CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: July 25, 2023
Expiration: July 24, 2024
Common and Notable Toxicities Associated With TROP-2‒Directed ADCs
Stephen Liu, MD:
We tend to focus on responses—and we have seen some exciting ones—but TROP-2‒directed ADCs potentially can be toxic drugs, and there are some AEs of which to be aware. As mentioned previously, the AEs are different for sacituzumab govitecan-hziy and datopotamab deruxtecan because they have different payloads. What are the most clinically concerning AEs associated with these TROP-2‒directed ADCs?
Rebecca S. Heist, MD, MPH:
Yes, even though they are both TROP-2‒directed ADCs, they have different toxicity profiles. The data we saw for datopotamab deruxtecan in the phase I TROPION-PanTumor01 trial showed grade ≥3 treatment-emergent AEs (TEAEs) in 49.4% of all patients with NSCLC (N = 180).21 Treatment discontinuation due to TEAEs occurred in 18.8% of patients. The most common any-grade TEAEs were nausea (55%), stomatitis (53%), alopecia (40%), fatigue (33%), and dry eye (22%), although the vast majority of these were grade 1/2. More rarely but still concerning was interstitial lung disease/pneumonitis, which was seen in 11% of all patients (3% grade ≥3), 3 of whom had grade 5.
The data on sacituzumab govitecan-hziy in the NSCLC cohort from the phase I IMMU-132-01 trial showed common any-grade TEAEs such as nausea (80%), diarrhea (61%), fatigue (46%), alopecia (39%), and vomiting (35%), with the vast majority grade 1/2.20 Treatment discontinuation due to TEAEs occurred in only 4% of patients. Of note, any-grade neutropenia was seen in 37% of patients (28% grade ≥3), including 2 with grade 3/4 febrile neutropenia. The other most common grade ≥3 TEAEs included pneumonia (9%), leukopenia (9%), nausea (7%), diarrhea (7%), and fatigue (6%).
Management of Neutropenia Associated With Sacituzumab Govitecan-hziy
Rebecca S. Heist, MD, MPH:
Neutropenia and febrile neutropenia have occurred with sacituzumab govitecan-hziy in the clinical trials for NSCLC and breast cancer, with grade 3-4 neutropenia in 49% of patients.13 In cases of grades 3-4 neutropenia, dose reduction and G-CSF are recommended. After multiple occurrences, drug discontinuation and G-CSF administration are recommended. Patients also should be monitored for anemia and thrombocytopenia.
Management of Diarrhea Associated With Sacituzumab Govitecan-hziy
Rebecca S. Heist, MD, MPH:
Sacituzumab govitecan-hziy contains SN-38, which is the active metabolite of irinotecan. Grade 3-4 diarrhea occurred in 11% of patients who received sacituzumab govitecan.13 In the case of grade 1-2 acute diarrhea and/or cholinergic symptoms (cramping, sweating, salivation), atropine should be administered. With more delayed diarrhea, loperamide can be used up to a maximum of 16 mg per day. With grade ≥3 diarrhea, consider hospital admission and provision of IV fluids and octreotide.
Management of Ocular Surface Toxicities Associated With Datopotamab Deruxtecan
Rebecca S. Heist, MD, MPH:
Ocular surface toxicities including dry eye, blurred vision, and keratitis occurred in the NSCLC cohort study with datopotamab deruxtecan.21
Management of Stomatitis/Mucositis Associated With Datopotamab Deruxtecan
Stephen Liu, MD:
Dr Levy, what TEAEs are you seeing with datopotamab deruxtecan in combination with immunotherapy?
Benjamin Levy, MD:
We are seeing the same general AEs that Dr Heist mentioned above. A challenge particular to datopotamab deruxtecan is stomatitis. Several of our patients have this; based on the data from TROPION-Lung02, 29% to 56% of patients have experienced this adverse event. If this drug gets approved, we need to learn a way to mitigate that toxicity, because it is a bit different from most of the other therapies we have in lung cancer. We stay on top of it with magic mouthwash and dexamethasone rinses. I do not know of a biological rationale for this AE. Some have postulated that there is TROP-2 overexpression in the oral mucosa, but if that is the case, why are we not seeing the same from sacituzumab govitecan-hziy? I think there is a lot to learn not only about efficacy, but also about the different toxicities that TROP-2‒directed ADCs may have.
Melissa L. Johnson, MD:
We have used dexamethasone rinses prophylactically for mucositis. I had a patient who was HER2 positive on clinical trial, and I wonder if his stomatitis had something to do with his prior therapies in a way that we do not understand. It was not like mucositis the way I was used to thinking about it. It can be terrible when it is bad—like a thrush, plaquing like an underlying erythematous base. It is no wonder people lose weight—they cannot eat because they cannot swallow.
Management of Interstitial Lung Disease Associated With Datopotamab Deruxtecan
Stephen Liu, MD:
Dr Johnson, what have you experienced with interstitial lung disease with these classes of drugs, and what should healthcare professionals be looking for?
Melissa L. Johnson, MD:
Truthfully, I have not observed much symptomatic pneumonitis. I had several patients with grade 1, and as we have become more aware, I have noticed CT scans with mild interstitial changes. Sometimes you can hold a dose, and the symptoms can wax and wane and go away. Early in clinical trial, I had a patient who died of pneumonia at an outside hospital, and we wondered, in retrospect, if there might have been more going on there.
Rebecca S. Heist, MD, MPH:
Awareness of the risk of interstitial lung disease is actually helping quite a bit. Early in the phase I experience, you can see some mild infiltrate, some reticulations, and nobody’s lungs are pristine, so you keep going until it becomes clinically apparent. Now with more awareness of this issue, if you see radiographic changes (ie, a true grade 1), you can identify that something is going on and it is probably an AE, and you can hold treatment. I think with the pneumonitis risk, just the awareness that it can happen makes a big difference in terms of decreasing the amount of clinically significant toxicity that is seen. What you need to do is stop the drug when you start to see radiographic evidence of pneumonitis. At this point, the multidisciplinary team can hold the drug, monitor the patient closely, and perform evaluations for other potential causes of the patient’s symptoms. The team can consider oral systemic corticosteroids. For higher grades of pulmonary toxicity, empiric high-dose corticosteroids such as methylprednisolone 2 mg/kg every 6-8 hours or equivalent should be implemented, in addition to permanent drug discontinuation.
Duration of TROP-2‒Directed ADC Treatment
Stephen Liu, MD:
Dr Johnson, how long do we continue TROP-2‒directed ADC therapy? Is there a finite course, as there is for immunotherapy, or do you continue it as long as it is tolerated and working?
Melissa L. Johnson, MD:
In the current clinical trial experience, we treat until progression or untoward toxicity, and that is a different amount of time in the second-line setting vs the first-line setting. The tolerability of pemetrexed allows us to use it for a long time in the maintenance setting, and I wonder if we will find TROP-2‒directed ADCs to be as tolerable. The dosage may be the key that we have not completely figured out; perhaps the same dose is not needed in induction and for maintenance, or maybe we can space treatments out a bit more to make them more tolerable. Unfortunately, there are some toxicities—mucositis and fatigue especially—that you cannot continue to dose through.
Long-term Tolerability of TROP-2‒Directed ADCs
Stephen Liu, MD:
Dr Heist, can you comment on the long term tolerability of datopotamab deruxtecan? Are there any cumulative AEs that you have seen?
Rebecca S. Heist, MD, MPH:
In my experience, some of the toxicities associated with datopotamab deruxtecan seem to be cumulative, but I have been told that stomatitis can happen throughout. Some of my patients who have responded the best and remained on the drug the longest do still struggle with the AEs. The dry eye, stomatitis, and mucositis tend to become more prominent the longer the patient is receiving therapy. I have had patients receive therapy for 1 year, and after such a long time, those symptoms can become really problematic. The challenge is that they also have received the benefit from the drug over that long period of time. Dr Johnson made a good point that adjustments of dose and treatment intervals are very important to improve quality of life for our patients.
Acquired Resistance to TROP-2‒Directed ADCs: 3 Main Mechanisms
Stephen Liu, MD:
Dr Borghaei, what do we know about intrinsic or acquired resistance to TROP-2‒directed ADCs?
Hossein Borghaei, MS, DO:
I think it is too early to understand the resistance mechanisms, and I do not expect information anytime soon. The last I checked, the postprogression biopsy rates have been very low, and we have not yet been able to develop a blood based assay to really examine the resistance mechanisms. If this is a targeted chemotherapy, the likely mechanism of resistance would involve the toxic payload or perhaps an issue with the target antigen not recirculating back on the cell surface. However, I have not seen data that can point to a clear mechanism of resistance for any of these drugs yet.
Melissa L. Johnson, MD:
Other than perhaps the disappearance of the target antigen, similar to PD 1 or HLA.
Stephen Liu, MD:
If you have progression on one TROP-2‒directed ADC, could you use another? Is there any information about that?
Hossein Borghaei, MS, DO:
Anecdotally, I can tell you that we have a couple of patients who already have received one HER2-targeted ADC, and now they are on a phase I trial for a different HER2-targeted ADC. I personally have not tried to go from one ADC to another; unless everything about the drug is different, to me it would be like going from pembrolizumab after progression to nivolumab. I am not really sure there would be any logic behind that, except maybe to try a different payload. If everything about it was different, maybe it would make sense.
Benjamin Levy, MD:
Yes, I think having a different payload, different linker, or different target antigen would have a bit more rationale for sequencing of ADCs.
Melissa L. Johnson, MD:
Also, the AE profiles of sacituzumab govitecan-hziy and
datopotamab deruxtecan are very different, which of course is likely related to their different payloads.
Rebecca S. Heist, MD, MPH:
What about switching to another ADC with the same payload? If you are using patritumab deruxtecan in a patient with an EGFR mutation, can you use datopotamab deruxtecan afterward? Or, if you are using trastuzumab deruxtecan in someone with a HER2 mutation, would you expect a drug such as datopotamab deruxtecan to work? They have the same deruxtecan payload and the same linker, so really you would just be changing tumor antigen. That is still an unanswered question.
Melissa L. Johnson, MD:
Most trials have excluded patients who have had prior deruxtecan-directed therapy. I agree with you that it is an interesting question—and one that people probably will need to explore a bit before we do a trial to specifically look at it.
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