis, but there was a little bit more pneumonitis. For grade 3/4, the rates were still very low [grade 3/4 pneumonitis, 3.4% vs 2.6%; grade 3/4 pneumonia, 4.4% vs 3.8%].

The NCCN [removed] recommendations to add full-dose chemotherapy if the patient had not received it before.

This was always listed as optional and was a very controversial thing. There were concerns that it would increase the risk of pneumonitis. I think that, by and large, consolidation chemotherapy went away with this study. It is an option after concurrent chemoradiotherapy, although there have been many negative studies.

What is your approach to management of pneumonitis in patients receiving single-agent checkpoint inhibitors?

[According to the American Society of Clinical Oncology guidelines for management of immune-related pneumonitis,] infectious workup should be considered, but this is different from reality.

 Especially because if these are outpatients, it’s always hard to get them scheduled, and by the time you get them scheduled—if this is pneumonitis—they have been on steroids and they are often better. But consider infectious workup with bronchoscopies, cultures, etc.

For grade 3/4 pneumonitis, permanently discontinue immune checkpoint inhibitors and provide supplemental oxygen. This information is all available [in the guidelines], and it [is] just a good reminder to take a look and [use] what’s out there.

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 4.2021. Accessed April 1, 2021. bit.ly/30sRU9e

2. Paz-Ares L, Villegas A, Daniel D, et al. 5638 - PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC. 

. 2017;28(suppl 5):v605-v649. doi:10.1093/annonc/mdx440

3. 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

4. Faivre-Finn C, Vicente D, Kurata T, et al. LBA49 - Durvalumab after chemora-diotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

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. 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 virtual Targeted Oncology Case-Based Roundtable event, Alexander Spira, MD, PhD, discusses when the use of durvalumab followed by chemoradiotherapy is appropriate for patients with unresectable stage III non–small cell lung cancer.

PACIFIC Regimen Is Appropriate for Use in Patients With Non–Small Cell Lung Cancer After Chemoradiation

Alexander Spira, MD, PhD, a medical oncologist and director of the Virginia Cancer Specialists Research Institute and the Phase 1 Trial Program, discusses how he chooses treatment for patients with lung cancer.

Spira says the treatment decisions for patients with lung cancer have become more complicated for the non-biomarker-driven patient population, or patients without an actionable mutation. For this population, physicians have to decide on whether or not to use chemotherapy or chemoimmunotherapy first. Most look at the patient’s PD-L1 expression since higher PD-L1 scores are likely to benefit from checkpoint inhibitors alone, possibly with ipilimumab (Yervoy). Mainly this is dependent upon the individual patient, their risk, how quickly the tumor is growing, and their level of interest in doing chemotherapy. That topic is hotly debated amongst oncologists in the targeted therapy space, he explains.

Targeted therapy is the best option for patients in all those situations, according to Spira. The physician can identify which biomarkers the patient has, either by tissue-based or by blood-based assays. It has been a struggle to get patient’s testing for all the biomarkers, and that's where he thinks liquid biopsies are coming to the forefront. However, most of the targeted options are the best. Spira says the 

 G12C drugs are likely be approved because the studies have been in second line, and once they are approved, there's going to be many studies looking at them in the first-line setting. This may be a non-chemotherapy option that directly targets the patient’s tumor type.

Alexander Spira, MD, PhD, discusses how he chooses treatment for patients with lung cancer.

Exploring Why Testing in Lung Cancer is Important to Treatment Decisions

Alexander Spira, MD, PhD, a medical oncologist and director of the Virginia Cancer Specialists Research Institute and the Phase 1 Trial Program, shares an important message with community oncologists regarding the treatment of patients with lung cancer.

Test, test, test, says Spira. In order to better treat these patients, physicians need to test advanced patients more appropriately. It’s very challenging to do, Spira admits, but if tests aren’t completed, physicians won’t detect mutations that might alter their treatment plan.

Spira says he can’t speak to how many patients have had a mutation that nobody picked up on, which is why it is so important to test. There are so many new treatments coming down the pike, with new opportunities for these patients with advanced lung cancer. Patients should be enrolling to clinical trials, which is another important thing to do for this patient population, Spira says.

Alexander Spira, MD, PhD, shares an important message with community oncologists regarding the treatment of patients with lung cancer.

Testing Early & Often Recommended for Patients With Lung Cancer

Alexander Spira, MD, PhD, a medical oncologist and director of the Virginia Cancer Specialists Research Institute and the Phase 1 Trial Program, discusses the phase 1 CHRYSALIS trial of amivantamab (JNJ-61186372) plus lazertinib (YH25448) in 2 

-mutant non–small cell lung cancer patient populations, which include patients with relapsed/refractory and those who are treatment-naive.

In the relapsed/refractory population, there was about a 36% or 37% response rate, with significantly more patients benefiting. This is good because it's designed as a non-chemotherapy option since chemotherapy would be the normal approach for these patients, according to Spira. Since the proof of concept worked, there is potential for a non-chemotherapy option in this setting.

Spira explains the investigators combined these drugs because amivantamab is a monoclonal antibody, which do not tend to penetrate the brain, and by continuing to administer with the small molecule lazertinib, the idea is that you could both overcome resistance, as well as prevent brain recurrence, in addition to having a 2-fold attack on tyrosine kinase inhibitor therapy.

The second patient population of those who were treatment naïve had a 100% response rate. Spira says this is almost unheard of. With this combination, standard EGFR toxicities were increased more than we would typically see. Most commonly, these included nail changes or a rash. Because of amivantamab is a fusional drug and a monoclonal antibody, there were some infusion-related reactions. With good monitoring, most patients were able to get the first dose split over 2 days.

Alexander Spira, MD, PhD, discusses the phase 1 CHRYSALIS trial of amivantamab plus lazertinib in 2 EGFR-mutant non–small cell lung cancer patient populations, which include patients with relapsed/refractory and those who are treatment-naive. 