Sunday, September 5, 2021

Ipilimumab or ipi/nivo combo after recurrence in patients previously treated with immunotherapy ~

How to treat a melanoma recurrence when you have already been treated with ipi or anti-PD-1 (nivo/Opdivo or pembro/Keytruda) as single agents or the ipi/nivo combo has been a question for sometime now.  From 2017 there were these:

Response to ipi or ipi/nivo after failing anti-PD1 as single agent in Stage IV melanoma

ASCO 2017: Nivo or Ipi/Nivo combo in melanoma after progression on ipi or anti-PD-1

ASCO 2017: ipi plus pembro, ipi after pembro and identifying markers for outcome with pembro for advanced melanoma

There was this in 2020:  How to deal with recurrence on or after anti-PD-1 as adjuvant or treatment for active melanoma disease

And also, this:  After progression on anti-PD1 / anti-PDL1 treatment of melanoma

Now, there are these:

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.  Da Silva, Ahmed, Reijers, et al.  Lancet Oncol.  June 2021.

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged greater/= to 18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162) or ipilimumab plus anti-PD-1 (n=193) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months, the objective response rate was higher with ipilimumab plus anti-PD-1 (60 of 193 patients) than with ipilimumab monotherapy (21 of 162 patients). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months) than with ipilimumab monotherapy (8·8 months). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months) than with ipilimumab (2·6 months). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. 

In this report, it is evident that the ipi/nivo combo did better as follow-up to progression on anti-PD-1 as a single agent, than the response that was provided by ipi alone.

Now, what to do if you took the combo from the start?

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.  Hepner, Atkinson, Larkin, et al.  Eur J Cancer.  Aug 2021.

Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.

Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.

Results: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%). Time to AR was 11 months. After a median follow-up of 16 months, responders to reinduction had a median progression-free survival of 14 months, and in the whole cohort, the median overall survival from reinduction was 17 months. Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.

Conclusions: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

This report notes that despite failing the ipi/nivo combo, a repeated course can provide response and disease control.

Here's something to consider if serious adverse reactions have been an impediment to repeating treatment using immunotherapy ~

Low-dose ipilimumab combined with anti-PD-1 immunotherapy in patients with metastatic melanoma following anti-PD-1 treatment failure.  Klee, Kurzhals, Hagelstein, et al.  Melanoma Res. July 2021.

Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immune-related colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure.

After progressing on anti-PD-1, these patients were treated with a low dose ipi/usual dose nivo combo.  Side effects were decreased and responses were attained.

Hang tough, peeps.  Melanoma doesn't make it easy, but there is hope.  - c

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